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Physiology and Pathophysiology of Potassium Channels in Gastrointestinal Epithelia

Institute of Physiology and Clinic and Policlinic for Internal Medicine II, Regensburg, Germany

ABSTRACT

I. INTRODUCTION

A. K+ Channel Families, Structures, and Expression Profiles Along the Gastrointestinal Tract

B. 6/7TM-1P Channels

C. 4TM-2P Channels (K2P)

D. 2TM-1P Channels

E. Ways of K+ Channel Regulation

1. Membrane voltage

2. Phosphorylation

3. Modification of the channel protein

4. Cytosolic Ca2+

5. Internal pH

6. External pH

7. Modifiers leading to inward rectification

8. Other ions

9. Lipids and derivatives

10. Hypoxia

11. G proteins

12. Cell swelling/shrinkage

13. Cell metabolism

14. Membrane surface targeting/retrieval from the membrane

F. Expression of K+ Channels in Gastrointestinal Epithelial Cells

G. Multifaceted Functions of Epithelial K+ Channels

1. Regulation of membrane voltage and electrical driving force

2. Recycling of K+ across the plasma membrane

3. K+ and salt handling

4. Cell volume regulation

5. Proliferation, differentiation, and cell death

6. Cell migration and wound healing

7. Functions of K+ channel proteins independent from K+ permeation?

II. K+ CHANNELS ACTING IN CONCERT WITH H+-K+-ATPase IN GASTRIC PARIETAL CELLS

A. Histology of Gastric Mucosa

B. Composition of Gastric Juice

C. Cellular Mechanisms of HCl Secretion by Parietal Cells

1. Luminal K+ recycling: a pivotal step for gastric acid secretion

D. Basolateral K+ Channels of Parietal Cells

E. Luminal K+ Channels of Parietal Cells

1. The KCNQ1/KCNE2 channel: a major player for parietal cell function

2. Regulation of heteromeric KCNE2/KCNQ1 channels in the luminal membrane of parietal cells

3. Other candidates for luminal K+ channels of parietal cells

F. Bicarbonate Secretion of Surface Cells in Gastric Mucosa

III. TRANSPORT ACROSS THE EPITHELIUM OF THE SMALL INTESTINE

A. Mechanisms of Cl– Secretion in Crypts of Small Intestine

B. Bicarbonate Secretion in Small Intestinal Villus Cells

C. Function of K+ Channels for Reabsorption and Secretion in Small Intestine

1. What are the mechanisms underlying K+ channel activation during reabsorptive activity of small intestinal enterocytes?

IV. K+ CHANNEL OF THE LARGE INTESTINE

A. Anatomy of the Colon

B. Pathways of Luminal K+ Secretion

1. Luminal KCNMA1 (MaxiK) channels

2. Luminal KCNN4 (IK1, SK4, KCa3.1) channels?

3. Evidence for other K+ channels in the luminal membrane?

C. Role of K+ Channels for Cl– Secretion in Colonic Crypt Cells

1. cAMP-mediated secretion

2. cGMP-stimulated secretion

3. Secretion in response to increases in cytosolic Ca2+

D. Do K+ Channels Influence Cell Fate, Proliferation, and Carcinogenesis?

V. EXOCRINE PANCREAS AND SALIVARY GLANDS: PARADIGMS FOR EXOCRINE SECRETION

A. Enzyme and Cl– Secretion in Pancreatic Acinar Cells

B. Role of the K+ Conductance for Bicarbonate Secretion in Pancreatic Ducts

1. What are the properties of the basolateral K+ conductance?

C. Fluid and Electrolyte Secretion in Salivary Glands

D. Formation of Primary Saliva by Acinus Cells

E. Modification of the Primary Saliva by Duct Epithelia

VI. CONCLUSIONS AND PERSPECTIVES

GRANTS

ACKNOWLEDGMENTS

REFERENCES

	ABSTRACT

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	I. INTRODUCTION

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A. K⁺ Channel Families, Structures, and Expression Profiles Along the Gastrointestinal Tract

The major tasks of the epithelia of the gastrointestinal tract are mass transport of salt, solutes, and water across epithelial cells which serve as barrier function between the "milieu interne" and the "milieu externe." To perform such mass transport of nutrients, chemical and electrical gradients are used as driving forces for salt and solute transport mechanisms. Those gradients are established by the activity of the basolateral Na⁺-K⁺-ATPase and epithelial K⁺-selective ion channels which hyperpolarize the plasma membrane thereby "charging the battery" for electrically driven transport. This review provides an overview of the molecular and functional diversity of K⁺ channels in epithelia of the gastrointestinal tract with focus on the physiological role of K⁺ channels.

K⁺ channels form the largest group of ion channels in the human genome. Unfortunately, the nomenclature of K⁺ channels is rather confusing and redundant, e.g., for many K⁺ channels four to six different aliases can be found in the literature. At present, two "competing" K⁺ channel classifications systems exist, encompassing all genes of pore-forming K⁺ channel subunits: one is published by the "Human Genome Organization" (HUGO; http://www.gene.ucl.ac.uk/nomenclature/genefamily/kcn.php), and the other one by the "International Union of Pharmacology" (IUPHAR; http://www.iuphar-db.org/iuphar-ic/index.html). For this review, we have decided to use the nomenclature proposed by HUGO because the "KCN" names allow quick access to information of transcriptome and gene databases hosted by the "National Center for Biotechnology Information" (NCBI; http://www.ncbi.nlm.nih.gov/). The "KCN" nomenclature of human K⁺ channel genes comprises 78 genes with the "P loop" signature of pore-forming -subunits and 13 genes for β-subunits. Based on the similarity in the amino acid sequence and functional properties, the genes of pore-forming subunits can be subdivided into three large families (Fig. 1): 1) channel subunits with six or seven transmembrane domains and one pore loop (6/7TM-1P): voltage-gated and Ca²⁺-activated K⁺ channels; 2) channel subunits with four transmembrane domains and two pore loops (4TM-2P): K2P channels; and 3) channel subunits with two transmembrane domains and one pore loop (2TM-1P): inwardly rectifying K⁺ channels.

View larger version (60K): [in this window] [in a new window]   FIG. 1. "KCN" K+ channel families. Phylogenetic tree of human K+ channels using the "KCN" nomenclature of the "Human Genome Organization." For simplicity, the letter code for K+ channels (KCN) has been omitted (e.g., KCNA1 is depicted as A1). The tree has been constructed using "UPGMA" (http://bibiserv.techfak.uni-bielefeld.de/dialign/) based on DIALIGN fragment weight scores on full-length protein sequences. In case of splice variants, transcript variant 1 (according to NCBI) has been used for the alignment.

Forty different genes of the human genome comprise the large group of voltage-gated K⁺ channels (200, 201): KCNA "Shaker";¹ KCNB "Shab"; KCNC "Shaw"; KCND "Shal"; KCNH "EAG, ERG, ELK"; and "modifiers" (KCNF, KCNG, KCNS, KCNV), which do not form functional channels as homomers (Fig. 1). Structurally, they are characterized by six (in the case of "Slo" family by 7) transmembrane domains and one pore-forming loop (6/7TM-1P), and they assemble into tetramers to build functional channels (376). Voltage-gated K⁺ channels are preferentially expressed in excitable cells, where they have an essential role for rapid repolarization of the plasma membrane during the action potential. Interestingly, expression of voltage-gated K⁺ channels is not restricted to excitable cells, but they are also found in nonexcitable cells such as the epithelia of the gastrointestinal tract. In epithelial cells of the gastrointestinal tract, they are implicated in a variety of cellular functions, e.g., electrolyte and substrate transport, cell volume regulation, cell migration, wound healing, proliferation, apoptosis, carcinogenesis, and oxygen-sensing (456). Among those epithelial voltage-gated K⁺ channels, KCNQ1 shows the highest levels of expression. Interestingly, KCNQ1 assembles in epithelia predominantly with β-subunits which convert the voltage-dependent KCNQ1 into a voltage-independent, constitutively open channel complex (549).

In addition to the group of voltage-gated channels, the family of 6/7TM-2P channels includes two subfamilies of Ca²⁺-activated channels, the small- to intermediate-conductance K⁺ channels (KCNN1–4), and the family "SLO"-type large-conductance channels (KCNMA1, KCNT1–2, KCNU1). In the pore-forming -subunit KCNMA1 (MaxiK), cytosolic Ca²⁺ activity is directly sensed by a distinct domain of the tail of the channel protein, the so-called "Ca²⁺ bowl" (20, 668). The other members of the "SLO" family, although structurally closely related to KCNMA1, do not show the same mechanism of Ca²⁺ regulation. In contrast to the "Ca²⁺ bowl" of KCNMA1, in KCNN channels the Ca²⁺ sensor is not located in the -subunit itself; the Ca²⁺ sensitivity is caused by tight coupling of the channel protein to calmodulin (calmodulin acts as a β-subunit of these channels) which results in functional channels with a very steep Ca²⁺ dependence (134, 269, 557, 676).

C. 4TM-2P Channels (K2P)

K2P channels are characterized by four transmembrane segments and two interspersed P loops between TM1 and -2 and TM3 and -4, respectively (tandem of two P-domains). The first members of this channel family have been identified in Saccharomyces cerevisiae and Caenorhabditis elegans in 1995 (280), followed by the first mammalian member which was named "TWIK1" for "Tandem of P domains in a Weak Inward rectifying K⁺ channel" in 1996 (340). In the human genome, the family of 4 transmembrane and 2-P domains K⁺ channels (4TM-2P) encompasses 15 members. Most likely, the channel proteins form dimers to build functional channels (341). They are believed to contribute to the background K⁺ conductance under resting conditions in many tissues (342). K2P channels are regulated by a variety of stimuli, e.g., KCNK1 and KCNK6 are activated by protein kinase C and inhibited by internal acidification (74, 341); KCNK2, KCNK4, and KCNK10 are mechano-sensitive channels and stimulated by arachidonic acid (381, 382); KCNK3 and KCNK9 are regulated by hypoxia (probably in an indirect and system-specific way) (56, 267, 335, 499, 641); and several members of the K2P channel family show activation upon external alkalinization (126, 127, 274, 430, 518) (Fig. 1). K2P channels in the central nervous system can be stimulated by volatile anesthetics like halothane (194, 483, 605), thereby silencing neuronal activity. K2P channels are supposed to be involved in various physiological and pathological processes, e.g., renal bicarbonate transport (661), general anesthesia (227, 483), neuroprotection (227), depression (228), pain sensation (9), oxygen sensing (56), apoptosis, and carcinogenesis (484). Although abundant evidence from animal models suggests that K2P channels have also important functions in humans, so far no direct link between mutations of K2P channels and human disease has been established. An overview on this group of channels is provided by several excellent reviews (26, 235, 343, 482, 484, 690) and is available on the internet (http://www.ipmc.cnrs.fr/duprat/).

D. 2TM-1P Channels

The 15 members of the 2TM-1P family are characterized by only two transmembrane domains: one pore loop and, as the most prominent biophysical feature, by inward rectification (306). Like voltage-gated K⁺ channels, functional 2TM-1P channels are believed to be tetramers. Several inward rectifiers have important physiological roles, and gene mutations have been linked to human diseases. Renal KCNJ1 channels are crucial for luminal K⁺ recycling in the thick ascending loop of Henle. Mutations of KCNJ1 (ROMK) can cause the salt-wasting "Bartter syndrome" (OMIM 600359, Ref. 576). Mutations in the gene of KCNJ2 are related to Andersen's syndrome, which is characterized by cardiac arrhythmia, periodic paralysis, and dysmorphic features (OMIM 170390, Refs. 30, 500). KCNJ8 channels are relevant for establishing physiological vascular tonus. KCNJ8 knockout mice show a phenotype similar to that of vasospastic "Prinzmetal" angina (OMIM 600935, Ref. 419); KCNJ11 associates with the sulfonylurea receptor (SUR) to form the ATP-sensitive K⁺ channel of insulin-producing β-cells of the islets of Langerhans: loss of function mutations of KCNJ11 have been found in patients suffering from hyperinsulinemic hypoglycemia (OMIM 600937, Ref. 617).

The large number of different K⁺ channel genes provides the basis for the precise adjustment of the K⁺ conductance to the cellular needs in various tissues. For several reasons, however, the diversity of K⁺ channels in native cells is even much larger than suggested just by the number of different channel genes: alternative splicing of mRNA, heteromeric assembly of subunits, and association with proteins not classified as members of the "KCN" gene family enlarge the variability of native K⁺ channels. In addition, several regulatory pathways and modifications of channel proteins can lead to dramatic changes of biophysical properties and membrane localization, thereby broadening functional diversity. Such multifaceted regulation comprises phosphorylation events (133, 346), ubiquitinylation (180, 225, 608), sumoylation (31, 506), palmitoylation (197, 603), and interaction with lipids (198, 344, 462).

E. Ways of K⁺ Channel Regulation

1. Membrane voltage

The effect of changes of the membrane voltage on the open probability represents the most important way to regulate channel activity of "voltage-gated K⁺ channels." Recently, the structural basis of voltage-sensing has been addressed in a large number of studies using a variety of different techniques, e.g., cysteine scans and X-ray analysis of crystallized channel proteins. In those tetrameric K⁺ channels, the pore domain is built by transmembrane helices 5 and 6 with the linker between both (pore loop) lining the conduction pathway. As a typical feature of voltage-sensitive K⁺ channels, the positively charged fourth transmembrane domain plays an important role in voltage-sensing. From the pioneering work of Roderick MacKinnon, who was the first performing X-ray analysis of crystallized K⁺ channels (120), we have already excellent information about the structure of the crystallized channels (262). However, the dynamic structure of the channel protein in native membranes and the precise mechanism of channel activation by depolarizing voltages are still a matter of debate (5, 32, 263, 361, 601).

2. Phosphorylation

A key feature of cellular signal transduction is the activation of protein kinases which change the function of target proteins by phosphorylation. K⁺ channels have been found to be modified by a variety of protein kinases, e.g., protein kinase A, protein kinase C, Ca²⁺/calmodulin-dependent kinases, tyrosine kinases, serum- and glucocorticoid-inducible kinases, and WNK [With-No-K(lysine)] kinases (133, 346, 350, 477).

3. Modification of the channel protein

For several K⁺ channels, covalent ubiquitin conjugation has been described as a way to modify channel activity by changing its surface expression (please refer to point 14). Recently, small ubiquitin-related modifier proteins (SUMOs) have also been reported to regulate channel function and biophysical properties of K⁺ channels (31, 506). However, the significance of sumoylation as a K⁺ channel-regulating protein modification is still a matter of debate (139).

