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Physiological Reviews, Vol. 81, No. 1, January 2001, pp. 239-297
Copyright ©2001 by the American Physiological Society
Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Brown, Edward M. and
R. John MacLeod.
Extracellular Calcium Sensing and Extracellular Calcium
Signaling. Physiol. Rev. 81: 239-297, 2001.
The cloning of a G protein-coupled extracellular
Ca2+ (Cao2+)-sensing receptor (CaR) has
elucidated the molecular basis for many of the previously recognized
effects of Cao2+ on tissues that maintain systemic
Cao2+ homeostasis, especially parathyroid chief cells
and several cells in the kidney. The availability of the cloned CaR
enabled the development of DNA and antibody probes for identifying the
CaR's mRNA and protein, respectively, within these and other tissues. It also permitted the identification of human diseases resulting from
inactivating or activating mutations of the CaR gene and the subsequent
generation of mice with targeted disruption of the CaR gene. The
characteristic alterations in parathyroid and renal function in these
patients and in the mice with "knockout" of the CaR gene have
provided valuable information on the CaR's physiological roles in
these tissues participating in mineral ion homeostasis. Nevertheless,
relatively little is known about how the CaR regulates other tissues
involved in systemic Cao2+ homeostasis, particularly
bone and intestine. Moreover, there is evidence that additional
Cao2+ sensors may exist in bone cells that mediate some
or even all of the known effects of Cao2+ on these
cells. Even more remains to be learned about the CaR's function in the
rapidly growing list of cells that express it but are uninvolved in
systemic Cao2+ metabolism. Available data suggest that
the receptor serves numerous roles outside of systemic mineral ion
homeostasis, ranging from the regulation of hormonal secretion and the
activities of various ion channels to the longer term control of gene
expression, programmed cell death (apoptosis), and cellular
proliferation. In some cases, the CaR on these "nonhomeostatic"
cells responds to local changes in Cao2+ taking place
within compartments of the extracellular fluid (ECF) that communicate
with the outside environment (e.g., the gastrointestinal tract). In
others, localized changes in Cao2+ within the ECF can
originate from several mechanisms, including fluxes of calcium ions
into or out of cellular or extracellular stores or across epithelium
that absorb or secrete Ca2+. In any event, the CaR and
other receptors/sensors for Cao2+ and probably for
other extracellular ions represent versatile regulators of numerous
cellular functions and may serve as important therapeutic targets.
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P. H. Lindfors, M. Lindahl, J. Rossi, M. Saarma, and M. S. Airaksinen Ablation of Persephin Receptor Glial Cell Line-Derived Neurotrophic Factor Family Receptor {alpha}4 Impairs Thyroid Calcitonin Production in Young Mice Endocrinology, May 1, 2006; 147(5): 2237 - 2244. [Abstract] [Full Text] [PDF]
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H. I. Abdullah, P. L. Pedraza, S. Hao, K. D. Rodland, J. C. McGiff, and N. R. Ferreri NFAT regulates calcium-sensing receptor-mediated TNF production Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1110 - F1117. [Abstract] [Full Text] [PDF]
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Y. Huang, J.-i. Niwa, G. Sobue, and G. E. Breitwieser Calcium-sensing Receptor Ubiquitination and Degradation Mediated by the E3 Ubiquitin Ligase Dorfin J. Biol. Chem., April 28, 2006; 281(17): 11610 - 11617. [Abstract] [Full Text] [PDF]
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 Y.-i. Nabeshima Toward a better understanding of klotho. Sci. Aging Knowl. Environ., March 22, 2006; 2006(8): pe11 - pe11. [Abstract] [Full Text]
