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Volume 270, Number 21, Issue of May 26, pp. 12919-12925, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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James E. Garrett , Irene V. Capuano , Lance G. Hammerland , Benjamin C. P. Hung , Edward M. Brown , Steven C. Hebert , Edward F. Nemeth , Forrest Fuller

Parathyroid cells express a cell surface receptor, coupled to the mobilization of intracellular Ca, that is activated by increases in the concentration of extracellular Ca and by a variety of other cations. This ``Ca receptor'' (CaR) serves as the primary physiological regulator of parathyroid hormone secretion. Alterations in the CaR have been proposed to underlie the increases in Ca set-point seen in primary hyperparathyroidism due to parathyroid adenoma. We have isolated human CaR cDNAs from an adenomatous parathyroid gland. The cloned receptor, expressed in Xenopus oocytes, responds to extracellular application of physiologically relevant concentrations of Ca and other CaR agonists. The rank order of potency of CaR agonists displayed by the native receptor (Gd > neomycin B > Ca > Mg) is maintained by the expressed receptor. The nucleotide sequence of the human CaR cDNA predicts a protein of 1078 amino acids with high sequence similarity to a bovine CaR, and displays seven putative membrane-spanning regions common to G protein-coupled receptors. The deduced protein sequence shows potential sites for N-linked glycosylation and phosphorylation by protein kinase C and has a low level of sequence similarity to the metabotropic glutamate receptors. Comparison of the cDNA sequence to that of the normal human CaR gene showed no alteration in the coding region sequence of the CaR in this particular instance of parathyroid adenoma. Human cDNA clones with differing 5`-untranslated regions were isolated, suggesting alternative splicing of the parathyroid CaR mRNA. A rare variant cDNA clone representing a 10 amino acid insertion into the extracellular domain was also isolated. Northern blot analysis of normal and adenomatous parathyroid gland mRNA identified a predominant transcript of 5.4 kilobases, and less abundant transcripts of 10, 4.8 and 4.2 kilobases in RNA from the adenoma. While there is no evidence for alteration of the primary amino acid sequence of the CaR in this adenoma, modulation of CaR biosynthesis through alternative RNA processing may play a role in set-point alterations.

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				M. Bai, S. Trivedi, C. R. Lane, Y. Yang, S. J. Quinn, and E. M. Brown Protein Kinase C Phosphorylation of Threonine at Position 888 in Ca2+o-Sensing Receptor (CaR) Inhibits Coupling to Ca2+ Store Release J. Biol. Chem., August 14, 1998; 273(33): 21267 - 21275. [Abstract] [Full Text] [PDF]

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				T. Watanabe, M. Bai, C. R. Lane, S. Matsumoto, K. Minamitani, M. Minagawa, H. Niimi, E. M. Brown, and T. Yasuda Familial Hypoparathyroidism: Identification of a Novel Gain of Function Mutation in Transmembrane Domain 5 of the Calcium-Sensing Receptor J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2497 - 2502. [Abstract] [Full Text]

				D. T. Ward, E. M. Brown, and H. W. Harris Disulfide Bonds in the Extracellular Calcium-Polyvalent Cation-sensing Receptor Correlate with Dimer Formation and Its Response to Divalent Cations in Vitro J. Biol. Chem., June 5, 1998; 273(23): 14476 - 14483. [Abstract] [Full Text] [PDF]

				L. G. Hammerland, J. E. Garrett, B. C. P. Hung, C. Levinthal, and E. F. Nemeth Allosteric Activation of the Ca2+ Receptor Expressed in Xenopus laevis Oocytes by NPS 467 or NPS 568 Mol. Pharmacol., June 1, 1998; 53(6): 1083 - 1088. [Abstract] [Full Text]

				M. M. Mupanomunda, Y. Wang, and R. D. Bukoski Effect of chronic sensory denervation on Ca2+-induced relaxation of isolated mesenteric resistance arteries Am J Physiol Heart Circ Physiol, May 1, 1998; 274(5): H1655 - H1661. [Abstract] [Full Text] [PDF]

