Abstract
The Ca2+-sensing receptor (the CaSR), a G-protein-coupled receptor, regulates Ca2+ homeostasis in the body by monitoring extracellular levels of Ca2+ ([Ca2+]o) and responding to a diverse array of stimuli. Mutations in the Ca2+-sensing receptor result in hypercalcemic or hypocalcemic disorders, such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and autosomal dominant hypocalcemic hypercalciuria. Compelling evidence suggests that the CaSR plays multiple roles extending well beyond not only regulating the level of extracellular Ca2+ in the human body, but also controlling a diverse range of biological processes. In this review, we focus on the structural biology of the CaSR, the ligand interaction sites as well as their relevance to the disease associated mutations. This systematic summary will provide a comprehensive exploration of how the CaSR integrates extracellular Ca2+ into intracellular Ca2+ signaling.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Ringer S. A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart. J Physiol, 1883, 4: 29–42
Krebs J, Michalak M, eds. Calcium: a matter of life or death. Elsevier, 2007
Smajilovic S, Tfelt-Hansen J. Calcium acts as a first messenger through the calcium-sensing receptor in the cardiovascular system. Cardiovasc Res, 2007, 75: 457–467
Koleganova N, Piecha G, Ritz E, Schmitt CP, Gross ML. A calcimimetic (R-568), but not calcitriol, prevents vascular remodeling in uremia. Kidney Int, 2009, 75: 60–71
Liao J, Schneider A, Datta NS, McCauley LK. Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis. Cancer Res, 2006, 66: 9065–9073
Ogata H, Ritz E, Odoni G, Amann K, Orth SR. Beneficial effects of calcimimetics on progression of renal failure and cardiovascular risk factors. J Am Soc Nephrol, 2003, 14: 959–967
Tharmalingam S, Daulat AM, Antflick JE, Ahmed SM, Nemeth EF, Angers S, Conigrave AD, Hampson DR. Calcium-sensing receptor modulates cell adhesion and migration via integrins. J Biol Chem, 2011, 286: 40922–40933
Francesconi A, Duvoisin RM. Divalent cations modulate the activity of metabotropic glutamate receptors. J Neurosci Res, 2004, 75: 472–479
Spilker C, Dresbach T, Braunewell KH. Reversible translocation and activity-dependent localization of the calcium-myristoyl switch protein VILIP-1 to different membrane compartments in living hippocampal neurons. J Neurosci, 2002, 22: 7331–7339
Zonta M, Sebelin A, Gobbo S, Fellin T, Pozzan T, Carmignoto G. Glutamate-mediated cytosolic calcium oscillations regulate a pulsatile prostaglandin release from cultured rat astrocytes. J Physiol, 2003, 553: 407–414
Wise A, Green A, Main MJ, Wilson R, Fraser N, Marshall FH. Calcium sensing properties of the GABA(B) receptor. Neuropharmacology, 1999, 38: 1647–1656
Hauache OM, Hu J, Ray K, Xie R, Jacobson KA, Spiegel AM. Effects of a calcimimetic compound and naturally activating mutations on the human Ca2+ receptor and on Ca2+ receptor/metabotropic glutamate chimeric receptors. Endocrinology, 2000, 141: 4156–4163
Parekh AB. Decoding cytosolic Ca2+ oscillations. Trends Biochem Sci, 2011, 36: 78–87
Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature, 1993, 366: 575–580
Muff R, Nemeth EF, Haller-Brem S, Fischer JA. Regulation of hormone secretion and cytosolic Ca2+ by extracellular Ca2+ in parathyroid cells and C-cells: role of voltage-sensitive Ca2+ channels. Arch Biochem Biophys, 1988, 265: 128–135
Nemeth EF, Scarpa A. Rapid mobilization of cellular Ca2+ in bovine parathyroid cells evoked by extracellular divalent cations. Evidence for a cell surface calcium receptor. J Biol Chem, 1987, 262: 5188–5196
Brown EM, MacLeod RJ. Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev, 2001, 81: 239–297
