http://physrev.physiology.org Physiological Reviews RSS feed -- recent issues 1522-1210 Physiological Reviews 0031-9333 http://physrev.physiology.org/icons/banner/title.gif http://physrev.physiology.org http://physrev.physiology.org/cgi/content/abstract/89/4/1079?rss=1 The mammalian brain is plastic in the sense that it shows a remarkable capacity for change throughout life. The contribution of neuronal activity to brain plasticity was first recognized in relation to critical periods of development, when manipulating the sensory environment was found to profoundly affect neuronal morphology and receptive field properties. Since then, a growing body of evidence has established that brain plasticity extends beyond development and is an inherent feature of adult brain function, spanning multiple domains, from learning and memory to adaptability of primary sensory maps. Here we discuss evolution of the current view that plasticity of the adult brain derives from dynamic tuning of transcriptional control mechanisms at the neuronal level, in response to external and internal stimuli. We then review the identification of "plasticity genes" regulated by changes in the levels of electrical activity, and how elucidating their cellular functions has revealed the intimate role transcriptional regulation plays in fundamental aspects of synaptic transmission and circuit plasticity that occur in the brain on an every day basis.

]]> 2009-09-29 info:doi/10.1152/physrev.00013.2009 American Physiological Society 4 89 1103 2009-10-01 1079 Articles http://physrev.physiology.org/cgi/content/abstract/89/4/1105?rss=1 Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrP^C) of the host. PrP^C is necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrP^C, and therefore, understanding the physiological role of PrP^C may help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics.

]]> 2009-09-29 info:doi/10.1152/physrev.00006.2009 American Physiological Society 4 89 1152 2009-10-01 1105 Articles http://physrev.physiology.org/cgi/content/abstract/89/4/1153?rss=1 Calcium-induced calcium release (CICR) was first discovered in skeletal muscle. CICR is defined as Ca²⁺ release by the action of Ca²⁺ alone without the simultaneous action of other activating processes. CICR is biphasically dependent on Ca²⁺ concentration; is inhibited by Mg²⁺, procaine, and tetracaine; and is potentiated by ATP, other adenine compounds, and caffeine. With depolarization of the sarcoplasmic reticulum (SR), a potential change of the SR membrane in which the luminal side becomes more negative, CICR is activated for several seconds and is then inactivated. All three types of ryanodine receptors (RyRs) show CICR activity. At least one RyR, RyR1, also shows non-CICR Ca²⁺ release, such as that triggered by the t-tubule voltage sensor, by clofibric acid, and by SR depolarization. Maximum rates of CICR, at the optimal Ca²⁺ concentration in the presence of physiological levels of ATP and Mg²⁺ determined in skinned fibers and fragmented SR, are much lower than the rate of physiological Ca²⁺ release. The primary event of physiological Ca²⁺ release, the Ca²⁺ spark, is the simultaneous opening of multiple channels, the coordinating mechanism of which does not appear to be CICR because of the low probability of CICR opening under physiological conditions. The coordination may require Ca²⁺, but in that case, some other stimulus or stimuli must be provided simultaneously, which is not CICR by definition. Thus CICR does not appear to contribute significantly to physiological Ca²⁺ release. On the other hand, CICR appears to play a key role in caffeine contracture and malignant hyperthermia. The potentiation of voltage-activated Ca²⁺ release by caffeine, however, does not seem to occur through secondary CICR, although the site where caffeine potentiates voltage-activated Ca²⁺ release might be the same site where caffeine potentiates CICR.

]]> 2009-09-29 info:doi/10.1152/physrev.00040.2008 American Physiological Society 4 89 1176 2009-10-01 1153 Articles http://physrev.physiology.org/cgi/content/abstract/89/4/1177?rss=1 It is now apparent that regulation of blood vessel growth contributes to the classical actions of hormones on development, growth, and reproduction. Endothelial cells are ideally positioned to respond to hormones, which act in concert with locally produced chemical mediators to regulate their growth, motility, function, and survival. Hormones affect angiogenesis either directly through actions on endothelial cells or indirectly by regulating proangiogenic factors like vascular endothelial growth factor. Importantly, the local microenvironment of endothelial cells can determine the outcome of hormone action on angiogenesis. Members of the growth hormone/prolactin/placental lactogen, the renin-angiotensin, and the kallikrein-kinin systems that exert stimulatory effects on angiogenesis can acquire antiangiogenic properties after undergoing proteolytic cleavage. In view of the opposing effects of hormonal fragments and precursor molecules, the regulation of the proteases responsible for specific protein cleavage represents an efficient mechanism for balancing angiogenesis. This review presents an overview of the actions on angiogenesis of the above-mentioned peptide hormonal families and addresses how specific proteolysis alters the final outcome of these actions in the context of health and disease.