4. Cytosolic Ca²⁺

Cytosolic Ca²⁺ activity is one of the most important second messengers, e.g., it couples activation of receptors or action potentials to specific cellular effector mechanisms such as activation of enzymes, exocytosis of transmitter-containing vesicles, muscle contraction, fluid and enzyme secretion, gene transcription, changes of ion conductances, etc. The open probability of very many K⁺ channels is directly or indirectly regulated by changes in cytosolic Ca²⁺ ranging from rather small changes of current amplitude to steep dependence of open probability on cytosolic Ca²⁺ activity. Among these channels, members of the KCNN subfamily and KCNMA1 exhibit the most impressive Ca²⁺ dependence (190). Similar to KCNN channels, members of the KCNQ family apparently interact with calmodulin; however, the Ca²⁺ dependence is less prominent compared with KCNN channels (166, 174, 568).

5. Internal pH

A large number of K⁺ channels are affected by internal pH changes, ranging from relatively slight changes of biophysical properties (e.g., current amplitude of some voltage-dependent channels, Ref. 635) up to dramatic changes of open probability of some members of the "inward rectifier" family (KCNJ). A prominent example of the latter group of channels is the "renal outer medulla K⁺ channel" (ROMK or KCNJ1), whose pH regulation has been analyzed in detail leading to the identification of amino acid residues which presumably serve as pH sensors. Those channels are inhibited by cytosolic acidification and are activated by internal alkalinization, respectively (41, 513, 551).

6. External pH

In many tissues, K⁺ channels have been found that are regulated by changes of the extracellular pH. Most of the channels showing very strong and steep regulation by external pH belong to the family of 2-P-domain channels: KCNK2 (TREK1), KCNK3 (TASK1), KCNK4 (TRAAK), KCNK5 (TASK2), KCNK9 (TASK3), KCNK10 (TREK2), KCNK16 (TALK1), KCNK17 (TALK2), and KCNK18 (TRESK). They all are characterized by the inhibition by external acidification and activation by external alkalinization (127, 428, 430, 449, 509). In contrast, KCNE/KCNQ1 channels exhibit a complex response to changes of extracellular pH which is dependent on the assembling β-subunit, e.g., KCNE2/KCNQ1 is activated by acidic external pH and KCNE3/KCNQ1 is completely pH insensitive (154, 220, 491). Also members of the inward rectifier family (2TM-1P) are activated by low extracellular pH (388).

7. Modifiers leading to inward rectification

Inwardly rectifying K⁺ channels exhibit a higher conductance for inward than for outward currents. This fascinating phenomenon can be caused by relief of block by Mg²⁺ or by polyamines such as spermine and spermidine at negative membrane voltages (363, 639).

8. Other ions

Interestingly, several K⁺ channels are affected by cytosolic Na⁺ activity, although those channels do not conduct Na⁺. This type of regulation has been observed for KCNK5 (TASK2) (429), Ca²⁺-activated K⁺ channels (277), and voltage-dependent K⁺ channels (KCNB1) (364). Moreover, "Slo-2"-type channels have been described to be activated by Na⁺ and by Cl^– (487, 691, 692).

9. Lipids and derivatives

Functional properties of a large number of K⁺ channels, perhaps of all channels, are dependent on the lipid composition of the membrane embedding the channel. Several derivatives of lipids serve as specific regulators (their action cannot be explained by changes of the fluidity of the membrane) which can have dramatic effects on basic biophysical properties of the respective K⁺ channels, e.g., phosphatidylinositol-4,5-bisphosphate (PIP₂), ceramide and its derivatives, arachidonic acid and its derivatives, lysophosphatidylcholine (LPC), and cholesterol (71, 78, 198, 215, 287, 318, 344, 367, 383, 462, 511, 648, 651, 652).

10. Hypoxia

K⁺ channels play an important role for sensing hypoxia in chemoreceptive cells of the carotid bodies or in the lung. Several different types of K⁺ channels have been shown to be modulated by hypoxia or hypoxia-induced signals [e.g., via changes is cytosolic ATP (641), via NADPH oxidase NOX4 (335), and via AMP-activated protein kinase (675)]: voltage-dependent K⁺ channels, MaxiK channels, and TASK-like channels (408, 481, 489).

11. G proteins

The best known example of a regulation of K⁺ channel by G proteins is the activation of K_ACh K⁺ channels (KCNJ3 and KCNJ5) (606) in the heart by pertussis toxin-sensitive heterotrimeric G proteins that mediate the effect of M2 muscarinic and A1-adenosine receptors (314). Similar regulation mechanisms have been found in a variety of ion channels (54, 118, 688).

12. Cell swelling/shrinkage

A large variety of K⁺ channels are activated by cell swelling, e.g., KCNN4 (669), KCNQ1 (191), and KCNK5 (448). Swelling-induced K⁺ channel activation then leads to loss of K⁺ as an osmolyte (together with Cl^– or other anions) and to regulatory volume decrease (215, 325).

13. Cell metabolism

In several cell types, K⁺ channel activity is coupled to metabolic state and energy metabolism. In β-cells of endocrine pancreas, muscle cells, and glucose-sensing hypothalamic neurons, inward rectifier K⁺ channels are regulated by the ATP-to-ADP ratio (14, 444, 480). In epithelial cells of renal proximal tubules and small intestine, basolateral K⁺ channel activity is regulated according to the transport activity (especially the activity of the Na⁺-K⁺-ATPase) and the metabolic state (185, 404, 555).

14. Membrane surface targeting/retrieval from the membrane

Mechanisms affecting targeting of the channel to the plasma membrane or retrieval from have been shown to play a major role for the regulation of the epithelial Na⁺ channel (ENaC) which is removed from the membrane after ubiquitin conjugation (384, 587). Apparently, K⁺ channel function is also dependent on insertion to and removal from the surface membrane (366). Specific sorting and targeting to the membrane can be mediated by signal motives of the pore-forming -subunit, ubiquitylation (71, 225, 260, 349), and assembly with β-subunits and adaptor proteins that modify surface localization of the channel complex (80, 366, 507, 516, 519, 549, 622).

F. Expression of K⁺ Channels in Gastrointestinal Epithelial Cells

Central for the understanding of the functional relevance of K⁺ channels in native tissue is the knowledge of their molecular nature and expression patterns. However, a complete and detailed analysis of epithelial K⁺ channel expression is not yet available. At present, three internet databases are commonly used to evaluate gene expression: the EST-based "Unigene" database which provides an "organized view of the transcriptome" (hosted by the National Center for Biotechnology Information "NCBI", http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unigene), and the gene array databases "Gene Expression Omnibus" (hosted by the NCBI, http://www.ncbi.nlm.nih.gov/geo/) and "GFN SymAtlas" [hosted by the Genomics Institute of the Novartis Research Foundation (593), http://symatlas.gnf.org/SymAtlas/]. These databases provide very useful information about tissue-dependent gene expression. Besides technique-immanent problems, the applicability of those data for epithelial physiology is yet limited by the fact that the gastrointestinal tissues have been mostly harvested "in toto" for those analyses including muscle layers, the enteric nervous tissue and other intrinsic cell types. Table 1 provides an overview of expression and function of K⁺ channels in the gastrointestinal tract. More comprehensive information from mainly hypothesis-driven experiments is discussed in the respective chapters on K⁺ channels of the stomach, small intestine, colon, and pancreas (see below).

In gastrointestinal epithelia, K⁺ channels are involved in a plethora of different physiological and pathophysiological processes. From a general perspective, the consequences of K⁺ channel activity encompass the electrical effect on the membrane potential and effects related to the transport of K⁺ as an ion and osmolyte. Dependent on the specific cellular context, epithelial K⁺ channels serve the following tasks (Fig. 2).

View larger version (9K): [in this window] [in a new window]   FIG. 2. Schematic illustration of K+ channel function in epithelia. A: K+ channels hyperpolarize the membrane voltage, thereby fueling electrogenic transport mechanisms such as Na+-coupled reabsorption of nutrients (not depicted) or luminal Cl– secretion. Basolateral K+ channels can hyperpolarize also the luminal membrane if the paracellular pathway allows ion currents to flow. In addition, they contribute to the establishment of a transepithelial voltage (Vte), which drives ions through the paracellular pathway. B: K+ channels as recycling pathways for K+: Na+-K+-ATPase and H+-K+-ATPase take up K+ in exchange for Na+ and H+, respectively. For ongoing activity of these ATPases, recycling of K+ is required to avoid depletion of K+ in the external fluid. Therefore, activity of the ATPases and K+ channels is often tightly coupled. C: luminal K+ channels in distal nephron and the colon are direct ways to eliminate K+. They hyperpolarize the luminal membrane and lead in concert with luminal Cl– channels to electroneutral KCl secretion. The driving force for paracellular transport, e.g., of Na+, is reduced (Vte in this model is only –12 mV compared with –20 mV in A). D: swelling-induced K+ channels participate in cell volume regulation. Many K+ channels are directly or indirectly (via swelling-induced increase in Ca2+) activated by cell swelling. K+ leaves the cell together with its counterion, and water follows these osmolytes: the cells perform regulatory volume decrease.

In practically all living cells, K⁺ channels play a pivotal role for generation and stabilization of a hyperpolarized membrane voltage. In epithelia, the hyperpolarized membrane voltage fuels so-called "secondary active" electrogenic transport systems which transport substrates against a chemical gradient. For example, in renal proximal tubular cells and enterocytes of small intestine, specific transport proteins reabsorb glucose, neutral amino acids, and other solutes together with Na⁺ across the luminal membrane. The coupling of substrate transport to the influx of Na⁺ (driven by the electrical and chemical gradient for Na⁺) provides a robust driving force, which, e.g., allows the Na⁺/glucose cotransporter of proximal tubular cells to build up a >100-fold gradient for glucose (42). On the other hand, the Na⁺ influx by such systems depolarizes the membrane, thereby reducing the driving force of further transport. In this situation, activation of K⁺ channels repolarizes the membrane and restores the driving force for ongoing electrogenic transport. It is not surprising that the K⁺ conductance of transporting epithelia is tightly coupled to transport activity. The coupling of transport activity and K⁺ conductance occurs via several mechanisms, e.g., activation by depolarization of the membrane (voltage-dependent K⁺ channels); activation by intermediates of energy metabolism (ATP-sensitive K⁺ channels); intracellular signaling such as pH, Ca²⁺, and other second messenger pathways; and changes in cell volume and membrane stretch (122, 185, 378, 661).

2. Recycling of K⁺ across the plasma membrane

In epithelial cells K⁺ is accumulated within the cytosol predominantly via three transport proteins, Na⁺-K⁺-ATPase, H⁺-K⁺-ATPase, and Na⁺-2Cl^–-K⁺ cotransporter. The resulting chemical K⁺ gradient is a prerequisite for the establishment of the normal membrane voltage via K⁺ channels. On the other hand, those transport proteins serve also other functions: the Na⁺-K⁺-ATPase is needed to eliminate Na⁺ from the cytosol and thus absorbs K⁺, H⁺-K⁺-ATPases are used to secrete H⁺, and Na⁺-2Cl^–-K⁺ cotransporters serve the uptake of Na⁺ and Cl^– into the cell. Sustained activity of Na⁺-K⁺- and H⁺-K⁺-ATPases and Na⁺-2Cl^–-K⁺ cotransporter requires a sufficient concentration of extracellular K⁺ which can become the rate-limiting factor of transport activity (438, 627). Under this condition, K⁺ channels can serve as an ideal pathway for recycling of K⁺ across the membrane. The most evident example for the function of K⁺ channels as K⁺ recycling pathway is the gastric parietal cell, where acid secretion by the H⁺-K⁺-ATPase is almost completely dependent on parallel export of K⁺ through luminal K⁺ channel (see below) (167).

3. K⁺ and salt handling

K⁺ channels in the luminal membrane of epithelial cells are an evident pathway for the exit of K⁺ out of the cell, and if not reabsorbed later on, for elimination of K⁺ from the body. Since plasma K⁺ homeostasis is an absolute crucial parameter for the survival of mammalian organisms, the elimination of K⁺ from the body is tightly controlled by several mechanisms. Among those, the regulation of luminal colonic K⁺ channels by the mineralocorticoid aldosterone has been the focus of research. In surface cells of colonic crypts, aldosterone leads to stimulation of Na⁺ reabsorption and concomitant K⁺ secretion; the latter one stabilizes the driving force for ongoing Na⁺ uptake. Additionally, there exist aldosterone-independent ways of regulation, which allow handling of K⁺ balance independent from the Na⁺ balance. However, the precise nature of the aldosterone-dependent and -independent regulation of intestinal K⁺ excretion still awaits detailed characterization.

4. Cell volume regulation

Transcellular transport of salt and substrates paralleled by osmotic water flow represents a continuous challenge for epithelial cells of the gastrointestinal tract to keep their cell volume constant. To achieve this goal, the precise adjustment of cellular uptake on the one hand and elimination of osmolytes on the other hand is necessary to avoid large changes of the cell volume with the risk of cellular damage. To stabilize normal cell volume, several types of transport proteins are regulated by cell swelling/shrinkage and, therefore, are able to counteract volume changes, e.g., Na⁺-2Cl^–-K⁺ cotransporters, Cl^– channels, and K⁺ channels (115, 203, 230, 322, 459). In intestinal epithelial cells, several types of volume-sensitive K⁺ channels are strongly expressed, e.g., TASK2 (KCNK5, Ref. 447), SK4 (KCNN4, Refs. 535, 669), and Kv7.1 (KCNQ1, Ref. 191). Activation of those channels by cell swelling results in the exit of K⁺ and the same amount of negatively charged counterions, which decreases the osmolality of the cytosol and induces water flux out of the cell: "regulatory volume decrease."

5. Proliferation, differentiation, and cell death

Proliferation, differentiation, and apoptosis of cells are essential processes for every multicellular organism. During these processes, K⁺ channel expression and K⁺ channel activity is tightly controlled to adapt membrane voltage and cell volume to the needs. On the other hand, changes of the expression pattern of K⁺ channels and their activity can have severe impact on the ability of cells to go through distinct parts of the cell cycle or to perform apoptosis (323). Therefore, it is not surprising that severe disturbances such as cancer can be accompanied by up- or downregulation of certain K⁺ channels genes (308, 472, 474, 484). So far, five different K⁺ channel genes have been the focus of most studies investigating the effect of K⁺ channel function on proliferation and tumorigenesis: KCNA3, KCNN4, KCNK9, KCNH1, and KCNH2 (591). In tissues such as muscle or the nervous system, the rate of proliferating cells is very low, and most of the cells live for many years in a postmitotic, terminal differentiated status. In intestinal epithelial cells, however, proliferation rate is very high, and renewal of the epithelium occurs in 2–3 days and 3–8 days in small and large intestine, respectively (352). The short life span of intestinal cells requires very precise and timely adjusted mechanisms for fine tuning of the cellular processes including ionic conductances which affect proliferation, differentiation, and finally apoptosis. As a consequence, pharmacological inhibition or overexpression of K⁺ channels can modify cell growth (474). In addition, blockade of K⁺ channels diminishes apoptotic K⁺ efflux which normally takes place as an early event during apoptosis and which is needed for the execution of later parts of the apoptotic program (IEC-6 cell line) (189). Disturbances of the cellular processes underlying growth, differentiation, and cell death have implications for diseases such as inflammatory bowel disease, adenoma formation, and carcinogenesis. Therefore, knowledge of the role of K⁺ channels for these basic processes shall lead to better understanding for the control of cell growth, cell fate, and cell death and finally could offer new therapeutic strategies for diseases of gastrointestinal epithelia.