				E. F. Nemeth, M. E. Steffey, L. G. Hammerland, B. C. P. Hung, B. C. Van Wagenen, E. G. DelMar, and M. F. Balandrin Calcimimetics with potent and selective activity on the parathyroid calcium receptor PNAS, March 31, 1998; 95(7): 4040 - 4045. [Abstract] [Full Text] [PDF]

				Y. Kubo, T. Miyashita, and Y. Murata Structural Basis for a Ca2+-Sensing Function of the Metabotropic Glutamate Receptors Science, March 13, 1998; 279(5357): 1722 - 1725. [Abstract] [Full Text]

				I. Cheng, M. E. Klingensmith, N. Chattopadhyay, O. Kifor, R. R. Butters, D. I. Soybel, and E. M. Brown Identification and Localization of the Extracellular Calcium-Sensing Receptor in Human Breast J. Clin. Endocrinol. Metab., February 1, 1998; 83(2): 703 - 707. [Abstract] [Full Text]

				S. E. McNeil, S. A. Hobson, V. Nipper, and K. D. Rodland Functional Calcium-sensing Receptors in Rat Fibroblasts Are Required for Activation of SRC Kinase and Mitogen-activated Protein Kinase in Response to Extracellular Calcium J. Biol. Chem., January 9, 1998; 273(2): 1114 - 1120. [Abstract] [Full Text] [PDF]

				N. Chattopadhyay, I. Cheng, K. Rogers, D. Riccardi, A. Hall, R. Diaz, S. C. Hebert, D. I. Soybel, and E. M. Brown Identification and localization of extracellular Ca2+-sensing receptor in rat intestine Am J Physiol Gastrointest Liver Physiol, January 1, 1998; 274(1): G122 - G130. [Abstract] [Full Text] [PDF]

				K. Ray, G.-F. Fan, P. K. Goldsmith, and A. M. Spiegel The Carboxyl Terminus of the Human Calcium Receptor. REQUIREMENTS FOR CELL-SURFACE EXPRESSION AND SIGNAL TRANSDUCTION J. Biol. Chem., December 12, 1997; 272(50): 31355 - 31361. [Abstract] [Full Text] [PDF]

				R. D. Bukoski, K. Bian, Y. Wang, and M. Mupanomunda Perivascular Sensory Nerve Ca2+ Receptor and Ca2+-Induced Relaxation of Isolated Arteries Hypertension, December 1, 1997; 30(6): 1431 - 1439. [Abstract] [Full Text]

				F. Farnebo, U. Enberg, L. Grimelius, M. Backdahl, M. Schalling, C. Larsson, and L.-O. Farnebo Tumor-Specific Decreased Expression of Calcium Sensing Receptor Messenger Ribonucleic Acid in Sporadic Primary Hyperparathyroidism J. Clin. Endocrinol. Metab., October 1, 1997; 82(10): 3481 - 3486. [Abstract] [Full Text] [PDF]

				L. Gama, L. M. Baxendale-Cox, and G. E. Breitwieser Ca2+-sensing receptors in intestinal epithelium Am J Physiol Cell Physiol, October 1, 1997; 273(4): C1168 - C1175. [Abstract] [Full Text] [PDF]

				S. J. Quinn, C.-P. Ye, R. Diaz, O. Kifor, M. Bai, P. Vassilev, and E. Brown The Ca2+-sensing receptor: a target for polyamines Am J Physiol Cell Physiol, October 1, 1997; 273(4): C1315 - C1323. [Abstract] [Full Text] [PDF]

				M. Mailland, R. Waelchli, M. Ruat, H. G. W. M. Boddeke, and K. Seuwen Stimulation of Cell Proliferation by Calcium and a Calcimimetic Compound Endocrinology, September 1, 1997; 138(9): 3601 - 3605. [Abstract] [Full Text] [PDF]

				F. De Luca, K. Ray, E. E. Mancilla, G.-F. Fan, K. K. Winer, P. Gore, A. M. Spiegel, and J. Baron Sporadic Hypoparathyroidism Caused by de Novo Gain- of-Function Mutations of the Ca2+-Sensing Receptor J. Clin. Endocrinol. Metab., August 1, 1997; 82(8): 2710 - 2715. [Abstract] [Full Text] [PDF]