]]> 2009-09-29 info:doi/10.1152/physrev.00024.2009 American Physiological Society 4 89 1215 2009-10-01 1177 Articles http://physrev.physiology.org/cgi/content/abstract/89/4/1217?rss=1 Myofibrillogenesis in striated muscles is a highly complex process that depends on the coordinated assembly and integration of a large number of contractile, cytoskeletal, and signaling proteins into regular arrays, the sarcomeres. It is also associated with the stereotypical assembly of the sarcoplasmic reticulum and the transverse tubules around each sarcomere. Three giant, muscle-specific proteins, titin (3–4 MDa), nebulin (600–800 kDa), and obscurin (~720–900 kDa), have been proposed to play important roles in the assembly and stabilization of sarcomeres. There is a large amount of data showing that each of these molecules interacts with several to many different protein ligands, regulating their activity and localizing them to particular sites within or surrounding sarcomeres. Consistent with this, mutations in each of these proteins have been linked to skeletal and cardiac myopathies or to muscular dystrophies. The evidence that any of them plays a role as a "molecular template," "molecular blueprint," or "molecular ruler" is less definitive, however. Here we review the structure and function of titin, nebulin, and obscurin, with the literature supporting a role for them as scaffolding molecules and the contradictory evidence regarding their roles as molecular guides in sarcomerogenesis.

]]> 2009-09-29 info:doi/10.1152/physrev.00017.2009 American Physiological Society 4 89 1267 2009-10-01 1217 Articles http://physrev.physiology.org/cgi/content/abstract/89/4/1269?rss=1 The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.

]]> 2009-09-29 info:doi/10.1152/physrev.00027.2008 American Physiological Society 4 89 1339 2009-10-01 1269 Articles http://physrev.physiology.org/cgi/content/abstract/89/4/1341?rss=1 Ca²⁺-ATPases (pumps) are key actors in the regulation of Ca²⁺ in eukaryotic cells and are thus essential to the correct functioning of the cell machinery. They have high affinity for Ca²⁺ and can efficiently regulate it down to very low concentration levels. Two of the pumps have been known for decades (the SERCA and PMCA pumps); one (the SPCA pump) has only become known recently. Each pump is the product of a multigene family, the number of isoforms being further increased by alternative splicing of the primary transcripts. The three pumps share the basic features of the catalytic mechanism but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca²⁺. The molecular understanding of the function of the pumps has received great impetus from the solution of the three-dimensional structure of one of them, the SERCA pump. These spectacular advances in the structure and molecular mechanism of the pumps have been accompanied by the emergence and rapid expansion of the topic of pump malfunction, which has paralleled the rapid expansion of knowledge in the topic of Ca²⁺-signaling dysfunction. Most of the pump defects described so far are genetic: when they are very severe, they produce gross and global disturbances of Ca²⁺ homeostasis that are incompatible with cell life. However, pump defects may also be of a type that produce subtler, often tissue-specific disturbances that affect individual components of the Ca²⁺-controlling and/or processing machinery. They do not bring cells to immediate death but seriously compromise their normal functioning.

]]> 2009-09-29 info:doi/10.1152/physrev.00032.2008 American Physiological Society 4 89 1378 2009-10-01 1341 Articles http://physrev.physiology.org/cgi/content/abstract/89/4/1379?rss=1 The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopiomelanocortin, proenkephalin, and prodynorphin. Opioid receptors are recruited in response to natural rewarding stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops. Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and relapse remain to be clarified. This review summarizes our present knowledge on brain sites where the endogenous opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain. We review 1) the latest data on the anatomy of the opioid system, 2) the consequences of local intracerebral pharmacological manipulation of the opioid system on reinforced behaviors, 3) the consequences of gene knockout on reinforced behaviors and drug dependence, and 4) the consequences of chronic exposure to drugs of abuse on expression levels of opioid system genes. Future studies will establish key molecular actors of the system and neural sites where opioid peptides and receptors contribute to the onset of addictive disorders. Combined with data from human and nonhuman primate (not reviewed here), research in this extremely active field has implications both for our understanding of the biology of addiction and for therapeutic interventions to treat the disorder.