6. Cell migration and wound healing

Cell migration and movement of cells is required to reseal mucosal defects after injury. Over the last years, there has been growing evidence for an important role of K⁺ channels during cell migration (558) and wound healing of epithelial cells (179, 365, 512, 572). Apparently, K⁺ channels and ion transporters are required for localized volume changes that play a role for single cell migration. However, the precise mechanisms by which K⁺ channels affect wound healing, and vice versa, still need to be elucidated.

7. Functions of K⁺ channel proteins independent from K⁺ permeation?

Very recently, evidence has been provided that interaction of KCNB1 (Kv2.1) K⁺ channels with the SNARE protein syntaxin facilitates exocytosis. Interestingly, this facilitation was not dependent on the function of KCNB1 as a K⁺ channel, because it could be observed even after disruption of the pore function of the channel (578). A qualitatively similar observation has been made for KCNK1 associated with ARF6/EFA6: KCNK1 expression interfered with the endocytosis of transferrin receptors irrespective of its function as an ion channel (94). It is possible that similar ion permeation-independent functions of channels as part of protein complexes will be discovered for other K⁺ channels in the future.

Over the last years, our knowledge about K⁺ channel genetics, structure, and molecular aspects of their various cellular functions has largely improved. In the following sections, we will provide an overview about the molecular physiology of K⁺ channels in epithelial cells of the gastrointestinal tract.

	II. K+ CHANNELS ACTING IN CONCERT WITH H+-K+-ATPase IN GASTRIC PARIETAL CELLS

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The stomach is important for storage, for milling and first digestion of the ingested food, and for appropriate delivery of the gastric content into the small intestine. Digestion and denaturation of food proteins is initiated by pepsins and acidic pH of the gastric juice, which also serves to diminish the number of possibly harmful microorganisms. In addition, intrinsic factor secreted by parietal cells promotes the absorption of vitamin B₁₂ in the terminal ileum. As an important protective measure against the acidic luminal content, gastric surface cells produce a bicarbonate-rich mucous secretion. During the last years, molecular techniques have allowed the identification of several K⁺ channels that are specifically expressed in the stomach. In this section, we discuss the functional role of those K⁺ channels during ion transport of gastric epithelial cells.

A. Histology of Gastric Mucosa

The stomach mucosa consists of so-called gastric glands, which are composed of several specialized cell types (Fig. 3). The luminal surface is covered by a layer of epithelial cells that secrete alkaline mucus to protect the mucosa against the acidic gastric juice. Secretion of protective mucus is the predominant function of the relatively short "cardiac" glands. Oxyntic glands in the "fundus" and the "corpus" of the stomach are longer, and they contain many parietal cells (50–60% of the cells) and chief cells. This type of gastric gland produces the vast majority of the gastric juice. Chief cells produce precursors for the protease pepsin and are located at the base of the gland. As a self-protection mechanism, surface mucous cells secrete gel-forming glycoproteins together with NaHCO₃, thereby forming an unstirred layer of acid-neutralizing mucous. Additionally, endocrine and paracrine cells within the epithelium play important regulatory roles for the gastric secretory function. In the "antrum," pyloric glands are the predominant gland type which contain (besides surface epithelial cells and mucous neck cells) gastrin-producing G cells. The population of small undifferentiated stem cells is located in the upper third of the gland (the so-called "neck region"). These stem cells are the progenitor cells of all gastric cell types (223, 224).

View larger version (39K): [in this window] [in a new window]   FIG. 3. Ion transport in gastric mucosal cells. A: histology of mouse gastric mucosa. Mucous-producing cells cover the surface of the gastric mucosa. Acid-producing parietal cells are shown as dark cells within the gastric glands. Chief cells (gray color) are mainly located in the lower part of the gland. The arrows point to cell type for which models are depicted in B and C. B: hypothetical model for bicarbonate secretion in gastric surface cells. In the luminal membrane, Cl– and HCO3– leave the cell through CFTR-dependent Cl– channels. Luminal anion exchangers replace luminal Cl– by HCO3–. Luminal anion exit through CFTR is energized by basolateral K+ channels. KCNE3/KCNQ1 K+ channels are probably together with others localized in the basolateral membrane. Basolateral Na+/HCO3– cotransporter and Na+/H+ exchanger serve the uptake of HCO3– and exit of H+, respectively. C: cell model for acid secretion of parietal cells. H+ is secreted by the H+-K+-ATPase in the luminal membrane in exchange for K+ which recycles through apical K+ channels. KCNE2/KCNQ1 (E2/Q1) and members of the KCNJ inward rectifier family (Jx) have been identified as luminal K+ channels. Cl– is secreted through apical Cl– channels. Basolateral anion exchanger exports HCO3– in exchange for Cl–.

The adult human stomach secretes 2–3 liters of gastric juice per day with differing acidity and ionic composition dependent on the secretory rate. The acidic, mucous-rich, and enzyme-containing fluid is secreted by different specialized cell types located in the so-called gastric glands. After stimulation, gastric parietal cells are able to produce the most acidic fluid found in human body, with a proton concentration up to 150–160 mM. The acid denaturates food proteins, promotes cleavage of pepsinogens to the active pepsins, and reduces the number of microorganisms ingested by the food (393). During stimulated secretion of parietal cells, the increase in H⁺ concentration of the secreted fluid is paralleled by a decline in Na⁺ concentration, a moderate increase in K⁺, and an enhanced output of intrinsic factor (451).

The control of gastric secretion can be divided into three phases: 1) cephalic phase, 2) gastric phase, and 3) intestinal phase. The cephalic phase is initiated by the brain through afferent stimuli from taste and smell receptors, which converge on the vagal nucleus in the medulla oblongata. Efferent fibers of the vagal nerve excite neurons in the myenteric and submucous plexus, leading to the liberation of acetylcholine, which in turn promotes the release of histamine from enterochromaffin-like cells in the gastric mucosa. In addition, gastrin is released from antral G cells. All three hormones lead to the stimulation of gastric secretion. The gastric phase is initiated mainly by the distension of the stomach by the food and the chemical nature of the nutrients. The distension leads to an intramural local and an extramural vago-vagal reflex response which supports secretion via the same mechanisms as the cephalic phase. G cells and the release of gastrin are activated by partially digested proteins and support ongoing HCl secretion. A decrease in luminal pH activates a negative-feedback mechanism via somatostatin produced by D cells in the antral and pyloric mucosa. Somatostatin acts as a paracrine hormone and turns off gastric acid secretion. Moreover, prostaglandin E₂ also inhibits acid secretion by activation of inhibitory G_i proteins. The predominant regulatory aspect of the intestinal phase is associated with inhibition of gastric secretion and regulated emptying of the stomach. Acidic pH, fat, and osmolality of the gastric content entering the duodenum are the major stimuli for a negative-feedback mechanism. This feedback inhibition of gastric secretion and motility is mediated by several hormones including secretin, cholecytokinin (CCK), and gastric inhibitory polypeptide (GIP). Secretin and GIP indirectly inhibit gastric acid secretion via a release of somatostatin. At higher doses, CCK acts as an antagonist of gastrin (88, 231, 237, 550).

C. Cellular Mechanisms of HCl Secretion by Parietal Cells

The stimulation of secretion involves two major signaling pathways: acetylcholine via M₃ receptors and gastrin via CCK-2 receptors lead to an increase of the cytosolic Ca²⁺ activity, whereas histamine via H₂ receptors increases cAMP. Both pathways end up in protein phosphorylation by protein kinase A or protein kinase C. In addition to these "classical" ways of activation of acid secretion, very recently evidence was provided for a role of calcium-sensing receptor (515) and amino acid transport in the modulation of acid secretion (60, 289). The activation process of parietal cells is accompanied by dramatic morphological changes (461, 636). During the transition from the resting to the stimulated state, H⁺-K⁺-ATPase-containing tubulovesicles fuse with each other and gain access to the apical surface. This impressive prolongation and extension of these secretory canaliculi largely increases the apical membrane compartment. By fusion of the tubulovesicles, the H⁺-pumping P-type ATPase, which consists of a catalytic - and a regulatory β-subunit, is translocated into the luminal membrane compartment (125). Because of the strict coupling of H⁺ export to uptake of K⁺, replenishment of luminal K⁺ is an absolute requirement for the activity of the H⁺-K⁺- ATPase. In the following, the mechanisms guaranteeing sufficient luminal K⁺ concentration for ongoing H⁺-K⁺- ATPase activity will be discussed in detail (686, 387).

1. Luminal K⁺ recycling: a pivotal step for gastric acid secretion

Starting in the 1930s, gastric acid secretion and the role of different ions for this process have been studied in vitro (100, 186). It has been observed that gastric acid secretion strongly depends on the presence of Ca²⁺ and K⁺. Although the importance of K⁺ for gastric acid secretion was evident, it was not yet clear "what aspect of potassium in the tissue is the determinant of secretion" (92). The gastric mucosa secretes hydrochloric acid against an enormous electrochemical gradient (1:1,000,000 from the cytosol to the luminal fluid). Therefore, it was postulated that an ATP-consuming protein is involved in this process. In 1967, purification and characterization of H⁺-K⁺-ATPase and later on the cloning of its - and β-subunits revolutionized our understanding of acid secretion in parietal cells (65, 150, 151, 574). The strict coupling of H⁺ secretion to K⁺ uptake by the H⁺-K⁺-ATPase explained the necessity of sufficient amounts of K⁺ in the luminal fluid, but still the way that K⁺ enters the lumen was not clear (167, 331, 531). Good evidence has been provided that Cl^– and K⁺ are secreted across the luminal membrane through specific conductive pathways that are activated during stimulation of acid secretion (514, 671, 101, 385, 386). It was suggested that the luminal K⁺ conductance is a rate-limiting step for H⁺ secretion (671).

D. Basolateral K⁺ Channels of Parietal Cells

With regard to the K⁺ conductance, hyperpolarization of the luminal and basolateral membrane was observed upon stimulation (102, 460). With the use of the patch-clamp technique, several different K⁺ channels have been measured in the basolateral membrane of Necturus oxyntic cells, among them a 40- to 70-pS K⁺ channel and an inwardly rectifying 30-pS K⁺ channel. The 40- to 70-pS K⁺ channel is activated by rises in cytosolic Ca²⁺; the open probability of the 30-pS K⁺ channel is increased by cAMP (597, 634). Similar channels have also been found in the basolateral membrane of oxyntic cells of the bullfrog (Rana catesbeiana). A frequently observed 60-pS K⁺ channel is Ca²⁺ regulated and stimulated by Mg²⁺/ATP from the cytosolic side (294, 418). Like oxyntic cells from Necturus, frog oxyntic cells have a 30-pS K⁺ channel that shows Mg²⁺-dependent inward rectification and activation by cAMP (418). Interestingly, those K⁺ channels were inhibited by the H⁺-K⁺-ATPase inhibitor omeprazole (294, 418). Relatively little is known about K⁺ channels of mammalian parietal cells. In the basolateral membrane of rabbit parietal cells, a 230-pS K⁺ channels has been observed as well as nonselective cation channels (532). In parietal cells from guinea pig, three types of K⁺ conductances have been observed in whole cell experiments: voltage-dependent inwardly and outwardly rectifying K⁺ conductances and a Ca²⁺-activated K⁺ conductance (298).

E. Luminal K⁺ Channels of Parietal Cells

Although the number of reports on basolateral K⁺ channels in parietal cells is very limited, the basolateral membrane is at least easily accessible with the patch-clamp pipette. For the luminal membrane, the situation is much more difficult, and access to the luminal membrane of parietal cells of intact glands is not possible. Over the last 6 years, several possible candidates for luminal K⁺ channels have been identified by molecular biology and immunofluorescence techniques. In addition, genetically modified animals and specific channel inhibitors have provided important information concerning the physiological significance of luminal K⁺ channels.

1. The KCNQ1/KCNE2 channel: a major player for parietal cell function

The first study suggesting a significant contribution of a K⁺ channel for parietal cell function was published in 2000 by Lee et al. (334). They reported that targeted disruption of the KCNQ1 gene causes deafness and gastric hyperplasia in mice (334). Originally, KCNQ1 (KvLQT1) has been cloned as a K⁺ channel responsible for a certain form of cardiac arrhythmia, the so-called "long QT syndrome type 1" (650). KCNQ1 belongs to a five members-containing subfamily of the 6/7TM-1P K⁺ channels, and it is expressed in the heart and a variety of epithelial tissues. The gastric mucosa of KCNQ1 –/– animals shows dramatic changes: severe mucosal hyperplasia and disorganization, hypertrophia of mucous cells, reduced parietal cell number, and vacuolation of parietal cells with a loss of H⁺-K⁺-ATPase staining. In addition, KCNQ1 –/– mice exhibited hypochlorhydria and had elevated plasma gastrin levels that likely reflects the impairment of gastric acid secretion. This study pointed to a pivotal function of KCNQ1 for gastric mucosa and acid secretion; however, the localization and cellular function of KCNQ1 in gastric mucosa was not yet elucidated. Shortly after, KCNQ1 was immunolocalized in the luminal membrane compartment of mouse parietal cells where it partially colocalized with the H⁺-K⁺-ATPase (96, 183). With the use of pharmacological inhibitors of KCNQ1, in a variety of species acid secretion can be almost completely blocked (183). Together with the observations made in KCNQ1 knockout mice, these reports clearly demonstrated the physiological significance of KCNQ1 for gastric acid secretion. For the first time, these reports convincingly unraveled the molecular identity and functional importance of a luminal K⁺ channel of parietal cells. In the luminal membrane of parietal cells, KCNQ1 assembles with its β-subunit KCNE2 (96, 183, 220). This assembly severely changes the biophysical properties of KCNQ1: the voltage-dependent and slowly activating KCNQ1 is transformed into a constitutively open, voltage-insensitive, and acid-resistant channel which is activated by cAMP and phospholipids (96, 220, 221, 621). Recently, it was shown by a gene chip analysis on cell-sorted rat parietal cells that KCNQ1 and KCNE2 are both strongly expressed in gastric mucosa and enriched in the parietal cell fraction. Moreover, pharmacological inhibition of KCNQ1 in isolated gastric glands led to similar blockade of acid secretion as it was observed with inhibitors of the H⁺-K⁺-ATPase or histamine receptor (H2) blockers (319). The final proof for the importance of the assembly of KCNQ1 with KCNE2 for parietal cell function has been recently provided by a nice study with a KCNE2 knockout mouse model: KCNE2 knockout mice display a severe gastric phenotype with impaired acid secretion, gastric mucosal hyperplasia, and an abnormal distribution of KCNQ1 (522).