Brown EM. The extracellular Ca2+-sensing receptor: central mediator of systemic calcium homeostasis. Annu Rev Nutr, 2000, 20: 507–533
Kifor O, Diaz R, Butters R, Kifor I, Brown EM. The calcium-sensing receptor is localized in caveolin-rich plasma membrane domains of bovine parathyroid cells. J Biol Chem, 1998, 273: 21708–21713
Riccardi D, Park J, Lee WS, Gamba G, Brown EM, Hebert SC. Cloning and functional expression of a rat kidney extracellular calcium/polyvalent cation-sensing receptor. Proc Natl Acad Sci USA, 1995, 92: 131–135
Butters RR Jr., Chattopadhyay N, Nielsen P, Smith CP, Mithal A, Kifor O, Bai M, Quinn S, Goldsmith P, Hurwitz S, Krapcho K, Busby J, Brown EM. Cloning and characterization of a calcium-sensing receptor from the hypercalcemic New Zealand white rabbit reveals unaltered responsiveness to extracellular calcium. J Bone Miner Res, 1997, 12: 568–579
Riccardi D, Hall AE, Chattopadhyay N, Xu JZ, Brown EM, Hebert SC. Localization of the extracellular Ca2+/polyvalent cation-sensing protein in rat kidney. Am J Physiol, 1998, 274: F611–622
Chattopadhyay N, Cheng I, Rogers K, Riccardi D, Hall A, Diaz R, Hebert SC, Soybel DI, Brown EM. Identification and localization of extracellular Ca(2+)-sensing receptor in rat intestine. Am J Physiol, 1998, 274: G122–130
Cima RR, Cheng I, Klingensmith ME, Chattopadhyay N, Kifor O, Hebert SC, Brown EM, Soybel DI. Identification and functional assay of an extracellular calcium-sensing receptor in Necturus gastric mucosa. Am J Physiol, 1997, 273: G1051–1060
Buchan AM, Squires PE, Ring M, Meloche RM. Mechanism of action of the calcium-sensing receptor in human antral gastrin cells. Gastroenterology, 2001, 120: 1128–1139
Busque SM, Kerstetter JE, Geibel JP, Insogna K. L-type amino acids stimulate gastric acid secretion by activation of the calcium-sensing receptor in parietal cells. Am J Physiol Gastrointest Liver Physiol, 2005, 289: G664–669
Justinich CJ, Mak N, Pacheco I, Mulder D, Wells RW, Blennerhassett MG, MacLeod RJ. The extracellular calcium-sensing receptor (CaSR) on human esophagus and evidence of expression of the CaSR on the esophageal epithelial cell line (HET-1A). Am J Physiol Gastrointest Liver Physiol, 2008, 294: G120–129
Chakrabarty S, Radjendirane V, Appelman H, Varani J. Extracellular calcium and calcium sensing receptor function in human colon carcinomas: promotion of E-cadherin expression and suppression of beta-catenin/TCF activation. Cancer Res, 2003, 63: 67–71
Kallay E, Kifor O, Chattopadhyay N, Brown EM, Bischof MG, Peterlik M, Cross HS. Calcium-dependent c-myc proto-oncogene expression and proliferation of Caco-2 cells: a role for a luminal extracellular calcium-sensing receptor. Biochem Biophys Res Commun, 1997, 232: 80–83
Yamaguchi T, Chattopadhyay N, Kifor O, Butters RR Jr., Sugimoto T, Brown EM. Mouse osteoblastic cell line (MC3T3-E1) expresses extracellular calcium (Ca2+o)-sensing receptor and its agonists stimulate chemotaxis and proliferation of MC3T3-E1 cells. J Bone Miner Res, 1998, 13: 1530–1538
Chattopadhyay N, Yano S, Tfelt-Hansen J, Rooney P, Kanuparthi D, Bandyopadhyay S, Ren X, Terwilliger E, Brown EM. Mitogenic action of calcium-sensing receptor on rat calvarial osteoblasts. Endocrinology, 2004, 145: 3451–3462
Dvorak MM, Siddiqua A, Ward DT, Carter DH, Dallas SL, Nemeth EF, Riccardi D. Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc Natl Acad Sci USA, 2004, 101: 5140–5145
Mentaverri R, Yano S, Chattopadhyay N, Petit L, Kifor O, Kamel S, Terwilliger EF, Brazier M, Brown EM. The calcium sensing receptor is directly involved in both osteoclast differentiation and apoptosis. FASEB J, 2006, 20: 2562–2564
Kameda T, Mano H, Yamada Y, Takai H, Amizuka N, Kobori M, Izumi N, Kawashima H, Ozawa H, Ikeda K, Kameda A, Hakeda Y, Kumegawa M. Calcium-sensing receptor in mature osteoclasts, which are bone resorbing cells. Biochem Biophys Res Commun, 1998, 245: 419–422