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J. Tfelt-Hansen, J. L. Hansen, S. Smajilovic, E. F. Terwilliger, S. Haunso, and S. P. Sheikh Calcium receptor is functionally expressed in rat neonatal ventricular cardiomyocytes Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1165 - H1171. [Abstract] [Full Text] [PDF]
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G. Valenti, G. Procino, G. Tamma, M. Carmosino, and M. Svelto Minireview: Aquaporin 2 Trafficking Endocrinology, December 1, 2005; 146(12): 5063 - 5070. [Abstract] [Full Text] [PDF]
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L. Rodriguez, C. Tu, Z. Cheng, T.-H. Chen, D. Bikle, D. Shoback, and W. Chang Expression and Functional Assessment of an Alternatively Spliced Extracellular Ca2+-Sensing Receptor in Growth Plate Chondrocytes Endocrinology, December 1, 2005; 146(12): 5294 - 5303. [Abstract] [Full Text] [PDF]
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C. Silve, C. Petrel, C. Leroy, H. Bruel, E. Mallet, D. Rognan, and M. Ruat Delineating a Ca2+ Binding Pocket within the Venus Flytrap Module of the Human Calcium-sensing Receptor J. Biol. Chem., November 11, 2005; 280(45): 37917 - 37923. [Abstract] [Full Text] [PDF]
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K. Ray, J. Tisdale, R. H. Dodd, P. Dauban, M. Ruat, and J. K. Northup Calindol, a Positive Allosteric Modulator of the Human Ca2+ Receptor, Activates an Extracellular Ligand-binding Domain-deleted Rhodopsin-like Seven-transmembrane Structure in the Absence of Ca2+ J. Biol. Chem., November 4, 2005; 280(44): 37013 - 37020. [Abstract] [Full Text] [PDF]
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 A. Gerbino, W. C. Ruder, S. Curci, T. Pozzan, M. Zaccolo, and A. M. Hofer Termination of cAMP signals by Ca2+ and G{alpha}i via extracellular Ca2+ sensors: a link to intracellular Ca2+ oscillations J. Cell Biol., October 24, 2005; 171(2): 303 - 312. [Abstract] [Full Text] [PDF]
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T. Bouschet, S. Martin, and J. M. Henley Receptor-activity-modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane J. Cell Sci., October 15, 2005; 118(20): 4709 - 4720. [Abstract] [Full Text] [PDF]
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T. Kawata, Y. Imanishi, K. Kobayashi, T. Kenko, M. Wada, E. Ishimura, T. Miki, N. Nagano, M. Inaba, A. Arnold, et al. Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism Eur. J. Endocrinol., October 1, 2005; 153(4): 587 - 594. [Abstract] [Full Text] [PDF]
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 N. Wettschureck and S. Offermanns Mammalian G Proteins and Their Cell Type Specific Functions Physiol Rev, October 1, 2005; 85(4): 1159 - 1204. [Abstract] [Full Text] [PDF]
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 A. H. Weston, M. Absi, D. T. Ward, J. Ohanian, R. H. Dodd, P. Dauban, C. Petrel, M. Ruat, and G. Edwards Evidence in Favor of a Calcium-Sensing Receptor in Arterial Endothelial Cells: Studies With Calindol and Calhex 231 Circ. Res., August 19, 2005; 97(4): 391 - 398. [Abstract] [Full Text] [PDF]
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E. M. Brown Medical Therapy of Primary Hyperparathyroidism: Are We There Yet? IBMS BoneKEy, August 1, 2005; 2(8): 5 - 8. [Full Text] [PDF]
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S. J. Marx and W. F. Simonds Hereditary Hormone Excess: Genes, Molecular Pathways, and Syndromes Endocr. Rev., August 1, 2005; 26(5): 615 - 661. [Abstract] [Full Text] [PDF]
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 Z. Wu, R. Tandon, J. Ziembicki, J. Nagano, K. M. Hujer, R. T. Miller, and C. Huang Role of ceramide in Ca2+-sensing receptor-induced apoptosis J. Lipid Res., July 1, 2005; 46(7): 1396 - 1404. [Abstract] [Full Text] [PDF]