2. Regulation of heteromeric KCNE2/KCNQ1 channels in the luminal membrane of parietal cells

As mentioned above, a key step during activation of acid secretion is the exocytotic event leading to the fusion of H⁺-K⁺-ATPase-carrying vesicles with the luminal membrane compartment. Since KCNQ1 colocalizes partially with the H⁺-K⁺-ATPase, it was evident to suggest a similar type of regulation for KCNQ1. Under resting conditions, KCNQ1 and H⁺-K⁺-ATPase show a distribution pattern suggestive for a localization in intracellular vesicles. Interestingly, KCNQ1 and H⁺-K⁺-ATPase are only partially colocalized, indicating that KCNQ1- and H⁺-K⁺-ATPase-carrying vesicles are not, or only to some extent, overlapping (319, 220). Upon stimulation of acid secretion, the H⁺-K⁺-ATPase is directed to the apical pole of the parietal cells and the distal parts of the canaliculi. The KCNQ1 staining does not show a similar strong redistribution. Although KCNQ1 and H⁺-K⁺-ATPase partially colocalize in the canaliculi compartment, the KCNQ1 staining appears to be less focused to the apical pole, and it is stronger in the distal part (close to the dead end) of the canaliculi (220). Therefore, we propose the following working model (Fig. 4): upon activation of secretion, parietal cells start to secrete a K⁺- and Cl^–-rich fluid at the end of the canaliculi. H⁺-K⁺-ATPases located at the apical pole of canaliculi then exchange K⁺ by H⁺. If this model is correct, high and potentially harmful concentrations of HCl are formed only at the very apical pole. This would lower the risk for parietal cell damage due to accidental leak of the canalicular membrane. The significance of such a leakage, however, has not yet been established. Probably, there is not only an intracellular gradient for the distribution of KCNQ1 and the H⁺-K⁺-ATPase but also a gradient along the gland axis. In most sections of mouse stomach, we observed a stronger staining for KCNQ1 in basal parietal cells and a more pronounced staining for H⁺-K⁺-ATPase in the apically localized parietal cells (unpublished data).

View larger version (31K): [in this window] [in a new window]   FIG. 4. Working model for acid secretion. Under resting conditions, the H+-K+-ATPase has no access to the luminal membrane. After stimulation of acid secretion, vesicles containing the H+-K+-ATPase fuse with the luminal membrane, and the H+-K+-ATPase is targeted to the apical pole. In the depth of the canaliculi, KCNE2/KCNQ1 channels in concert with Cl– channels secrete a KCl-rich fluid. Then H+-K+-ATPase activity leads to replacement of K+ by H+. [Model adapted from Heitzmann et al. (220).]

3. Other candidates for luminal K⁺ channels of parietal cells

Over the last 6 years, good evidence has been provided for an important role of luminal KCNE2/KCNQ1 K⁺ channels as a limiting factor for gastric acid secretion in various species. However, there is also evidence for other K⁺ channels in the luminal membrane of parietal cells. Several members of the inward rectifier family (2TM-1P) are expressed in stomach mucosa, and inwardly rectifying K⁺ channels have been described as candidates for luminal K⁺ channels: KCNJ1 (Kir1.1, ROMK) (4), KCNJ2 (Kir2.1) (388), KCNJ10 (Kir4.1) (159), KCNJ15 (Kir4.2) (172), KCNJ13 (Kir7.1) (171), and KCNJ16 (Kir5.1) (319). With the use of immunofluorescence and immunoelectron microscopy, KCNJ10 has been found to colocalize with the H⁺-K⁺-ATPase in the luminal membrane compartment (159). In a recent gene expression study on stomach mucosa and parietal cell-enriched cell fractions, several K⁺ channels appeared to be specifically enriched in parietal cells compared with whole stomach mucosa. With the use of array and real-time PCR techniques, three K⁺ channel genes were the most promising parietal cell-specific candidates: KCNQ1, KCNE2, and KCNJ16 (319). It might well be that heteromeric KCNJ15/KCNJ16 channels or other members of the inward rectifier family are involved in luminal K⁺ recycling of parietal cells. Supporting that, very recently it has been suggested that CFTR plays a role in gastric acid secretion by modulating a K_ATP-like K⁺ conductance (575). The functional data on KCNE2/KCNQ1 indicate that this channel complex is absolutely necessary for physiological acid output under stimulated conditions. Therefore, KCNE2/KCNQ1 could act in concert with inward rectifiers. Or the predominant role of inward rectifiers is to support secretion at basal conditions or sustained secretion. Moreover, some of the channels mentioned above, for which the subcellular distribution is not yet known, might be localized in the basolateral membrane. Ongoing studies on knockout mice will probably shed some light on the physiological role of the various K⁺ channels in gastric parietal cells.

F. Bicarbonate Secretion of Surface Cells in Gastric Mucosa

The mechanism of bicarbonate secretion in gastric surface cells probably resembles very much those of bicarbonate secretion in small intestine. Therefore, the principles of cellular bicarbonate transport will be discussed in more detail in section IIIB. In the stomach, secretion of the bicarbonate-rich mucus is the most important line of defense against the aggressive gastric juice. Unfortunately, very little is known about the role of K⁺ channels for gastric bicarbonate secretion. On the basis of immunofluorescence data, KCNQ1 appears to be present in gastric surface cells. Probably associated with its "intestinal"-type β-subunit KCNE3, KCNQ1 is localized in the basolateral membrane (183). In the basolateral membrane of surface cells, the Ca²⁺-regulated KCNN4 channel is expressed (163). Probably, KCNQ1 channels are activated after stimulation of the cAMP pathway and KCNN4 after increases of cytosolic Ca²⁺. When activated, both K⁺ conductances hyperpolarize the basolateral membrane, thereby providing the driving force for luminal Cl^– exit which augments Cl^–/HCO₃^– exchange resulting in net secretion of HCO₃^– across the luminal membrane (Fig. 3B).

	III. TRANSPORT ACROSS THE EPITHELIUM OF THE SMALL INTESTINE

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The small intestine is the part of the gastrointestinal tract where most of the ingested food is digested into its constituents. Cleavage by enzymes of the pancreatic juice and of small intestinal enterocytes leads to the breakdown of macromolecules into reabsorbable units. Moreover, there is an impressive movement of water across the epithelia of the gastrointestinal tract: 2–3 liters of water are ingested by the food per day, and 7–8 liter of water from secretions enter the lumen of the gastrointestinal tract. The majority of these 10 liters of water is reabsorbed by the epithelial cells of the small intestine, 1.5–2 liters are reabsorbed in the large intestine, and only 0.15–0.2 liters are excreted by feces (18). Most of the water reabsorption probably occurs passively driven by the osmotic gradient that is generated by reabsorption of nutrients and salt. In addition, a substantial amount of water might be directly reabsorbed by solute transporters cotransporting water together with their substrates, e.g., the Na⁺-dependent glucose transporter (414, 326, 362). However, more recent studies have questioned the concept of secondarily active water transport through cotransporters (73, 165). The passive component of water reabsorption occurs paracellularly and probably transcellularly through aquaporins (a very good overview on intestinal aquaporins is provided by Matsuzaki et al., Ref. 402). The molecular identification of proteins forming cell-to-cell contacts and tight junctions has largely improved our understanding of the paracellular pathway. Among those proteins, claudins form the most diverse group with some 20 members. Several claudins show very specific expression patterns along the crypt-surface-villus axis and vary in the different segments of the gastrointestinal tract. Thus claudins are probably important structural determinants underlying the specific functional properties of the paracellular pathway (161, 505, 164, 233).

In addition to reabsorptive processes that take place mainly in the enterocytes of villus cells, intestinal crypt cells produce a bicarbonate- and Cl^–-rich secretion. For neutralization of the luminal contents of the stomach, bulk secretion of bicarbonate into the lumen by Brunner's glands, pancreas, and liver are of importance. In addition to that, bicarbonate secretion that is derived from surface cells ensures a neutral juxtamucosal pH within the mucus-bicarbonate barrier. To understand the physiological regulation of transport processes in the small intestine, an integrative approach is required taking into account the complex and multifaceted interactions between mucosal cells, endocrine cells, neurons, cells of the immune system, blood and lymphatic vessels, and smooth muscles which are responsible for gastrointestinal motility (18). In many cases, mediators and hormones affect more than one of those cell types, and therefore, the in vivo response upon a given stimulus might substantially differ from the response of an isolated mucosal preparation in vitro. Nevertheless, studies on ex vivo epithelial preparations are the basis for understanding function and regulation of epithelial transport. In the following, we will discuss the mechanisms of Cl^– and bicarbonate secretion and electrogenic nutrient reabsorption.

A. Mechanisms of Cl^– Secretion in Crypts of Small Intestine

Although the small intestinal mucosa performs net reabsorption, secretion formed by crypt cells is of physiological and especially pathophysiological relevance. Cl^– and to a lesser extent HCO₃^– are the ions whose transcellular transport dominates the secretion of crypt cells. The basic concept of transcellular Cl^– transport in crypt cells of small intestine resembles the one for the colon (Fig. 5): basolaterally, Cl^– is taken up by the Na⁺-2Cl^–-K⁺ cotransporter (NKCC1) and the A2 anion exchanger (645, 679). At the luminal side, Cl^– leaves the cell through cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR)-dependent Cl^– channels. The cAMP pathway is activated by a variety of hormones and mediators, e.g., prostaglandin E₂, serotonin, vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), and by bacterial toxins, e.g., cholera toxin (for review, see Refs. 143, 312). Interestingly, the effect of cholera toxin is not restricted to epithelial cells, but it also increases intestinal blood supply and affects the gut nervous system. The importance of the enteric nervous system for the effect of cholera toxin is highlighted by the fact that blockade of the enteric nervous system inhibits cholera toxin-mediated fluid secretion (67, 68). Although the villi are probably still absorbing during cholera secretion (369), cholera toxin, by this "combined approach" on epithelial cells and enteric nervous system, leads to overwhelming and sustained activation of secretion. This results in a severe impairment of the net absorptive function of the small intestine (18, 182, 501, 696, 143).

View larger version (89K): [in this window] [in a new window]   FIG. 5. Cl– secretion in crypt cells of small intestine. A: section through mouse duodenum. Reabsorption occurs in enterocytes of the large villi; Cl– secretion occurs mainly in the short duodenal crypts at the bottom of the mucosa. B: model for Cl– secretion in crypt cells. For transcellular Cl– transport, Cl– is taken up mainly by the Na+-2Cl–-K+ cotransporter (NKCC1) and to some extent by Cl–/anion exchanger (AE2). Cl– exits the cell predominantly through cAMP-stimulated CFTR Cl– channels. The role of Ca2+-activated Cl– channels, e.g., Bestrophin 1 (Vmd2), for secretion in small intestinal crypt cells is still a matter of debate. The luminal Cl– exit is driven by the hyperpolarized membrane voltage generated by basolateral and possibly luminal K+ channels. From functional studies, heteromeric KCNE3/KCNQ1 channels substantially contribute to the basolateral K+ conductance during cAMP-stimulated secretion. During Ca2+-activated secretion, activity of Ca2+-dependent KCNN4 tightly follows the changes of cytosolic Ca2+. Probably, KCNE3/KCNQ1 channels are also active during Ca2+-induced secretion. The role of luminal channels is still questionable, because K+ secretion through channels appears to be very low in the small intestine (70, 629).

B. Bicarbonate Secretion in Small Intestinal Villus Cells

The acidic pH and peptic activity of the gastric contents entering the small intestine are a severe challenge for the enterocytes and mucosal integrity. The duodenal protection against gastric acid consist of two major components: the unstirred gel layer of mucus reducing the penetration of acid and pepsins and neutralization of the acidic contents by secreted bicarbonate. The mucus layer consists of a loosely adherent superficial layer (thickness: 150 µm), mainly acting as lubricant and a firmly adherent layer, acting as a stable and protective line of defense (thickness: 15 µm). An excellent review on the gastrointestinal mucus and bicarbonate barrier has been provided by Allen and Flemström (7). In the following, we will discuss the cellular mechanisms of bicarbonate secretion in small intestine.

Bicarbonate is taken up via basolateral Na⁺-dependent transporters in electroneutral (NBCn1) and electrogenic (NBC1) ways (Fig. 6). Basolateral K⁺ channels are needed to restore the driving force for sustained bicarbonate uptake by electrogenic NBC1 transporters, and they serve as a recycling pathway for K⁺ taken up by the Na⁺-K⁺-ATPase. Ca²⁺-activated KCNN4 channels (e.g., activated via cholinergic stimulation, Ref. 119) and members of the inward rectifier family (KCNJ) have been found in villus cells. Additionally, data from KCNQ1 knockout mice suggest a basolateral localization of KCNQ1 channels in small intestinal enterocytes (638); however, expression of KCNQ1 channels in villus cells is very low compared with crypt cells (96, 663). With the use of patch-clamp on enterocytes, several different K⁺ channels have been observed: Ca²⁺-dependent ones (427, 571), inward rectifiers (566), Ca²⁺-independent large- (422) and small-conductance K⁺ channels (119, 611), and ATP-sensitive large-conductance K⁺ channels (405). Besides electrogenic NBC1 transporters, bicarbonate and protons can be generated by the conversion of CO₂ and H₂O catalyzed by intracellular carbonic anhydrase. Basolateral and luminal Na⁺/H⁺ exchangers are engaged in the maintenance of the cellular pH homeostasis.

View larger version (48K): [in this window] [in a new window]   FIG. 6. Mechanisms of bicarbonate secretion in small intestine. Bicarbonate secretion takes place in small intestinal crypt and villus cells. HCO3– is taken up by basolateral Na+-dependent transporters. Basolateral K+ channels fuel electrogenic bicarbonate uptake and recycle K+ taken up by the Na+-K+-ATPase. In addition, HCO3– and H+ are generated from CO2 and H2O; Na+/H+ exchanger activity guarantees intracellular pH homeostasis. Luminal HCO3– exit occurs through Cl– channels and Cl–/bicarbonate exchangers (AE4; DRA=SLC26A3; PAT-1=SLC26A6). HCO3– enters the lumen across the paracellular pathway fueled by hydrostatic pressure and by the chemical gradient for HCO3–. Transport processes that probably are of minor importance are depicted with dotted arrows.