Yano S, Brown EM, Chattopadhyay N. Calcium-sensing receptor in the brain. Cell Calcium, 2004, 35: 257–264
Chang W, Tu C, Cheng Z, Rodriguez L, Chen TH, Gassmann M, Bettler B, Margeta M, Jan LY, Shoback D. Complex formation with the Type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor. Studies with HEK-293 cells and neurons. J Biol Chem, 2007, 282: 25030–25040
Gama L, Wilt SG, Breitwieser GE. Heterodimerization of calcium sensing receptors with metabotropic glutamate receptors in neurons. J Biol Chem, 2001, 276: 39053–39059
Washburn DL, Anderson JW, Ferguson AV. A subthreshold persistent sodium current mediates bursting in rat subfornical organ neurones. J Physiol, 2000, 529 (Pt 2): 359–371
Vassilev PM, Ho-Pao CL, Kanazirska MP, Ye C, Hong K, Seidman CE, Seidman JG, Brown EM. Cao-sensing receptor (CaR)-mediated activation of K+ channels is blunted in CaR gene-deficient mouse neurons. Neuroreport, 1997, 8: 1411–1416
Ye C, Ho-Pao CL, Kanazirska M, Quinn S, Seidman CE, Seidman JG, Brown EM, Vassilev PM. Deficient cation channel regulation in neurons from mice with targeted disruption of the extracellular Ca2+-sensing receptor gene. Brain Res Bull, 1997, 44: 75–84
Wang R, Xu C, Zhao W, Zhang J, Cao K, Yang B, Wu L. Calcium and polyamine regulated calcium-sensing receptors in cardiac tissues. Eur J Biochem, 2003, 270: 2680–2688
Wang LN, Wang C, Lin Y, Xi YH, Zhang WH, Zhao YJ, Li HZ, Tian Y, Lv YJ, Yang BF, Xu CQ. Involvement of calcium-sensing receptor in cardiac hypertrophy-induced by angiotensinII through calcineurin pathway in cultured neonatal rat cardiomyocytes. Biochem Biophys Res Commun, 2008, 369: 584–589
Lu F, Tian Z, Zhang W, Zhao Y, Bai S, Ren H, Chen H, Yu X, Wang J, Wang L, Li H, Pan Z, Tian Y, Yang B, Wang R, Xu C. Calcium-sensing receptors induce apoptosis in rat cardiomyocytes via the endo(sarco)plasmic reticulum pathway during hypoxia/reoxygenation. Basic Clin Pharmacol Toxicol, 2010, 106: 396–405
Bai M, Quinn S, Trivedi S, Kifor O, Pearce SH, Pollak MR, Krapcho K, Hebert SC, Brown EM. Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor. J Biol Chem, 1996, 271: 19537–19545
Ray K, Clapp P, Goldsmith PK, Spiegel AM. Identification of the sites of N-linked glycosylation on the human calcium receptor and assessment of their role in cell surface expression and signal transduction. J Biol Chem, 1998, 273: 34558–34567
Bai M, Trivedi S, Brown EM. Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J Biol Chem, 1998, 273: 23605–23610
Huang Y, Zhou Y, Wong HC, Castiblanco A, Chen Y, Brown EM, Yang JJ. Calmodulin regulates Ca2+-sensing receptor-mediated Ca2+ signaling and its cell surface expression. J Biol Chem, 2010, 285: 35919–35931
Hofer AM, Brown EM. Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol, 2003, 4: 530–538
Ward DT. Calcium receptor-mediated intracellular signalling. Cell Calcium, 2004, 35: 217–228
Hu J, Spiegel AM. Structure and function of the human calcium-sensing receptor: insights from natural and engineered mutations and allosteric modulators. J Cell Mol Med, 2007, 11: 908–922
Ray K, Hauschild BC, Steinbach PJ, Goldsmith PK, Hauache O, Spiegel AM. Identification of the cysteine residues in the amino-terminal extracellular domain of the human Ca(2+) receptor critical for dimerization. Implications for function of monomeric Ca(2+) receptor. J Biol Chem, 1999, 274: 27642–27650
Reyes-Cruz G, Hu J, Goldsmith PK, Steinbach PJ, Spiegel AM. Human Ca(2+) receptor extracellular domain. Analysis of function of lobe I loop deletion mutants. J Biol Chem, 2001, 276: 32145–32151