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S. Canadillas, A. Canalejo, R. Santamaria, M. E. Rodriguez, J. C. Estepa, A. Martin-Malo, J. Bravo, B. Ramos, E. Aguilera-Tejero, M. Rodriguez, et al. Calcium-Sensing Receptor Expression and Parathyroid Hormone Secretion in Hyperplastic Parathyroid Glands from Humans J. Am. Soc. Nephrol., July 1, 2005; 16(7): 2190 - 2197. [Abstract] [Full Text] [PDF]
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O. Rey, S. H. Young, J. Yuan, L. Slice, and E. Rozengurt Amino Acid-stimulated Ca2+ Oscillations Produced by the Ca2+-sensing Receptor Are Mediated by a Phospholipase C/Inositol 1,4,5-Trisphosphate-independent Pathway That Requires G12, Rho, Filamin-A, and the Actin Cytoskeleton J. Biol. Chem., June 17, 2005; 280(24): 22875 - 22882. [Abstract] [Full Text] [PDF]
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L.-J. Xiao, J.-X. Yuan, Y.-C. Li, R. Wang, Z.-Y. Hu, and Y.-X. Liu Extracellular Ca2+-sensing receptor expression and hormonal regulation in rat uterus during the peri-implantation period Reproduction, June 1, 2005; 129(6): 779 - 788. [Abstract] [Full Text] [PDF]
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Y.-H. H. Lien, A. L. Silva, and D. Whittman Effects of cinacalcet on bone mineral density in patients with secondary hyperparathyroidism Nephrol. Dial. Transplant., June 1, 2005; 20(6): 1232 - 1237. [Abstract] [Full Text] [PDF]
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J. G. J. Hoenderop and R. J. M. Bindels Is vitamin D indispensable for Ca2+ homeostasis: lessons from knockout mouse models? Nephrol. Dial. Transplant., May 1, 2005; 20(5): 864 - 867. [Full Text] [PDF]
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C. Thomee, S. W. Schubert, J. Parma, P. Q. Le, S. Hashemolhosseini, M. Wegner, and M. J. Abramowicz GCMB Mutation in Familial Isolated Hypoparathyroidism with Residual Secretion of Parathyroid Hormone J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2487 - 2492. [Abstract] [Full Text] [PDF]
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M. Cifuentes, C. Albala, and C. Rojas Calcium-Sensing Receptor Expression in Human Adipocytes Endocrinology, May 1, 2005; 146(5): 2176 - 2179. [Abstract] [Full Text] [PDF]
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J. J. Yao, S. Bai, A. J. Karnauskas, D. A. Bushinsky, and M. J. Favus Regulation of Renal Calcium Receptor Gene Expression by 1,25-Dihydroxyvitamin D3 in Genetic Hypercalciuric Stone-Forming Rats J. Am. Soc. Nephrol., May 1, 2005; 16(5): 1300 - 1308. [Abstract] [Full Text] [PDF]
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 G. J. Strewler A 64-Year-Old Woman With Primary Hyperparathyroidism JAMA, April 13, 2005; 293(14): 1772 - 1779. [Full Text] [PDF]
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L. Canaff and G. N. Hendy Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1{beta}: ROLE OF THE NF-{kappa}B PATHWAY AND {kappa}B ELEMENTS J. Biol. Chem., April 8, 2005; 280(14): 14177 - 14188. [Abstract] [Full Text] [PDF]
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B. J. Arey, R. Seethala, Z. Ma, A. Fura, J. Morin, J. Swartz, V. Vyas, W. Yang, J. K. Dickson Jr., and J. H. M. Feyen A Novel Calcium-Sensing Receptor Antagonist Transiently Stimulates Parathyroid Hormone Secretion in Vivo Endocrinology, April 1, 2005; 146(4): 2015 - 2022. [Abstract] [Full Text] [PDF]
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J. Ohanian, K. M. Gatfield, D. T. Ward, and V. Ohanian Evidence for a functional calcium-sensing receptor that modulates myogenic tone in rat subcutaneous small arteries Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1756 - H1762. [Abstract] [Full Text] [PDF]
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M. Zhang and G. E. Breitwieser High Affinity Interaction with Filamin A Protects against Calcium-sensing Receptor Degradation J. Biol. Chem., March 25, 2005; 280(12): 11140 - 11146. [Abstract] [Full Text] [PDF]
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