Several physiological and pathophysiological stimuli are involved in the complex regulation of duodenal bicarbonate secretion, e.g., prostaglandin E₂, VIP, and cholera toxin via the cAMP pathway (628); heat-stable enterotoxin of Escherichia coli and guanylin via the cGMP pathway (631, 196); acetylcholine and prostaglandin EP4 by stimulation of the Ca²⁺ pathway (560); capsaicin via stimulation of vanilloid receptors (272); and luminal acid and sham feeding (7, 595). The most powerful way of stimulation of bicarbonate secretion appears to occur via activation of the cGMP-dependent kinase II; activation of secretion via protein kinase A and Ca²⁺-dependent pathways is less potent (497). Probably, basolateral K⁺ channels are directly involved in this regulation of bicarbonate secretion. Blockers of Ca²⁺-activated KCNN4 channels, such as clotrimazole and TRAM34, inhibit duodenal bicarbonate transport induced by stimulation of the Ca²⁺ pathway; however, these blockers have no effect on cAMP and cGMP-activated secretion. On the other hand, Ca²⁺ ionophores and 1-EBIO, an activator of Ca²⁺-activated KCNNx channels, stimulated bicarbonate secretion (119).

C. Function of K⁺ Channels for Reabsorption and Secretion in Small Intestine

Na⁺-dependent solute transporters fueled by the chemical gradient of Na⁺ and by the hyperpolarized membrane voltage are powerful mechanisms to reabsorb nutrients almost completely, even against the concentration gradient of the respective substrate (403, 469). The entry of a positive net charge by these transport systems depolarizes the luminal membrane resulting in a transepithelial voltage difference (V_te; see Fig. 7) which consecutively drives paracellular electrogenic transport, i.e., transport of Cl^– (33, 202). On the other hand, increasing depolarization by electrogenic transport reduces the driving force for further transcellular transport. Moreover, the uptake of substrates, Na⁺, and water leads to osmotic cell swelling. Under these conditions, concomitant activation of K⁺ channels restores a hyperpolarized membrane voltage and the transepithelial voltage. The efflux of K⁺ as an osmolyte counteracts cell swelling. Therefore, it is not surprising that K⁺ channel activity in the small intestine appears to follow the transport activity of the enterocytes (185, 199, 377, 378, 405, 556). Due to the low electrical resistance of the paracellular pathway, luminal and basolateral K⁺ channels are able to repolarize the luminal membrane in a similar way. In other respects, the consequences of activation of luminal versus basolateral K⁺ channels are not identical: luminal K⁺ channel activation directly hyperpolarizes the luminal membrane and thereby reduces the difference between the luminal and basolateral potential (i.e., a low transepithelial voltage, which cannot drive paracellular voltage-dependent reabsorption); and K⁺ is secreted into the lumen. Basolateral K⁺ channel activation primarily hyperpolarizes the basolateral membrane and increases the transepithelial voltage that drives an ionic current across the paracellular pathway. Dependent on the ion selectivity of the paracellular pathway, the transepithelial voltage can drive reabsorption of anions or secretion of cations. This paracellular current decreases the V_te; it leads to hyperpolarization of the luminal membrane and depolarization of the basolateral one. In contrast to luminal K⁺ channels, basolateral K⁺ channel activity increases the K⁺ concentration in the basolateral space, but K⁺ is not "lost" into the lumen. Since luminal application of substrates, which are reabsorbed in a Na⁺-dependent manner, results in a substantial increase of the transepithelial voltage, activation of the basolateral K⁺ conductance probably supports this transepithelial voltage effect (185, 638).

View larger version (49K): [in this window] [in a new window]   FIG. 7. Reabsorptive function of small intestinal villus cells. Villus enterocytes reabsorb glucose and neutral amino acids in a Na+-dependent manner leading to depolarization of the luminal membrane (218, 292). On the basolateral side, glucose and amino acids leave the cells by Na+-independent carriers (510, 619). Since the basolateral pathway in small intestine has a relatively high permeability for ions and does not lead to electrical separation of luminal and basolateral membranes (24, 144, 158, 328), basolateral and luminal K+ channels are able to repolarize the luminal membrane. The transepithelial voltage preferentially drives reabsorption of anions through the paracellular pathway; water flux-induced solvent drag can lead to reabsorption of anions and cations. Likely candidates for basolateral K+ channels are KCNN4, KCNK5, KCNE3/KCNQ1, and inward rectifiers (KCNJ family). Functionally, MaxiK channels have been observed too. Basolateral K+ channels are activated during substrate transport leading to stabilization of membrane voltage and cell volume, generation of the transepithelial voltage, and recycling of K+ which has been taken up by the Na+-K+-ATPase. Candidates for luminal channels could be KCNK1, KCNE1/KCNQ1, and inward rectifiers. However, so far no data are available supporting the functional relevance of luminal K+ channels. Therefore, relevant expression of K+ channels in the luminal membrane of villus cells is questionable.

1. What are the mechanisms underlying K⁺ channel activation during reabsorptive activity of small intestinal enterocytes?

To fulfill varying physiological needs, the reabsorptive capacity of small intestinal epithelial cells is regulated by transcriptional and nontranscriptional mechanisms. The expression of transporters can vary over a broad range depending on the functional requirements (45, 238, 301, 467, 470, 646). To our knowledge, nothing is known about adaptive changes of K⁺ channel expression in small intestinal enterocytes, and most of the studies have focused on nontranscriptional mechanisms of intestinal K⁺ channel regulation. There is good evidence for upregulation of K⁺ channels in response to increased transcellular reabsorption and stimulated basolateral Na⁺-K⁺-ATPase activity ("pump-leak parallelism," Ref. 185). Also, pharmacological activation of basolateral K⁺ channels by cromakalim (543), pinacidil, BRL 38227 (234), and diazoxide (405) has been shown to enhance Na⁺-coupled transport. Physiologically, the basolateral K⁺ conductance is stimulated by reduction of the cytosolic ATP concentration (405), by swelling-induced membrane stretch, and interaction with the cytoskeleton (379, 185), intracellular alkalinization (378), stimulation of Ca²⁺/calmodulin kinase II, cytosolic Ca²⁺ (377), and the cGMP pathway (543). Schultz and Dubinsky (556) have suggested that cell swelling might be a key event for the upregulation of basolateral K⁺ channels because swelling itself induces several cellular changes such as reorganization of the cytoskeleton, membrane stretch, and changes in cytosolic Ca²⁺, which all by itself stimulate the K⁺ conductance. Therefore, coordinated activation of K⁺ channels and Na⁺-K⁺-ATPase possibly contributes to the phenomenon of the "pump-(K⁺)-leak parallelism" (556). In the luminal membrane of small intestinal cells, K⁺ channels probably play no or only a minor role. It has been suggested that K⁺ secretion detectable in rat jejunum does not occur through luminal K⁺ channels but via a pH-regulated and channel-independent process. This process potentially involves K⁺/H⁺ exchange mechanism that is H⁺-K⁺-ATPase independent (35, 70). Taken together, K⁺ channel regulation in small intestinal villus cells appears to be modulated dependent on the reabsorptive activity of the enterocytes. By this mechanism, the basolateral K⁺ conductance guarantees 1) a stable driving force for voltage-dependent transport activity, 2) it serves cell volume homeostasis, and 3) it recycles K⁺ which is constantly taken up by the Na⁺-K⁺-ATPase.

	IV. K+ CHANNEL OF THE LARGE INTESTINE

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The main physiological task of the colonic mucosa is reabsorption of Na⁺, Cl^–, short-chain fatty acids (SCFA, derived from bacterial fermentation), and water as well as secretion of K⁺, HCO₃^–, and mucus (36, 662). The transport of these electrolytes is closely linked to the function of K⁺ channels in the basolateral and luminal membranes of colonic enterocytes. Under normal conditions, the colon performs net reabsorption: from the 1.5–2 liter of water per day entering the colon, only some 0.1–0.2 liter of water is finally excreted via the feces. Under pathophysiological states, such as secretory diarrhea, colonic secretion strongly increases. As a consequence, vectorial transport of Na⁺, Cl^–, HCO₃^–, and water is reversed and stool volume can increase up to sixfold and more: the body loses salt, water, and bicarbonate. In colonic mucosa, K⁺ channels are a prerequisite for electrogenic transport. In addition, they are involved in cell volume regulation and influence very important cellular functions such as proliferation, differentiation, apoptosis, and carcinogenesis. Over the last decades, colonic K⁺ channels have been studied extensively, which is mirrored by more than 500 publications on that specific issue. Nevertheless, a variety of K⁺ channel-related functions are still a matter of debate, e.g., 1) contribution of specific K⁺ channels to K⁺ secretion and vectorial transport; 2) missing function of channels which are strongly expressed, e.g., KCNH8; or 3) changes in K⁺ channel expression: cause or consequence of carcinogenesis? In this section, we outline the role of K⁺ channels for the function of colonic enterocytes.

A. Anatomy of the Colon

Cecum, proximal, and distal colon exhibit different functional properties. Cecum and proximal colon have an intermediate resistance of 100 ·cm², and the distal colon has a fourfold higher resistance (83, 158). In the cecum, Na⁺ is reabsorbed electrogenically and electroneutrally. Na⁺ or cation-selective channels that are different from the ENaC are believed to underlie the electrogenic reabsorption (82, 563–565). Electroneutral reabsorption involves Na⁺/H⁺ and Cl^–/HCO₃^– exchange in the luminal membrane. In the small intestine and colonic crypt surface cells, the Na⁺/H⁺ exchanger type 3 (NHE3) is the major isoform (170); in colonic crypt cells, NHE2 is the dominant isoform in the luminal membrane (195) (Fig. 8). In proximal colon, also KCl cotransport has been proposed as a luminal K⁺ secretory pathway. In the proximal colon, Na⁺ is predominantly reabsorbed in an electroneutral fashion, again via luminal Na⁺/H⁺ exchange in concert with Cl^–/HCO₃^– exchangers. The major luminal Cl^–/HCO₃^– exchanger is SLC26A3 (DRA) (559). As a basolateral export system for Na⁺ and HCO₃^–, a Na⁺(HCO₃^–)_x cotransporter has been proposed that is stimulated by epinephrine (153, 561, 562). Na⁺ reabsorption through apical Na⁺ channels is of minor importance. Moreover, aldosterone apparently increases only electroneutral reabsorption of Na⁺ but not the electrogenic one (124, 153). In proximal colon, Ca²⁺-regulated K⁺ channels have been found in the luminal and basolateral membrane. As in the distal colon, the total basolateral K⁺ conductance is decreased by agonists stimulating the cAMP pathway (554). The distal colon is responsible for fine tuning of the salt and water reabsorption and, when stimulated, the colonic mucosa secretes mucus and fluid to facilitate the passage of the feces. As the distal nephron and sweat gland ducts, this segment of the gut is a target tissue of mineralocorticoids that control Na⁺ reabsorption and K⁺ secretion. Additionally, a variety of other hormones and mediators modulate colonic transport (Table 2). The colonic mucosa consists of crypts, which can be divided into crypt surface, crypt middle, and crypt base. Along the crypt axis, the differences in transport properties reflect a differentiation process that occurs in the short life span (3–8 days in human, Refs. 320, 352) of the crypt cells. The colonic crypt encompasses at least three cell lineages: enterocytes, endocrine cells, and mucus-producing goblet cells. Renewal of crypt cells by proliferation of stem cells (located in a niche at the crypt base), migration and differentiation, apoptosis, and exfoliation have to be tightly controlled to avoid ulceration on the one hand and carcinogenesis on the other hand (226, 623). With their migration (4.5 µm/h) from the crypt base towards the surface, the functional properties of the enterocytes change (520, 626). At the crypt base, cells predominantly perform electrogenic Cl^– secretion. The major task of surface cells is to reabsorb Na⁺ and SCFA and to secrete HCO₃^– and K⁺. However, this "classical view" of a strict functional gradient along the crypt axis is probably not correct: under certain conditions, surface cells also contribute to Cl^– secretion, and crypt cells can fulfill reabsorptive tasks, e.g., Na⁺ reabsorption via NHE2 (172, 195).

View larger version (24K): [in this window] [in a new window]   FIG. 8. Principles of colonic ion transport. A: picture of an isolated colonic crypt. The arrows point to cells which correspond to the cell models shown in B–D. B: transport model of a colonic crypt cell. Cl– secretion in colonic crypt cells has three major components: luminal cAMP-activated CFTR-dependent Cl– channels, basolateral K+ channels (predominantly KCNE3/KCNQ1 and KCNN4), and Na+-2Cl–-K+ cotransporter (NKCC1) as main Cl– uptake system. HCO3– transporters are found in the luminal and basolateral membrane and the Na+/H+ exchanger type 2 (NHE2) in the luminal membrane. K+ channels are also localized in the luminal membrane. C: ion transport in surface cells of proximal colon. Na+ is mainly reabsorbed electroneutrally via apical Na+/H+ exchangers (mainly NHE3). Cl–/HCO3– exchangers (mainly DRA) and Cl–/small-chain fatty acid (SCFA) exchangers have been observed in the luminal membrane, too. KCNMA1 (MaxiK) K+ channels appear to be a major pathway for luminal K+ secretion. In the basolateral membrane, KCNE3/KCNQ1, KCNN4, and probably KCNK5 support electrogenic transport by hyperpolarizing the membrane voltage. D: in surface cells of distal colon, Na+ reabsorption mainly occurs in an electrogenic way through epithelial sodium channels (ENaC) in exchange for K+ (leaving the cell through apical K+ channels). Luminal H+-K+-ATPases (colonic type) are engaged in K+ reabsorption, which is of importance during K+ deprivation (416).

B. Pathways of Luminal K⁺ Secretion

During the last years, much attention has been paid to the regulation of colonic K⁺ secretion. This function of colonocytes, which is controlled by mineralocorticoids, is important for the maintenance of body K⁺ homeostasis. In addition, luminal K⁺ channels are necessary to establish a sufficient driving force for Na⁺ reabsorption through ENaC channels (210, 312, 359). However, the molecular identity of the luminal K⁺ channels underlying this K⁺ secretion is still a question of debate. The investigation of luminal K⁺ channels in the colon is hampered by the fact that patch-clamp experiments of luminal membrane patches of native crypts are extremely difficult because mucus and microvilli strongly impair seal formation. Therefore, most data have been obtained from isolated cells, cultured cells, or from Ussing chamber experiments. At present, several K⁺ channels are "hot" candidates as luminal K⁺ channels: 1) KCNMA1 (MaxiK) (63, 210, 400, 542), 2) KCNN4 (IK1 or SK4) (97, 163, 268), 3) a chromanol 293B-sensitive K⁺ conductance (112) (which was not observed in another study, Ref. 391), 4) a inwardly rectifying K⁺ channel probably belonging to the KCNJ family (662), and 5) perhaps members of the KCNK family (unpublished data).