Pace AJ, Gama L, Breitwieser GE. Dimerization of the calcium-sensing receptor occurs within the extracellular domain and is eliminated by Cys → Ser mutations at Cys101 and Cys236. J Biol Chem, 1999, 274: 11629–11634
Zhang Z, Sun S, Quinn SJ, Brown EM, Bai M. The extracellular calcium-sensing receptor dimerizes through multiple types of intermolecular interactions. J Biol Chem, 2001, 276: 5316–5322
Fan GF, Ray K, Zhao XM, Goldsmith PK, Spiegel AM. Mutational analysis of the cysteines in the extracellular domain of the human Ca2+ receptor: effects on cell surface expression, dimerization and signal transduction. FEBS Lett, 1998, 436: 353–356
Hu J, Hauache O, Spiegel AM. Human Ca2+ receptor cysteine-rich domain. Analysis of function of mutant and chimeric receptors. J Biol Chem, 2000, 275: 16382–16389
Heath H, 3rd, Odelberg S, Jackson CE, Teh BT, Hayward N, Larsson C, Buist NR, Krapcho KJ, Hung BC, Capuano IV, Garrett JE, Leppert MF. Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. J Clin Endocrinol Metab, 1996, 81: 1312–1317
Hu J, McLarnon SJ, Mora S, Jiang J, Thomas C, Jacobson KA, Spiegel AM. A region in the seven-transmembrane domain of the human Ca2+ receptor critical for response to Ca2+. J Biol Chem, 2005, 280: 5113–5120
Pin JP, Galvez T, Prezeau L. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther, 2003, 98: 325–354
Ray K, Fan GF, Goldsmith PK, Spiegel AM. The carboxyl terminus of the human calcium receptor. Requirements for cell-surface expression and signal transduction. J Biol Chem, 1997, 272: 31355–31361
Awata H, Huang C, Handlogten ME, Miller RT. Interaction of the calcium-sensing receptor and filamin, a potential scaffolding protein. J Biol Chem, 2001, 276: 34871–34879
Hjalm G, MacLeod RJ, Kifor O, Chattopadhyay N, Brown EM. 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, 2001, 276: 34880–34887
Bai M, Trivedi S, Lane CR, Yang Y, Quinn SJ, Brown EM. Protein kinase C phosphorylation of threonine at position 888 in Ca2+o-sensing receptor (CaR) inhibits coupling to Ca2+ store release. J Biol Chem, 1998, 273: 21267–21275
Bosel J, John M, Freichel M, Blind E. Signaling of the human calcium-sensing receptor expressed in HEK293-cells is modulated by protein kinases A and C. Exp Clin Endocrinol Diabetes, 2003, 111: 21–26
Stepanchick A, McKenna J, McGovern O, Huang Y, Breitwieser GE. Calcium sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif. Cell Physiol Biochem, 2010, 26: 363–374
Hu J, Spiegel AM. Naturally occurring mutations of the extracellular Ca2+-sensing receptor: implications for its structure and function. Trends Endocrinol Metab, 2003, 14: 282–288
Silve C, Petrel C, Leroy C, Bruel H, Mallet E, Rognan D, Ruat M. Delineating a Ca2+ binding pocket within the venus flytrap module of the human calcium-sensing receptor. J Biol Chem, 2005, 280: 37917–37923
Huang Y, Zhou Y, Yang W, Butters R, Lee HW, Li S, Castiblanco A, Brown EM, Yang JJ. Identification and dissection of Ca(2+)-binding sites in the extracellular domain of Ca(2+)-sensing receptor. J Biol Chem, 2007, 282: 19000–19010
Huang Y, Zhou Y, Castiblanco A, Yang W, Brown EM, Yang JJ. Multiple Ca(2+)-binding sites in the extracellular domain of the Ca(2+)-sensing receptor corresponding to cooperative Ca(2+) response. Biochemistry, 2009, 48: 388–398
Zhang C, Huang Y, Jiang Y, Mulpuri N, Wei L, Hamelberg D, Brown EM, Yang JJ. Identification of an L-phenylalanine binding site enhancing the cooperative responses of the calcium-sensing receptor to calcium. J Biol Chem, 2014, 289: 5296–5309
Hu J, Reyes-Cruz G, Chen W, Jacobson KA, Spiegel AM. Identification of acidic residues in the extracellular loops of the seven-transmembrane domain of the human Ca2+ receptor critical for response to Ca2+ and a positive allosteric modulator. J Biol Chem, 2002, 277: 46622–46631