]]> 2009-09-29 info:doi/10.1152/physrev.00005.2009 American Physiological Society 4 89 1412 2009-10-01 1379 Articles http://physrev.physiology.org/cgi/content/abstract/89/3/759?rss=1 The mechanical properties of lung tissue are important determinants of lung physiological functions. The connective tissue is composed mainly of cells and extracellular matrix, where collagen and elastic fibers are the main determinants of lung tissue mechanical properties. These fibers have essentially different elastic properties, form a continuous network along the lungs, and are responsible for passive expiration. In the last decade, many studies analyzed the relationship between tissue composition, microstructure, and macrophysiology, showing that the lung physiological behavior reflects both the mechanical properties of tissue individual components and its complex structural organization. Different lung pathologies such as acute respiratory distress syndrome, fibrosis, inflammation, and emphysema can affect the extracellular matrix. This review focuses on the mechanical properties of lung tissue and how the stress-bearing elements of lung parenchyma can influence its behavior.

]]> 2009-07-07 info:doi/10.1152/physrev.00019.2007 American Physiological Society 3 89 775 2009-07-01 759 Articles http://physrev.physiology.org/cgi/content/abstract/89/3/777?rss=1 Research on the LKB1 tumor suppressor protein mutated in cancer-prone Peutz-Jeghers patients has continued at a feverish pace following exciting developments linking energy metabolism and cancer development. This review summarizes the current state of research on the LKB1 tumor suppressor. The weight of the evidence currently indicates an evolutionary conserved role for the protein in the regulation of various aspects of cellular polarity and energy metabolism. We focus on studies examining the concept that both cellular polarity and energy metabolism are regulated through the conserved LKB1-AMPK signal transduction pathway. Recent studies from a variety of model organisms have given new insight into the mechanism of polyp development and cancer formation in Peutz-Jeghers patients and the role of LKB1 mutation in sporadic tumorigenesis. Conditional LKB1 mouse models have outlined a tissue-dependent context for pathway activation and suggest that LKB1 may affect different AMPK isoforms independently. Elucidation of the molecular mechanism responsible for Peutz-Jeghers syndrome will undoubtedly reveal important insight into cancer development in the larger population.

]]> 2009-07-07 info:doi/10.1152/physrev.00026.2008 American Physiological Society 3 89 798 2009-07-01 777 Articles http://physrev.physiology.org/cgi/content/abstract/89/3/799?rss=1 The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes (MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.

]]> 2009-07-07 info:doi/10.1152/physrev.00030.2008 American Physiological Society 3 89 845 2009-07-01 799 Articles http://physrev.physiology.org/cgi/content/abstract/89/3/847?rss=1 Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises four members (HCN1-4) that are expressed in heart and nervous system. The current produced by HCN channels has been known as I_h (or I_f or I_q). I_h has also been designated as pacemaker current, because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. Extensive studies over the last decade have provided convincing evidence that I_h is also involved in a number of basic physiological processes that are not directly associated with rhythmicity. Examples for these non-pacemaking functions of I_h are the determination of the resting membrane potential, dendritic integration, synaptic transmission, and learning. In this review we summarize recent insights into the structure, function, and cellular regulation of HCN channels. We also discuss in detail the different aspects of HCN channel physiology in the heart and nervous system. To this end, evidence on the role of individual HCN channel types arising from the analysis of HCN knockout mouse models is discussed. Finally, we provide an overview of the impact of HCN channels on the pathogenesis of several diseases and discuss recent attempts to establish HCN channels as drug targets.

]]> 2009-07-07 info:doi/10.1152/physrev.00029.2008 American Physiological Society 3 89 885 2009-07-01 847 Articles http://physrev.physiology.org/cgi/content/abstract/89/3/887?rss=1 Quantitative differences in gene expression emerge as a significant source of variation in natural populations, representing an important substrate for evolution and accounting for a considerable fraction of phenotypic diversity. However, perturbation of gene expression is also the main factor in determining the molecular pathogenesis of numerous aneuploid disorders. In this review, we focus on Down syndrome (DS) as the prototype of "genomic disorder" induced by copy number change. The understanding of the pathogenicity of the extra genomic material in trisomy 21 has accelerated in the last years due to the recent advances in genome sequencing, comparative genome analysis, functional genome exploration, and the use of model organisms. We present recent data on the role of genome-altering processes in the generation of diversity in DS neural phenotypes focusing on the impact of trisomy on brain structure and mental retardation and on biological pathways and cell types in target brain regions (including prefrontal cortex, hippocampus, cerebellum, and basal ganglia). We also review the potential that genetically engineered mouse models of DS bring into the understanding of the molecular biology of human learning disorders.