1. Luminal KCNMA1 (MaxiK) channels

Among the above-mentioned presumably luminal K⁺ channels, KCNMA1 is the one for which localization and function in the luminal membrane is documented best. By immunofluorescence, a KCNMA1-specific staining was consistently observed in colonic surface cells (146), especially in the apical membrane (210, 503, 542). However, the localization of KCNMA1 in the luminal membrane of crypt cells described in these studies is controversial. Recent studies provided evidence for alteration of KCNMA1 localization by ulcerative colitis and end-stage renal disease. In normal tissue, KCNMA1 was restricted to surface cells; however, in ulcerative colitis and end-stage renal disease, the KCNMA1 signal was also detected in crypt cells. The authors concluded that the changes in KCNMA1 expression might contribute to the fecal loss of K⁺ observed in patients suffering from ulcerative colitis and end-stage renal disease (398, 536). The functional importance of KCNMA1 as luminal K⁺ channel of colonic crypts has been highlighted by numerous studies. In the luminal membrane of colonic crypt cells, a large-conductance (200–240 pS) K⁺ channel has been described that is voltage dependent and regulated by pH, Ca²⁺, and the cholesterol content of the membrane. Its abundance is increased by high dietary K⁺ load, by aldosterone, and probably also by glucocorticoids (63, 359, 537, 34, 318). Moreover, KCNMA1 channels mediate K⁺ secretion upon stimulation with luminal purines. This type of Ca²⁺-mediated K⁺ secretion is missing in KCNMA1 knockout mice (542). These data are suggestive of a prominent role of KCNMA1 during K⁺ secretion across the luminal membrane of colonocytes. However, there is also evidence that luminal K⁺ secretion is more complex and probably consists of several components (552).

2. Luminal KCNN4 (IK1, SK4, K_Ca3.1) channels?

In two studies, the localization of KCNN4 in rat colonic mucosa has been investigated; however, the staining pattern differed. Using isolated crypts, Joiner et al. (268) observed a strong basolateral staining in crypt cells and a more diffuse pattern in surface cells. Furness et al. (163) used tissue sections for immunohistochemistry. They observed a KCNN4 staining at the luminal and basolateral membrane of enterocytes with a weaker signal at the crypt base. Unfortunately, tissues from KCNN4 knockout mice were not used as negative controls. Is KCNN4 a pathway for luminal K⁺ secretion? Based on pharmacology and immunofluorescence, it has been concluded that KCNN4 contributes to K⁺ secretion (268). However, two other studies are questioning this conclusion. In colonic mucosa of KCNN4 knockout mice, carbachol was still able to activate luminal K⁺ channels, but the activation of basolateral K⁺ channels was absent (146, 147, 400). The data from KCNN4 knockout mice clearly point to the relevance of KCNN4 as a basolateral channel. A major contribution of KCNN4 to Ca²⁺-induced K⁺ secretion in surface cells appears to be unlikely because this type of secretion was virtually absent in KCNMA1 but not in KCNN4 knockout mice (400).

3. Evidence for other K⁺ channels in the luminal membrane?

Analysis of K⁺ channel gene expression in colonic mucosa suggests that, besides KCNN4 and KCNMA1, members of the KCND, KCNH, KCNJ, and KCNK families are also expressed (406). At present, functional data indicating a role for one or several of those channels for K⁺ secretion in the native tissue are not yet available.

C. Role of K⁺ Channels for Cl^– Secretion in Colonic Crypt Cells

1. cAMP-mediated secretion

In crypt cells of large and small intestine, stimulation of the cAMP pathway leads to sustained and strong secretion of electrolytes and water (Fig. 9). The primary ion that is transported transcellularly is Cl^– and, therefore, this type of secretion is called Cl^– secretion. The key event for Cl^– secretion is the activation of the CFTR-dependent Cl^– conductance in the luminal membrane. In cystic fibrosis patients, whose CFTR is defective, this type of secretion is strongly diminished or absent (312). Upon activation of the Cl^– conductance, Cl^– leaves the cell into the lumen, thus depolarizing the luminal membrane towards the equilibrium potential of Cl^–. At the equilibrium potential of Cl^–, further Cl^– exit would be impossible. Basolateral (and luminal) K⁺ channels hyperpolarize the membrane, thereby energizing further luminal Cl^– exit. There is evidence from KCNQ1 knockout mice and pharmacological data obtained from rat, rabbit, and human tissue indicating that cAMP-activated Cl^– secretion largely depends on the activity of basolateral heteromeric KCNE3/KCNQ1 channels (357, 38, 112, 309, 380, 389, 549, 638). Only in guinea pig colon, no such function for KCNE3/KCNQ1 has been observed (348).

View larger version (31K): [in this window] [in a new window]   FIG. 9. cAMP- and Ca2+-stimulated Cl– secretion of colonocytes. A: cAMP-mediated Cl– secretion, e.g., by stimulation with prostaglandin E2 (PGE2). A primary event of cAMP-induced secretion is the activation of the luminal CFTR-dependent Cl– conductance. In the basolateral membrane, KCNE3/KCNQ1 channels are activated and hyperpolarize the basolateral membrane, thereby fueling luminal Cl– exit. Na+ follows through the paracellular pathway. In colonocytes, increases in cAMP lead to reduction of cytosolic Ca2+ activity. By this mechanism, luminal and basolateral Ca2+-regulated K+ channels close. HCO3– can be secreted through CFTR or in exchange for Cl–. B: Ca2+-mediated secretion after stimulation with acetylcholine. In contrast to cAMP stimulation, Ca2+ is not able to activate CFTR. Activity of basolateral KCNN4 K+ channels mirrors the time course of acetylcholine-induced Ca2+ increase. KCNE3/KCNQ1 channels are also activated by increased cytosolic Ca2+ activity. In the luminal membrane, Ca2+-regulated K+ channels are stimulated and lead to electroneutral transcellular secretion of KCl. As a consequence of luminal K+ channel activity, the transepithelial voltage difference is small, and paracellular Na+ transport decreases.

2. cGMP-stimulated secretion

Stimulation of proximal colonic mucosa by agonists acting via cGMP, e.g., guanylin (6, 152), leads to strong secretion due to activation of CFTR Cl^– conductance. The Escherichia coli heat-stable enterotoxin apparently also activates secretion as an exogenous agonist of guanylin receptors. The effects of guanylin are virtually absent in mice lacking intact CFTR (90). The effect of guanylin on K⁺ channels in colonic mucosa has not yet been directly tested, but presumably, KCNE3/KCNQ1 is responsible for cGMP-mediated secretion too.

3. Secretion in response to increases in cytosolic Ca²⁺

Upon stimulation with agonists raising intracellular Ca²⁺, colonic crypt cells hyperpolarize close to the equilibrium potential of K⁺ (Fig. 9B). The hyperpolarization is due to a large increase in whole cell K⁺ conductance: Ca²⁺ strongly activates Ca²⁺-sensitive basolateral (and to lesser extent also luminal) K⁺ channels (662). With the use of the patch-clamp technique, the most frequently observed K⁺ channel in the basolateral membrane of mammalian colonic crypts is a 10- to 25-pS small- to intermediate-conductance K⁺ channel that is steeply regulated by Ca²⁺ in the physiological range (half-maximal activation at 300 nM free Ca²⁺, Hill coefficient of 3) (40, 57, 106, 538). In cell-attached recordings, open probability of this channel is increased by agonists increasing cytosolic Ca²⁺, e.g., carbachol, or by cell swelling (535, 669). In excised patches, the channels show a run-down, but channel activity can be refreshed by application of ATP, suggesting that phosphorylation/dephosphorylation might regulate the channel. The nature of the respective protein kinase is still a matter of debate: the human channel has been reported to be activated by protein kinase A (360, 538); however, this has not been observed for the rat channel (446). Moreover, protein kinase C appears to be not involved in this regulation (107, 446). Probably, the ATP effect is rather complex: a COOH-terminal domain of the channel confers the ATP sensitivity without being phosphorylated itself (173). Interestingly, aldosterone has been claimed to inhibit the human Ca²⁺-activated K⁺ channel by a nongenomic mechanism (48, 49). Pharmacologically, the Ca²⁺-activated K⁺ channel of colonic crypts is blocked by Ba²⁺ (90% inhibition at 100 µM), charybdotoxin, TEA, clotrimazole (IC₅₀ 60 nM), quinine, and quinidine. The channel is insensitive to the chromanol 293B (inhibitor of KCNQ1 channels) and activated by 1-EBIO (probably by shifting the Ca²⁺ sensitivity) (40, 108, 109, 128, 644, 662, 665). The functional properties of the colonic Ca²⁺-activated K⁺ channel resemble those of cloned human and mouse KCNN4 (SK4, IK1, K_Ca3.1) channels (244, 270, 355, 356, 640), and in fact, the rat KCNN4 was cloned from colonic crypts (644, 665). Interestingly, the KCNN4 protein itself is not sensing Ca²⁺, but it becomes Ca²⁺-regulated by association with calmodulin (134, 269, 281). The relevance of KCNN4 as basolateral K⁺ channel has been highlighted by recent studies on two knockout models for this channel gene. Disruption of KCNN4 severely impaired carbachol-induced short-circuit current in Ussing chamber experiments. In wild-type animals, carbachol leads to a strong (and transient) lumen-negative transepithelial voltage (induced by the large increase in basolateral KCNN4 conductance). In KCNN4 knockout mice, this lumen-negative transepithelial voltage deflection is strongly reduced (400) or even absent (146), but carbachol induced a lumen-positive transepithelial voltage deflection due to activation of luminal Ca²⁺-regulated K⁺ channels (probably KCNMA1) (400).

Besides hyperpolarization for energizing the transport, a luminal Cl^– conductance is needed for the induction of electrogenic Cl^– secretion. Ca²⁺-activated Cl^– channels are not expressed in normal mucosa of distal colon, or only at very low levels. However, there appears to be expression of Ca²⁺-regulated Cl^– channels in proximal colon, e.g., members of the ClCa family (132). Very recently, it was shown that bestrophin 1 is another good candidate to underlie this conductance (23, 312, 313). Under experimental conditions allowing detection of small increases in luminal Cl^– conductance, Schultheiss et al. (553) have observed activation of luminal Cl^– channels by cholinergic stimulation. This Cl^– conductance was NO dependent and had pharmacological characteristics different from CFTR (553). Ca²⁺-activated Cl^– channels can be hardly detected in normal distal colon, but expression of those channels is increased after induction of carcinogenesis, and a variety of cell lines derived from intestinal tumors exhibit Ca²⁺-activated Cl^– channels (23, 39). If Ca²⁺-activated Cl^– channels are very weakly expressed under physiological conditions, how do Ca²⁺-stimulating agonists stimulate Cl^– secretion in distal colon? The Ca²⁺-rising agonists predominantly activate basolateral K⁺ channels (and to less extent luminal K⁺ channels). Thereby, they increase the driving force for luminal Cl^– exit through open Cl^– channels. The major luminal Cl^– conductance is CFTR dependent, but CFTR is not Ca²⁺ stimulated in colonocytes. Therefore, Ca²⁺-stimulated Cl^– secretion necessitates residual costimulation with cAMP to keep CFTR active. Inhibition of the endogenous cAMP production by indomethacin (indomethacin inhibits the generation of the cAMP-rising prostaglandin E₂) abolishes cholinergic Cl^– secretion. In the absence of a relevant luminal Cl^– conductance, only the Ca²⁺-induced activation of luminal K⁺ channels can be observed in transepithelial voltage measurements (391).

What is the physiological significance of Ca²⁺-induced Cl^– secretion in colonic mucosa? Compared with cAMP-stimulated secretion, the effect of increased Ca²⁺ appears to be less important, because it is transient, and it needs cAMP costimulation. Under physiological conditions, stimulation with acetylcholine leads to Ca²⁺-activated flush secretion of electrolytes, water, and mucus. In addition, acetylcholine stimulates contraction of colonic muscle and propulsion of the feces. In this regard, Ca²⁺-induced secretion is probably important to guarantee low friction for the propulsion of feces. Longer lasting or repetitive activation of the Ca²⁺ pathway probably leads to modification of the composition of the secreted fluid due to activation of luminal K⁺ channels and reduction of the paracellular Na⁺ flux: under such conditions, the mucosa secretes a KCl-rich fluid instead of NaCl.

D. Do K⁺ Channels Influence Cell Fate, Proliferation, and Carcinogenesis?

Over the last years, changes of K⁺ channel expression have been shown to be associated with cancer in a growing number of publications. Apparently, the control of the cell voltage and cell volume by K⁺ channels greatly affects the regulation of the cell cycle, proliferation, and apoptosis (189, 324, 456, 672). With regard to determination of cellular fate and cell differentiation, only a few examples of primary involvement of K⁺ channels have been described so far (30, 219).

In the colon, stem cells in the crypt base region exhibit a very high proliferation rate; the daughter cells differentiate and lose their proliferative capacity during their migration to the surface. Finally, the surface cells undergo apoptosis and are replaced by their successors. In normal colon, exfoliation of nonapoptotic cells is believed to be a rare event. In tumor tissue, cells do not lose their capacity to proliferate, and the initiation of apoptosis appears to be retarded: transformed colonocytes accumulate and large numbers of not yet apoptotic cells are exfoliated into the lumen (320, 358). In renal proximal tubular cells, KCNK5 (TASK2) K⁺ channels are required for apoptotic volume decrease, which is a key event during the process of apoptosis (316). So far, it is not known whether KCNK5 plays a similar role for apoptotic volume decrease in small and large intestine, where the channel is also expressed. The changes in the cellular program during carcinogenesis go along with changes of protein expression and electrical properties. Several K⁺ channels have been found to be overexpressed in cancer tissue, e.g., members of the "EAG" family (KCNH1 and KCNH2) (76, 473, 474), KCNC1 and KCNC4 (Kv3.1 and Kv3.4) (465, 586), KCNA5 (Kv1.5) (465, 586), KCNMA1 (MaxiK) (43), and KCNK9 (TASK3) (329, 432, 484). Although the changes in K⁺ channel expression are well documented, it is often not clear whether those changes are causative for carcinogenesis or an epiphenomenon reflecting dedifferentiation and ongoing proliferation. Analysis of gene expression profiles including K⁺ channels will help to improve our knowledge about the cellular phenomena underlying carcinogenesis. Moreover, tumor-associated K⁺ channels could serve as useful tumor markers and possible targets for local treatment of colonic cancer (591).

	V. EXOCRINE PANCREAS AND SALIVARY GLANDS: PARADIGMS FOR EXOCRINE SECRETION

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Over the past decades, studies of ion transport mechanisms in exocrine pancreas and salivary glands have promoted our understanding of the principles underlying exocrine secretion of epithelial cells. In the following, we will delineate the putative roles of K⁺ channels in acinar and duct cells of exocrine pancreas and salivary glands and their contribution to transepithelial ion transport.