Conigrave AD, Mun HC, Brennan SC. Physiological significance of L-amino acid sensing by extracellular Ca(2+)-sensing receptors. Biochem Soc Trans, 2007, 35: 1195–1198
Conigrave AD, Quinn SJ, Brown EM. L-amino acid sensing by the extracellular Ca2+-sensing receptor. Proc Natl Acad Sci USA, 2000, 97: 4814–4819
Breitwieser GE. Calcium sensing receptors and calcium oscillations: calcium as a first messenger. Curr Top Dev Biol, 2006, 73: 85–114
Zhang Z, Qiu W, Quinn SJ, Conigrave AD, Brown EM, Bai M. Three adjacent serines in the extracellular domains of the CaR are required for L-amino acid-mediated potentiation of receptor function. J Biol Chem, 2002, 277: 33727–33735
Mun HC, Franks AH, Culverston EL, Krapcho K, Nemeth EF, Conigrave AD. The Venus Fly Trap domain of the extracellular Ca2+-sensing receptor is required for L-amino acid sensing. J Biol Chem, 2004, 279: 51739–51744
Mun HC, Culverston EL, Franks AH, Collyer CA, Clifton-Bligh RJ, Conigrave AD. A double mutation in the extracellular Ca2+-sensing receptor’s venus flytrap domain that selectively disables L-amino acid sensing. J Biol Chem, 2005, 280: 29067–29072
Petrel C, Kessler A, Dauban P, Dodd RH, Rognan D, Ruat M. Positive and negative allosteric modulators of the Ca2+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain. J Biol Chem, 2004, 279: 18990–18997
Miedlich SU, Gama L, Seuwen K, Wolf RM, Breitwieser GE. Homology modeling of the transmembrane domain of the human calcium sensing receptor and localization of an allosteric binding site. J Biol Chem, 2004, 279: 7254–7263
Conigrave AD, Franks AH, Brown EM, Quinn SJ. L-amino acid sensing by the calcium-sensing receptor: a general mechanism for coupling protein and calcium metabolism? Eur J Clin Nutr, 2002, 56: 1072–1080
Conigrave AD, Brown EM. Taste receptors in the gastrointestinal tract. II. L-amino acid sensing by calcium-sensing receptors: implications for GI physiology. Am J Physiol Gastrointest Liver Physiol, 2006, 291: G753–761
Conigrave AD, Quinn SJ, Brown EM. Cooperative multi-modal sensing and therapeutic implications of the extracellular Ca(2+) sensing receptor. Trends Pharmacol Sci, 2000, 21: 401–407
McArthur KE, Isenberg JI, Hogan DL, Dreier SJ. Intravenous infu sion of L-isomers of phenylalanine and tryptophan stimulate gastric acid secretion at physiologic plasma concentrations in normal subjects and after parietal cell vagotomy. J Clin Invest, 1983, 71: 1254–1262
Broadhead GK, Mun H, Avlani VA, Jourdon O, Church WB, Christopoulos A, Delbridge L, Conigrave AD. Allosteric modulation of the calcium-sensing receptor by γ-glutamyl peptides: inhibition of PTH secretion, suppression of intracellular cAMP levels, and a common mechanism of action with L-amino acids. J Biol Chem, 2011, 286: 8786–8797
Pi M, Spurney RF, Tu Q, Hinson T, Quarles LD. Calcium-sensing receptor activation of rho involves filamin and rho-guanine nucleotide exchange factor. Endocrinology, 2002, 143: 3830–3838
Rey O, Young SH, Yuan J, Slice L, Rozengurt E. Amino acidstimulated 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, 2005, 280: 22875–22882
Huang C, Wu Z, Hujer KM, Miller RT. Silencing of filamin A gene expression inhibits Ca2+-sensing receptor signaling. FEBS Lett, 2006, 580: 1795–1800
Zhang M, Breitwieser GE. High affinity interaction with filamin A protects against calcium-sensing receptor degradation. J Biol Chem, 2005, 280: 11140–11146
Huang C, Sindic A, Hill CE, Hujer KM, Chan KW, Sassen M, Wu Z, Kurachi Y, Nielsen S, Romero MF, Miller RT. Interaction of the Ca2+-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function. Am J Physiol Renal Physiol, 2007, 292: F1073–1081
Huang Y, Niwa J, Sobue G, Breitwieser GE. Calcium-sensing receptor ubiquitination and degradation mediated by the E3 ubiquitin ligase dorfin. J Biol Chem, 2006, 281: 11610–11617