]]> 2009-07-07 info:doi/10.1152/physrev.00032.2007 American Physiological Society 3 89 920 2009-07-01 887 Articles http://physrev.physiology.org/cgi/content/abstract/89/3/921?rss=1 In recent years, considerable progress has been achieved in the comprehension of the profound effects of pheromones on reproductive physiology and behavior. Pheromones have been classified as molecules released by individuals and responsible for the elicitation of specific behavioral expressions in members of the same species. These signaling molecules, often chemically unrelated, are contained in body fluids like urine, sweat, specialized exocrine glands, and mucous secretions of genitals. The standard view of pheromone sensing was based on the assumption that most mammals have two separated olfactory systems with different functional roles: the main olfactory system for recognizing conventional odorant molecules and the vomeronasal system specifically dedicated to the detection of pheromones. However, recent studies have reexamined this traditional interpretation showing that both the main olfactory and the vomeronasal systems are actively involved in pheromonal communication. The current knowledge on the behavioral, physiological, and molecular aspects of pheromone detection in mammals is discussed in this review.

]]> 2009-07-07 info:doi/10.1152/physrev.00037.2008 American Physiological Society 3 89 956 2009-07-01 921 Articles http://physrev.physiology.org/cgi/content/abstract/89/3/957?rss=1 An important factor in the transition from an open to a closed circulatory system was a change in vessel wall structure and composition that enabled the large arteries to store and release energy during the cardiac cycle. The component of the arterial wall in vertebrates that accounts for these properties is the elastic fiber network organized by medial smooth muscle. Beginning with the onset of pulsatile blood flow in the developing aorta, smooth muscle cells in the vessel wall produce a complex extracellular matrix (ECM) that will ultimately define the mechanical properties that are critical for proper function of the adult vascular system. This review discusses the structural ECM proteins in the vertebrate aortic wall and will explore how the choice of ECM components has changed through evolution as the cardiovascular system became more advanced and pulse pressure increased. By correlating vessel mechanics with physiological blood pressure across animal species and in mice with altered vessel compliance, we show that cardiac and vascular development are physiologically coupled, and we provide evidence for a universal elastic modulus that controls the parameters of ECM deposition in vessel wall development. We also discuss mechanical models that can be used to design better tissue-engineered vessels and to test the efficacy of clinical treatments.

]]> 2009-07-07 info:doi/10.1152/physrev.00041.2008 American Physiological Society 3 89 989 2009-07-01 957 Articles http://physrev.physiology.org/cgi/content/abstract/89/3/991?rss=1 The human transglutaminase (TG) family consists of a structural protein, protein 4.2, that lacks catalytic activity, and eight zymogens/enzymes, designated factor XIII-A (FXIII-A) and TG1-7, that catalyze three types of posttranslational modification reactions: transamidation, esterification, and hydrolysis. These reactions are essential for biological processes such as blood coagulation, skin barrier formation, and extracellular matrix assembly but can also contribute to the pathophysiology of various inflammatory, autoimmune, and degenerative conditions. Some members of the TG family, for example, TG2, can participate in biological processes through actions unrelated to transamidase catalytic activity. We present here a comprehensive review of recent insights into the physiology and pathophysiology of TG family members that have come from studies of genetically engineered mouse models and/or inherited disorders. The review focuses on FXIII-A, TG1, TG2, TG5, and protein 4.2, as mice deficient in TG3, TG4, TG6, or TG7 have not yet been reported, nor have mutations in these proteins been linked to human disease.

]]> 2009-07-07 info:doi/10.1152/physrev.00044.2008 American Physiological Society 3 89 1023 2009-07-01 991 Articles http://physrev.physiology.org/cgi/content/abstract/89/3/1025?rss=1 The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) β heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochemical pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the molecular basis for AMP binding to the enzyme's subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examination of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.

]]> 2009-07-07 info:doi/10.1152/physrev.00011.2008 American Physiological Society 3 89 1078 2009-07-01 1025 Articles