A. Enzyme and Cl^– Secretion in Pancreatic Acinar Cells

In humans, the epithelial cells of the exocrine pancreas secrete 2 liters of alkaline and enzyme-rich fluid per day. During the interdigestive phases, the secretory rate is rather low (0.2–0.3 ml/min). After ingestion of food, the secretion rate increases 10-fold. Morphologically and functionally, the exocrine pancreas consists of two parts, the acinar cells forming a NaCl- and enzyme-rich fluid and duct epithelial cells that produce bicarbonate-rich secretion. The major task of pancreatic acinar cells is the secretion of digestive enzymes and zymogens via exocytosis of enzyme-containing vesicles (so-called zymogen granules, Fig. 10A) and transepithelial transport of NaCl and water (496). The mechanisms by which zymogen granules fuse with the apical membrane and release their content have been studied extensively (for review, see Ref. 257). Upon the fusion event, activation of ion conductances and water channels in the granule membrane is believed to facilitate the wash-out of the vesicle, thereby discharging zymogens and enzymes into the lumen (258) (however, it should be stated that the major component of the luminal agonist-elicited Cl^– conductance is independent from vesicular conductances, Ref. 253). With the use of molecular and biochemical approaches, ClC-2 and ClC-3 Cl^– channels, aquaporin-1 water channels KCNJ8 (=Kir6.1), and KCNQ1 K⁺ channels have been identified in the vesicle membrane (614, 615). A recent patch-clamp study has highlighted the putative role of KCNJ8 K⁺ channels and ClC-2 and ClC-3 Cl^– channels in freshly isolated zymogen granules (279). The regulation of zymogen granule release is mainly triggered by agonists leading to an IP₃-mediated rise of cytosolic Ca²⁺, e.g., acetylcholine (via M1 and M3 muscarinic receptors, Refs. 169, 252) and CCK (via CCK1 and CCK2 receptors; however, the role of CCK in stimulating human acinar cells has been questioned, Refs. 261, 517, 647).

View larger version (38K): [in this window] [in a new window]   FIG. 10. Ion transport in exocrine pancreas. A: histology of a pancreatic acinus cells. Zymogen-containing vesicles are localized at the apical pole of the cells. B: model for Cl– secretion in pancreatic acinar cells. Agonists raising cytosolic Ca2+ induce the opening of luminal Ca2+-regulated Cl– channels which depolarize the membrane close to the equilibrium potential of Cl–. Basolateral K+ channels [KCNE1/KCNQ1, KCNMA1 (MaxiK), and others] hyperpolarize the membrane voltage below the equilibrium potential of Cl–, thus powering luminal Cl– exit. Stimulation of the cAMP pathway stimulates basolateral KCNQ1 channels. Ca2+-regulated nonselective cation channels probably play a minor role (478). Cl–/HCO3– exchanger (AE2), Na+-2Cl–-K+ (NKCC1), and NaCl (NCC) cotransporters serve as Cl– uptake mechanisms in the basolateral membrane. C: model of transepithelial bicarbonate in pancreatic duct cells. At the basolateral membrane, bicarbonate is taken up by a Na+-2HCO3– cotransporter (NBC). Additionally, intracellular carbonic anhydrase accelerates formation of bicarbonate from CO2. Na+/H+ exchangers (NHE) extrude the H+ across the basolateral membrane. Ca2+-activated KCNN4 (IK1) and large-conductance K+ channels (MaxiK) hyperpolarize the basolateral membrane and create the driving force for luminal anion exit. In the luminal membrane, Cl–/HCO3– exchangers (SLC26A3 and SLC26A6; Ref. 431) secrete bicarbonate in exchange for Cl–, which leaves the cell through luminal CFTR-type Cl– channels. In addition, non-CFTR-like channels might be also present. During stimulated secretion, bicarbonate transport probably does not occur via Cl–/HCO3– exchangers but predominantly through a CFTR-dependent luminal HCO3– conductance. In addition, Ca2+-regulated Cl– channels appear to play a role during Ca2+-mediated secretion. Na+ follows through the paracellular pathway fueled by the transepithelial voltage.

As for enzyme release, hormonal stimulation by acetylcholine or CCK, which leads to rises of cytosolic Ca²⁺, plays the central role for activating electrogenic Cl^– secretion (175, 423, 493, 496). In fact, the acetylcholine signaling cascade involving a pivotal contribution of IP₃ as a messenger releasing Ca²⁺ from internal stores has been described for the first time in this tissue (590). Increases in cytosolic Ca²⁺ activity induce impressive changes of the ion conductance of pancreatic acinar cells. In the relatively small surface of the luminal membrane, a large number of Cl^– channels open in response to the rise of Ca²⁺ (478), thus depolarizing the membrane voltage from some –40 to –20 mV (580). The luminal Cl^– channels have been shown to have a very small single-channel conductance (1–2 pS, Ref. 394), and they are not inhibited by typical Cl^– channel inhibitors such as DIDS, NPPB, and glibenclamide (693). From the halide permeability sequence it was deduced that the CFTR Cl^– channel does not underlie this conductance (693). In another study on pig pancreatic acini, a ClC-2-like Cl^– channel has been described (66). In parallel to activation of luminal Cl^– channels, Ca²⁺ stimulates K⁺ channels in the basolateral membrane. This K⁺ conductance is required to hyperpolarize the membrane voltage below the equilibrium potential to fuel luminal Cl^– exit. In pancreatic acinar cells of various species, a Ca²⁺-regulated large-conductance K⁺ channel (200 pS) has been observed upon stimulation with the Ca²⁺ agonists acetylcholine, CCK, and bombesin (254, 255, 396, 492, 494, 495, 599). In rodents, this large-conductance K⁺ channel appears to be expressed in an age-dependent manner with low expression levels in young and increased expression in adult animals (463). A less frequent 50-pS K⁺ channel, which is voltage and Ca²⁺ activated, has been found in human and guinea pig pancreatic acinar cells (495, 599). In mouse pancreatic acini, voltage-activated K⁺ channels (620) as well as pH-regulated inwardly rectifying K⁺ channels have been observed that were not regulated by cAMP and cytosolic Ca²⁺ activity (545). It has been suggested that besides members of the inward rectifier family also 2-P domain K⁺ channels contribute to the pH-regulated K⁺ conductance of pancreatic acinar cells (126). Apparently different from the K⁺ channels described above, a slowly activating and voltage-dependent component of the K⁺ conductance in pancreatic acinar cells is augmented after cholinergic stimulation. This current can be inhibited by the KCNQ1 blocker 293B, and single-channel amplitude is very small, both suggesting that KCNQ1 underlies this voltage-dependent K⁺ conductance of acinar cells (284, 302). The peculiar current kinetics and the fact that this current is diminished in KCNE1 knockout mice speak in favor for an assembly of KCNQ1 with its β-subunit KCNE1 (663).

In addition to hormone receptors coupling to the IP₃/Ca²⁺ pathway, pancreatic acinar cells express receptors whose stimulation leads to generation of cAMP, e.g., receptors for secretin and VIP. Compared with the prominent regulation by cytosolic Ca²⁺, stimulation of the cAMP pathway is considered to be of minor importance for the activation of Cl^– secretion (496). Interestingly, the increase of cytosolic cAMP concentration strongly augments the voltage-dependent and slowly activating K⁺ current carried by heteromeric KCNE1/KCNQ1 K⁺ channels, but cAMP is not able to stimulate luminal Ca²⁺-regulated Cl^– channels (286). Therefore, cAMP on its own is not capable to induce transcellular Cl^– secretion, but it probably enhances Ca²⁺-activated Cl^– secretion by increasing the driving force for luminal Cl^– exit. The KCNE1/KCNQ1 K⁺ current is inhibited by somatostatin and prostaglandin E₂ (probably via EP3 receptors), likely because those receptors reduce the intracellular cAMP concentration via inhibitory G proteins (330, 332). Although the above-mentioned studies suggest a substantial contribution of KCNE1/KCNQ1 to Cl^– secretion of acinar cells, KCNQ1 inhibitors do not have a relevant impact on fluid and enzyme secretion of rat exocrine pancreas (333). Therefore, KCNE1/KCNQ1 channels are not the bottle neck limiting acetylcholine-induced secretion, and their inhibition can be compensated. Further studies are needed to identify and to characterize other basolateral K⁺ channels. Taken together, Ca²⁺ and cAMP pathways act, at least in part, in concert for inducing a strong electrolyte secretion in pancreatic acinar cells.

B. Role of the K⁺ Conductance for Bicarbonate Secretion in Pancreatic Ducts

Pancreatic duct cells secrete a very alkaline fluid that contains up to 140 mM bicarbonate under stimulated conditions. Under resting conditions, the bicarbonate concentration is in the range of 30–60 mM. Although the composition of pancreatic juice during stimulated secretion has been known for a long time, it is still a matter of debate by which mechanisms the ducts cells achieve such high bicarbonate secretion (Fig. 10C). An excellent overview about the current knowledge of bicarbonate transport in pancreatic ducts is provided by Steward, Ishiguro, and Case (588). Under resting conditions with relatively low luminal concentrations of bicarbonate, a luminal Cl^–/HCO₃^– exchanger (working in a 1:1 stoichiometry) is able to transport HCO₃^– into the lumen energized by the concentration gradient of Cl^–. Under stimulated conditions with high luminal bicarbonate and low Cl^– concentrations, however, such a Cl^–/HCO₃^– exchanger would import bicarbonate. Therefore, other transport mechanisms are needed to explain the secretion of HCO₃^– against the chemical gradient (243, 588). One possibility is the presence of electrogenic Cl^–/HCO₃^– exchangers with a stoichiometry of 1:2 (e.g., SLC26A6), which are fueled by the membrane voltage (243, 588). Such a secretion mode is possible, if 1) Cl^– taken up by the Cl^–/HCO₃^– exchanger does not accumulate in the cytosol (luminal Cl^– channels are required as exit or recycling pathway) and 2) the luminal membrane voltage is sufficiently hyperpolarized (probably in the range of –45 mV) to drive the negative net charge out of the cell. Which mechanisms are responsible for hyperpolarizing the luminal membrane? Most likely, the luminal membrane is hyperpolarized below the equilibrium potential of Cl^– by basolateral K⁺ channels (454). Those basolateral K⁺ channels can also induce luminal hyperpolarization because the luminal and basolateral membrane are not electrically separated but connected via a Na⁺-permeable paracellular pathway (454).

Another possibility for achieving high luminal HCO₃^– concentrations would be a transport model with a HCO₃^–-permeable ion conductance in the luminal membrane. The likely candidate for such a luminal HCO₃^–-permeable channel is CFTR, which has been shown to conduct not only Cl^– but also HCO₃^– (502, 582). Moreover, patients suffering from cystic fibrosis display reduced alkalinization of pancreatic fluid (266, 297). Also for this model of HCO₃^– secretion, hyperpolarization of the luminal membrane below the equilibrium potential of HCO₃^– is required to energize luminal HCO₃^– exit. Again, basolateral K⁺ channels are probably responsible for hyperpolarizing the luminal membrane. Interestingly, data from knockout mice suggest a functional interplay between CFTR and the Cl^–/HCO₃^– exchanger SLC26A6 (653). Further work is needed to elucidate the exciting and complex interactions of Cl^–- and HCO₃^–-transporting membrane proteins in the luminal membrane of pancreatic duct cells.

1. What are the properties of the basolateral K⁺ conductance?

According to impalement studies on isolated perfused rat pancreatic ducts, resting pancreatic duct cells have a hyperpolarized basolateral membrane voltage of –60 to –70 mV due to a high K⁺ conductance leading to a basolateral resistance of 90–120 ·cm² (453, 454). The luminal membrane of resting duct cells has a very high electrical resistance of 2,000 ·cm² and probably no significant K⁺ conductance. The paracellular pathway, as mentioned in the last paragraph, is Na⁺ permeable with an estimated resistance of 50–80 ·cm². Several hormones stimulating secretion in acinar cells via increases in cytosolic Ca²⁺ such as CCK, bombesin, and substance P have no effect on duct cells (468). However, cholinergic stimulation of the Ca²⁺ pathway and, more importantly, increases in cAMP by stimulation with secretin, VIP, and adrenaline (via β-receptors) lead to dramatic changes of the electrical properties of duct cells: the basolateral K⁺ conductance is increased leading to a small hyperpolarization which is followed by depolarization caused by strong activation of a luminal Cl^– conductance (452, 468). The impressive increase in luminal ion conductance is mirrored by a drop of the luminal resistance from 2,000 to 80 ·cm². There is experimental evidence for activation of the luminal Cl^– conductance by cAMP and Ca²⁺ pathways (148, 468, 664). The cAMP-induced increase in basolateral K⁺ conductance is probably caused by activation of MaxiK channels via cAMP-dependent phosphorylation. It has been suggested that phosphorylation of MaxiK channels alters the Ca²⁺ responsiveness of the channel (187). Additional candidates for basolateral K⁺ channels are Ca²⁺-regulated KCNN4 (IK1) and pH- and cell volume-sensitive KCNK5 (TASK2) channels (148, 618). Interestingly, the K⁺ conductance of pancreatic duct cells can be inhibited by ATP via purinergic receptor stimulation (probably P2Y₂ or P2Y₄, Refs. 216, 584). ATP is released from acinar cells after cholinergic stimulation and might act as a paracrine factor coordinating acinar and duct cell function (585). In contrast to basolateral receptors, luminal puringeric receptors (probably P2X7 and P2X4) lead to depolarization of the membrane and increases in whole cell conductance (216).

Taken together, sufficient activity of basolateral K⁺ channels is a prerequisite to drive apical electrogenic Cl^– and HCO₃^– secretion. Furthermore, hyperpolarization of the basolateral membrane and depolarization of the luminal membrane establish a transepithelial voltage difference that in turn leads to paracellular Na⁺ flux into the lumen. By these mechanisms, apical, basolateral, and paracellular ways of ion transport cooperate to establish secretion of HCO₃^– up to 150 mM.