McCullough J, Clague MJ, Urbe S. AMSH is an endosome-associated ubiquitin isopeptidase. J Cell Biol, 2004, 166: 487–492
Herrera-Vigenor F, Hernandez-Garcia R, Valadez-Sanchez M, Vazquez-Prado J, Reyes-Cruz G. AMSH regulates calcium-sensing receptor signaling through direct interactions. Biochem Biophys Res Commun, 2006, 347: 924–930
Reyes-Ibarra AP, Garcia-Regalado A, Ramirez-Rangel I, Esparza-Silva AL, Valadez-Sanchez M, Vazquez-Prado J, Reyes-Cruz G. Calcium-sensing receptor endocytosis links extracellular calcium signaling to parathyroid hormone-related peptide secretion via a Rab11a-dependent and AMSH-sensitive mechanism. Mol Endocrinol, 2007, 21: 1394–1407
DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Beta-arrestins and cell signaling. Annu Rev Physiol, 2007, 69: 483–510
Morfis M, Christopoulos A, Sexton PM. RAMPs: 5 years on, where to now? Trends Pharmacol Sci, 2003, 24: 596–601
Bouschet T, Martin S, Henley JM. Receptor-activity-modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane. J Cell Sci, 2005, 118: 4709–4720
Shenoy SK, Lefkowitz RJ. beta-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci, 2011, 32: 521–533
Shukla AK, Xiao K, Lefkowitz RJ. Emerging paradigms of beta-arrestin-dependent seven transmembrane receptor signaling. Trends Biochem Sci, 2011, 36: 457–469
Skach WR. Cellular mechanisms of membrane protein folding. Nat Struct Mol Biol, 2009, 16: 606–612
Ulloa-Aguirre A, Conn PM. Targeting of G protein-coupled receptors to the plasma membrane in health and disease. Front Biosci (Landmark Ed), 2009, 14: 973–994
Stepanchick A, Breitwieser GE. The cargo receptor p24A facilitates calcium sensing receptor maturation and stabilization in the early secretory pathway. Biochem Biophys Res Commun, 2010, 395: 136–140
Zhuang X, Chowdhury S, Northup JK, Ray K. Sar1-dependent trafficking of the human calcium receptor to the cell surface. Biochem Biophys Res Commun, 2010, 396: 874–880
Zhuang X, Adipietro KA, Datta S, Northup JK, Ray K. Rab1 small GTP-binding protein regulates cell surface trafficking of the human calcium-sensing receptor. Endocrinology, 2010, 151: 5114–5123
Grant MP, Stepanchick A, Cavanaugh A, Breitwieser GE. Agonist-driven maturation and plasma membrane insertion of calcium-sensing receptors dynamically control signal amplitude. Sci Signal, 2011, 4: ra78
Blum R, Pfeiffer F, Feick P, Nastainczyk W, Kohler B, Schafer KH, Schulz I. Intracellular localization and in vivo trafficking of p24A and p23. J Cell Sci, 1999, 112(Pt 4): 537–548
Strating JR, Martens GJ. The p24 family and selective transport processes at the ER-Golgi interface. Biol Cell, 2009, 101: 495–509
Arulpragasam A, Magno AL, Ingley E, Brown SJ, Conigrave AD, Ratajczak T, Ward BK. The adaptor protein 14-3-3 binds to the calcium-sensing receptor and attenuates receptor-mediated Rho kinase signalling. Biochem J, 2012, 441: 995–1006
Jung SY, Kwak JO, Kim HW, Kim DS, Ryu SD, Ko CB, Cha SH. Calcium sensing receptor forms complex with and is up-regulated by caveolin-1 in cultured human osteosarcoma (Saos-2) cells. Exp Mol Med, 2005, 37: 91–100
Kifor O, Kifor I, Moore FD Jr., Butters RR Jr., Brown EM. m-Calpain colocalizes with the calcium-sensing receptor (CaR) in caveolae in parathyroid cells and participates in degradation of the CaR. J Biol Chem, 2003, 278: 31167–31176
Sun J, Murphy E. Calcium-sensing receptor: a sensor and mediator of ischemic preconditioning in the heart. Am J Physiol Heart Circ Physiol, 2010, 299: H1309–1317
Tu CL, Chang W, Bikle DD. The calcium-sensing receptor-dependent regulation of cell-cell adhesion and keratinocyte differentiation requires Rho and filamin A. J Invest Dermatol, 2011, 131: 1119–1128