				M. Kobayashi, H. Tanaka, K. Tsuzuki, M. Tsuyuki, H. Igaki, Y. Ichinose, K. Aya, N. Nishioka, and Y. Seino Two Novel Missense Mutations in Calcium-Sensing Receptor Gene Associated with Neonatal Severe Hyperparathyroidism J. Clin. Endocrinol. Metab., August 1, 1997; 82(8): 2716 - 2719. [Abstract] [Full Text] [PDF]

				G. Fan, P. K. Goldsmith, R. Collins, C. K. Dunn, K. J. Krapcho, K. V. Rogers, and A. M. Spiegel N-Linked Glycosylation of the Human Ca2+ Receptor Is Essential for Its Expression at the Cell Surface Endocrinology, May 1, 1997; 138(5): 1916 - 1922. [Abstract] [Full Text] [PDF]

				S. H.S. Pearce, C. Williamson, O. Kifor, M. Bai, M. G. Coulthard, M. Davies, N. Lewis-Barned, D. McCredie, H. Powell, P. Kendall-Taylor, et al. A Familial Syndrome of Hypocalcemia with Hypercalciuria Due to Mutations in the Calcium-Sensing Receptor N. Engl. J. Med., October 10, 1996; 335(15): 1115 - 1122. [Abstract] [Full Text] [PDF]

				M. Bai, S. Quinn, S. Trivedi, O. Kifor, S. H.S. Pearce, M. R. Pollak, K. Krapcho, S. C. Hebert, and E. M. Brown Expression and Characterization of Inactivating and Activating Mutations in the Human Ca2+o-sensing Receptor J. Biol. Chem., August 9, 1996; 271(32): 19537 - 19545. [Abstract] [Full Text] [PDF]

				J. Hu, G. Reyes-Cruz, P. K. Goldsmith, and A. M. Spiegel The Venus's-flytrap and Cysteine-rich Domains of the Human Ca2+ Receptor Are Not Linked by Disulfide Bonds J. Biol. Chem., March 2, 2001; 276(10): 6901 - 6904. [Abstract] [Full Text] [PDF]

				J. Hu, O. Hauache, and A. M. Spiegel Human Ca2+ Receptor Cysteine-rich Domain. ANALYSIS OF FUNCTION OF MUTANT AND CHIMERIC RECEPTORS J. Biol. Chem., May 19, 2000; 275(21): 16382 - 16389. [Abstract] [Full Text] [PDF]

				N. Solban, H.-P. Jia, S. Richard, S. Tremblay, A. M. Devlin, J. Peng, F. Gossard, D.-F. Guo, G. Morel, P. Hamet, et al. HCaRG, a Novel Calcium-regulated Gene Coding for a Nuclear Protein, Is Potentially Involved in the Regulation of Cell Proliferation J. Biol. Chem., October 6, 2000; 275(41): 32234 - 32243. [Abstract] [Full Text] [PDF]

				Z. Huang, S.-L. Cheng, and E. Slatopolsky Sustained Activation of the Extracellular Signal-regulated Kinase Pathway Is Required for Extracellular Calcium Stimulation of Human Osteoblast Proliferation J. Biol. Chem., June 8, 2001; 276(24): 21351 - 21358. [Abstract] [Full Text] [PDF]

				G. Hjalm, R. J. MacLeod, O. Kifor, N. Chattopadhyay, and E. M. Brown Filamin-A Binds to the Carboxyl-terminal Tail of the Calcium-sensing Receptor, an Interaction That Participates in CaR-mediated Activation of Mitogen-activated Protein Kinase J. Biol. Chem., September 7, 2001; 276(37): 34880 - 34887. [Abstract] [Full Text] [PDF]

				C.-L. Tu, W. Chang, and D. D. Bikle The Extracellular Calcium-sensing Receptor Is Required for Calcium-induced Differentiation in Human Keratinocytes J. Biol. Chem., October 26, 2001; 276(44): 41079 - 41085. [Abstract] [Full Text] [PDF]