C. Fluid and Electrolyte Secretion in Salivary Glands

In humans, per day more than 1 liter of saliva is produced mainly by three pairs of large salivary glands, i.e., sublingual, submandibular, and parotid glands. The saliva is a watery secretion containing electrolytes, proteins, and mucus. The secretion of saliva is a highly regulated process (via autonomic innervation) with relatively low rates between the meals and a very high secretion after stimulation, which is initiated by food-related thoughts, smell and taste of food, and by mastication. Cholinergic stimulation is a major way for activation (547), but a variety of other factors and hormones also modulate saliva production, e.g., β-adrenergic stimulation (104, 264), substance P (265), and purinergic signaling (680). Saliva is required to hydrate and to protect the mucosa of the oral cavity, to facilitate milling and transport of the ingested food, to dissolve gustatory substances, to initiate digestion, and to protect against microbial, mechanical, and chemical insults (415, 548). The physiological importance of saliva is highlighted by diseases of the salivary glands which result in reduced saliva production, e.g., Sjögren's syndrome (OMIM no. 270150), cystic fibrosis (OMIM no. 219700), and chemotherapy and irradiation for head and neck tumors. Clinical symptoms encompass oral dryness (xerostomia), dysphagia, adherence of food to the oral mucosa, oral burning, dental caries, changes in taste, inability to eat dry food, intolerance to spicy food, inability to speak for long periods, and chronic esophagitis due to reduced clearance and buffering of gastric acid leaking back into the esophagus (53). Like the secretory mechanism in exocrine pancreas, saliva secretion involves two stages (613). First, a fluid of plasmalike electrolyte composition is formed by salivary acinar cells. Afterwards, the secretion is modified during its passage through the ducts: NaCl is reabsorbed and K⁺ and HCO₃^– are secreted by the duct epithelial cells (392). Below, the basic principles of saliva formation and its modification along the ducts will be outlined.

D. Formation of Primary Saliva by Acinus Cells

The principles of saliva production have been the focus of several excellent reviews (392, 410, 415, 439, 504, 548, 609, 630), and useful lists of salivary gland-specific gene expression and protein localization have been provided (214, 437). For primary saliva formation, the transcellular movement of Cl^– represents a pivotal step (Fig. 11). For this purpose, Cl^– is taken up basolaterally via the Na⁺-2Cl^–-K⁺ cotransporter [NKCC1 (424) and the Cl^–/HCO₃^– exchanger AE2 (214, 443)]. NKCC1 activity is increased during muscarinergic and β-adrenergic stimulation (131, 488). Data from NKCC1-deficient mice have highlighted the importance of NKCC1 as Cl^– uptake mechanism: saliva flow of the parotid gland was reduced by some 60% in knockout mice, although these mice showed a compensatory increase in basolateral Cl^–/HCO₃^– exchange (130). At the luminal pole, Cl^– leaves the cell through Ca²⁺-activated Cl^– channels. The BEST2 (vitelliform macular dystrophy 2-like protein 1) gene product has been proposed to underlie this Ca²⁺-activated Cl^– conductance, but this is still a matter of debate (415, 437). Other Cl^– channels that expressed salivary glands are ClC2 and ClC3 (437, 440). The luminal Cl^– exit is energized by basolateral K⁺ channels that hyperpolarize the membrane voltage below the Cl^– equilibrium potential. With the use of patch-clamp techniques, Ca²⁺- and voltage-activated K⁺ channels of large conductance (KCNMA1 = MaxiK = BK = Slo1, associated with the β-subunits KCNMB1 and KCNMB4) have been described in the basolateral membrane of parotid and submandibular acinus cells (395, 441, 475). A second type of K⁺ channel frequently observed in salivary glands is the Ca²⁺-activated K⁺ channel of intermediate single-channel conductance (KCNN4 = IK1 = SK4) (213, 246, 259, 441, 602). Besides Ca²⁺, KCNN4 has been proposed to be activated by protein kinase A in submandibular acinus cells (212). Only in bovine parotid glands, an additional inwardly rectifying K⁺ channel (KCNJ2) has been found (211). For a long time, the relative contributions of the major channels, MaxiK and IK1, for the basolateral K⁺ conductance was a matter of debate (245, 247, 592). In recent years, several interesting studies on genetically modified mice have shed light on the role of these channels during secretion. Interestingly, KCNN4 (IK1) knockout mice displayed normal activated fluid secretion in parotid glands, although the linear (KCNN4-specific) K⁺ current component was diminished (27). Also KCNMA1 (MaxiK) knockout mice showed a mild phenotype with a normal secretion rate and slight changes of the ionic composition of the saliva (523). However, KCNMA1/KCNN4 double knockout mice exhibited a severely reduced secretion rate of parotid (523) and submandibular glands (524), indicating that both channels are important. The membrane voltage of acinar cells of double knockout mice was depolarized. Upon cholinergic stimulation, the cells depolarized further, which is indicative of the activation of Ca²⁺-regulated Cl^– channels in the absence of Ca²⁺-regulated K⁺ conductance (523, 524). In conclusion, MaxiK and IK1 K⁺ channels underlie the Ca²⁺-regulated basolateral K⁺ conductance in salivary glands and contribute to the electrical driving force for luminal Cl^– exit. The Cl^– channel-induced depolarization of the luminal membrane and the K⁺ channel-induced hyperpolarization of the basolateral membrane establish a lumen-negative V_te that drives Na⁺ through the paracellular pathway into the lumen (492, 630). Parallel to the Ca²⁺-induced cellular changes leading to NaCl secretion, rises in Ca²⁺ stimulate the insertion of AQP5 into the luminal membrane (249, 401). The increased cellular water permeability and the osmotic gradient built by the secretion of NaCl result in a water flux into the lumen. Although a variety of different aquaporins are expressed in salivary glands (99), the severely impaired water flux observed in AQP5-deficient mice underlines the importance of AQP5 for fluid secretion of acinar cells (303, 372). Additionally, there is evidence for a paracellular water flux in submandibular gland (434). Taken together, the Ca²⁺-induced concerted activation of luminal and basolateral transport systems results in the secretion of large amounts of isotonic NaCl-rich fluid. Additionally, salivary proteins are secreted in acinar cells via exocytosis of zymogen-containing granules. The secretion of salivary proteins is stimulated in response to rises of cAMP, e.g., after VIP or β-adrenergic stimulation (248, 415).

View larger version (26K): [in this window] [in a new window]   FIG. 11. Mechanisms of saliva formation. A: simplified scheme of saliva formation. In acinus cells, a NaCl-rich fluid is secreted. Duct cells reabsorb Na+ and Cl– transcellularly and secrete K+ and HCO3–. B: transport model of a salivary acinus cells. Cl– is taken up by the basolateral Na+-2Cl–-K+ cotransporter (NKCC1) and by the anion exchanger (AE2) (214). HCO3– is formed from CO2 in a carbonic anhydrase-dependent way (not shown); the H+ leaves the cell through a basolateral Na+/H+ exchanger (NHE1). Additionally, a basolateral Na+-HCO3– cotransporter has been described (NBC1, Ref. 476; not shown in the model). Ca2+-activated Cl– channels (perhaps BEST2, Ref. 437) serve as luminal Cl– exit pathway. Na+ enters the lumen across the paracellular pathway driven by the transepithelial voltage; water follows probably transcellularly through aquaporins (probably mainly AQP5, Ref. 99) [Adapted from Nakamoto et al. (437) and Turner and Sugiya (630).] C: working model of salivary duct function during stimulated saliva production. Na+ is reabsorbed through ENaC and luminal Na+/H+ exchangers; Cl– is reabsorbed by CFTR. HCO3– is taken up by basolateral Na+-HCO3– cotransporters (NBC) secreted into the lumen via CFTR (370, 570). The basolateral Na+/H+ exchanger (NHE1) is involved in the regulation of the cytosolic pH. The molecular nature of the luminal K+ channels is not precisely known. Ducts are relatively impermeable to water; therefore, net absorption of ions results in hypotonic saliva.

The major task of salivary gland duct epithelia is to modify the plasmalike fluid secreted by acinar cells. Final saliva composition and ion transport in ducts are dependent on the secretory status of the gland. At "low flow" resting conditions, the ionic composition of the final saliva is (in mM): 3 Na⁺, 25 K⁺, 24 Cl^–, and 3 HCO₃^–, pH 6.5; after stimulation of saliva secretion by the autonomic nervous system, the saliva flow largely increases and the ionic composition changes (in mM): 45 Na⁺, 21 K⁺, 40 Cl^–, 26 HCO₃^–, pH 7.5 (410). This modification of primary saliva during the passage through the duct system encompasses reabsorption of Na⁺ and Cl^– and secretion of K⁺ and HCO₃^– (613). Water is not reabsorbed or only very little. Since the reabsorption of NaCl exceeds the secretion of K⁺ and HCO₃^–, the final saliva becomes hypotonic. In the luminal membrane, Na⁺ is reabsorbed through ENaC (84, 123). Cl^– enters the cells probably mainly via the CFTR-dependent Cl^– conductance (695). In addition, ClCA Cl^– channels have been described (242, 681). Basolaterally, Na⁺ is extruded by the Na⁺-K⁺-ATPase; Cl^– leaves the cell most likely through Cl^– channels. For the luminal secretion of HCO₃^–, it has been suggested that similar to pancreatic ducts luminal CFTR is involved in this process (570, 695). In the luminal and basolateral membrane of duct cells, several Na⁺-HCO₃^– cotransporting systems (NBC family, Ref. 525) have been found whose expression patterns appear to vary in a gland-, segment-, and species-dependent manner (3, 296, 347, 433, 476, 528, 530). Basolateral NBC transporters act as uptake systems for HCO₃^–, and luminal NBC transporters have been suggested to work as salvage mechanism: in the resting gland, ducts appear to reabsorb HCO₃^– rather than secreting it, resulting in a relatively low pH (6.5) of the final saliva at these conditions (370, 613). Electrogenic NBC transporters (229), e.g., NBC1 in the luminal membrane of ducts of guinea pig parotid gland, could, in principle, participate in luminal HCO₃^– secretion (dependent on a sufficiently hyperpolarized luminal membrane) (347, 525). Relatively little is known about the K⁺ channels underlying luminal K⁺ secretion (486) (for an overview of the expression of K⁺ channel in salivary glands, see Table 1). In duct cells, K⁺ channels are needed to energize voltage-dependent transport processes, e.g., luminal HCO₃^– exit and Na⁺ uptake as well as basolateral uptake of HCO₃^– by electrogenic members of the NBC transporter family. Furthermore, luminal K⁺ channels are the likely pathway for K⁺ secretion, and basolateral K⁺ channels are needed to recycle K⁺ that has been taken up by the Na⁺-K⁺-ATPase. As such a way for luminal K⁺ secretion, KCNJ1 (ROMK)-like channels have been described in human submandibular cells (353). With the use of immunofluorescence techniques, a KCNN4 (IK1, SK4)-specific strong signal was observed in intercalated ducts of the submandibular gland (618); however, functional data evaluating the significance of KCNN4 in salivary ducts have not yet been published. Further studies are needed to evaluate the functional contribution of KCNJ1 and KCNN4 channels and to identify additional K⁺ channel candidates supporting the ion transport in salivary ducts.

	VI. CONCLUSIONS AND PERSPECTIVES

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Advances in electrophysiological and molecular techniques as well as genomics and proteomics approaches have enormously improved our understanding of K⁺ channels over the last 25 years. In the epithelia of the gastrointestinal tract, K⁺ channels serve a variety of important functions, and their large molecular diversity allows precise adaptation to the complex needs. Such vital functions of K⁺ channels encompass 1) the K⁺ channel-mediated hyperpolarization as a prerequisite of vectorial transport across the epithelial cells. By this mechanism, many different K⁺ channels energize voltage-driven transport processes, e.g., electrogenic glucose reabsorption in small intestine, colonic Na⁺ reabsorption by epithelial Na⁺ channels, and Cl^– secretion in crypt cells or exocrine glands. Moreover, the polarized activation of K⁺ channels in basolateral or luminal membranes is a critical factor for the establishment of a transepithelial voltage difference that is needed to drive ion transport across the paracellular pathway. 2) Luminal MaxiK channels in the colonic surface cells act as an exit pathway for K⁺. These mineralocorticoids-controlled channels play a significant role for the fine-tuning of the electrolyte homeostasis. 3) Several K⁺ channels act in concert with K⁺-transporting ATPases by allowing K⁺ recycling across the plasma membrane. A prominent example for this function is the KCNE2/KCNQ1 heteromeric K⁺ channel, whose activity is indispensable for gastric acid secretion by the H⁺-K⁺-ATPase. 4) K⁺ channels play a role in cellular volume regulation. During reabsorption of nutrients, epithelial cells transport vast amounts of osmolytes and, therefore, they are continuously challenged by changes of cell volume. Cell volume-dependent activation of K⁺ channels is needed to counterbalance the cellular increase in osmolytes and induces regulatory volume decrease after cell swelling. 5) K⁺ channels are involved in the control of cell differentiation, proliferation, and carcinogenesis. Unfortunately, in many cases it is not clear whether changes in K⁺ function are causative or secondary. Nevertheless, few examples have illustrated the potential of K⁺ channels to play a crucial role for differentiation, apoptosis, and carcinogenesis.

The information about the expression, function, and regulation of gastrointestinal K⁺ channels is still incomplete and fragmentary, not at least because the experimental approach is complicated by the functional and morphological diversity of the tissues (e.g., crypt and villus cells) and the high fragility of freshly isolated tissues and cells. Generation and phenotypical analysis of transgenic and knockout mice have turned out to be very powerful tools to study the relevance of K⁺ channels in gastrointestinal epithelia. Data from genetically modified animals enabled us to bridge the gap between physiology and clinically relevant pathophysiology. The exciting discovery of small interfering RNAs (siRNA) as a novel way of posttranscriptional regulation of gene expression and the availability of the siRNA technique to knock-down already synthesized RNA offer new perspectives for basic and applied research. In the future, the integrative use of molecular and functional techniques and of modern methods of the postgenome era will further improve our knowledge about the multifaceted functions of gastrointestinal K⁺ channels and their potential clinical implications.

	GRANTS

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This work was supported by Deutsche Forschungsgemeinschaft Grant SFB699.

	ACKNOWLEDGMENTS

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We thank Dr. Weber for critically reading the manuscript and Prof. Dr. Kunzelmann for fruitful discussions.

Address for reprint requests and other correspondence: R. Warth, Institute of Physiology, Universitaetstrasse 31, 93053 Regensburg, Germany (e-mail: richard.warth{at}vkl.uni-regensburg.de).

	FOOTNOTES

 
¹ Origin of the channel names: "Shaker": Drosophila melanogaster carrying a mutated "shaker" channel gene exhibited shaking behavior when recovering from diethylether anesthesia (471); "Shab": Shaker cognate B; "Shaw" Shaker cognate W; "Shal" Shaker cognate L (61); "EAG" (ether à go-go gene): flies carrying a mutated "eag" channel gene exhibited movements during recovery from diethylether anesthesia which were reminiscent of dancers at the "Whisky-à-Go-Go" night club (West Hollywood) (276, 673); "ERG": "ether à go-go related gene" (658); "ELK": "ether à go-go like gene" (658); "Slo" (slowpoke): a slow, noninactivating Ca²⁺-dependent K⁺ current orignally descirbed in flies (16, 129).

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