Lorenz S, Frenzel R, Paschke R, Breitwieser GE, Miedlich SU. Functional desensitization of the extracellular calcium-sensing receptor is regulated via distinct mechanisms: role of G protein-coupled receptor kinases, protein kinase C and beta-arrestins. Endocrinology, 2007, 148: 2398–2404
Pi M, Oakley RH, Gesty-Palmer D, Cruickshank RD, Spurney RF, Luttrell LM, Quarles LD. Beta-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitization. Mol Endocrinol, 2005, 19: 1078–1087
Nesbit MA, Hannan FM, Howles SA, Reed AA, Cranston T, Thakker CE, Gregory L, Rimmer AJ, Rust N, Graham U, Morrison PJ, Hunter SJ, Whyte MP, McVean G, Buck D, Thakker RV. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet, 2013, 45: 93–97
Zhuang X, Northup JK, Ray K. Large putative PEST-like sequence motif at the carboxyl tail of human calcium receptor directs lysosomal degradation and regulates cell surface receptor level. J Biol Chem, 2012, 287: 4165–4176
Hanyaloglu AC, von Zastrow M. Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu Rev Pharmacol Toxicol, 2008, 48: 537–568
Moore CA, Milano SK, Benovic JL. Regulation of receptor trafficking by GRKs and arrestins. Annu Rev Physiol, 2007, 69: 451–482
Ardley HC, Robinson PA. E3 ubiquitin ligases. Essays Biochem, 2005, 41: 15–30
Geoffrey N. Hendy VG, Lucie Canaff. Calcium-sensing receptor and associated diseases. In: Progress in Molecular Biology and Translational Science. Vol. 89. Elsevier Inc., 2009. 31–95
Thakker RV. Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium, 2004, 35: 275–282
Kemp EH, Gavalas NG, Krohn KJ, Brown EM, Watson PF, Weetman AP. Activating autoantibodies against the calcium-sensing re ceptor detected in two patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab, 2009, 94: 4749–4756
Kemp EH, Gavalas NG, Akhtar S, Krohn KJ, Pallais JC, Brown EM, Watson PF, Weetman AP. Mapping of human autoantibody binding sites on the calcium-sensing receptor. J Bone Miner Res, 2010, 25: 132–140
Ward BK, Magno AL, Blitvich BJ, Rea AJ, Stuckey BG, Walsh JP, Ratajczak T. Novel mutations in the calcium-sensing receptor gene associated with biochemical and functional differences in familial hypocalciuric hypercalcaemia. Clin Endocrinol (Oxf), 2006, 64: 580–587
Hendy GN, D’Souza-Li L, Yang B, Canaff L, Cole DE. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat, 2000, 16: 281–296
Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T. Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet, 2002, 360: 692–694
Hannan FM, Nesbit MA, Zhang C, Cranston T, Curley AJ, Harding B, Fratter C, Rust N, Christie PT, Turner JJ, Lemos MC, Bowl MR, Bouillon R, Brain C, Bridges N, Burren C, Connell JM, Jung H, Marks E, McCredie D, Mughal Z, Rodda C, Tollefsen S, Brown EM, Yang JJ, Thakker RV. Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites. Hum Mol Genet, 2012, 21: 2768–2778
Rogers A, Nesbit MA, Hannan FM, Howles SA, Gorvin CM, Cranston T, Allgrove J, Bevan JS, Bano G, Brain C, Datta V, Grossman AB, Hodgson SV, Izatt L, Millar-Jones L, Pearce SH, Robertson L, Selby PL, Shine B, Snape K, Warner J, Thakker RV. Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3). J Clin Endocrinol Metab, 2014, 99: E1300–1305
Strauss A, Bitsch F, Cutting B, Fendrich G, Graff P, Liebetanz J, Zurini M, Jahnke W. Amino-acid-type selective isotope labeling of proteins expressed in Baculovirus-infected insect cells useful for NMR studies. J Biomol NMR, 2003, 26: 367–372
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published with open access at link.springer.com
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Zhang, C., Miller, C.L., Brown, E.M. et al. The calcium sensing receptor: from calcium sensing to signaling. Sci. China Life Sci. 58, 14–27 (2015). https://doi.org/10.1007/s11427-014-4779-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-014-4779-y