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Calcium

Extracellular calcium sensing and signalling

Nature Reviews Molecular Cell Biology volume 4, pages 530–538 (2003)Cite this article

Key Points

  • Ca2+ is a multipurpose messenger that exerts its effects not only inside the cell (in the cytoplasm and subcellular compartments), but also outside the cell. It functions through the extracellular calcium-sensing receptor (CaR) and other Ca2+ 'sensors'.

  • The CaR was cloned in 1993 from the parathyroid gland, and it is the best characterized of the extracellular Ca2+ sensors. This unusual receptor is widely expressed in many different cell types.

  • Mutations in the CaR are linked to inherited disorders of systemic Ca2+ homeostasis in humans. In fish, the CaR might function as an olfactory detector for Ca2+ in the aquatic environment.

  • The CaR is a promiscuous receptor, which is activated not only by Ca2+, but also by other divalent and trivalent cations, amino acids, polyamines and other polycationic ligands. It is coupled to many different intracellular signalling cascades through heterotrimeric G proteins.

  • Recent evidence indicates that the extracellular Ca2+ concentration can undergo substantial fluctuations in the local microenvironment outside a cell during intracellular Ca2+-signalling events and neuronal activity. Ca2+ might potentially function as a paracrine or autocrine messenger under these circumstances, which works to activate or inactivate the CaR.

  • Information about other sensors of extracellular Ca2+, which are distinct from the CaR, is now beginning to emerge. These include gap-junction hemichannels, the acid-sensing ion channels ASIC1a and ASIC1b, a 36pS cation channel found in hippocampal neurons, and a cell-surface-expressed form of the ryanodine receptor.

Abstract

Ca2+ is well established as an intracellular second messenger. However, the molecular identification of a detector for extracellular Ca2+ — the extracellular calcium-sensing receptor — has opened up the possibility that Ca2+ might also function as a messenger outside cells. Information about the local extracellular Ca2+ concentration is conveyed to the interior of many cell types through this unique G-protein-coupled receptor. Here, we describe new emerging concepts concerning the signalling function of extracellular Ca2+, with particular emphasis on the extracellular calcium-sensing receptor.

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Figure 1: The structure of the CaR.
Figure 2: Signal transduction mediated by the CaR.
Figure 3: Ca2+ oscillations.
Figure 4: Ca2+ as a potential paracrine messenger.

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References

  1. Nemeth, E. F. & 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. 262, 5188–5196 (1987). Some of the first clear evidence that extracellular Ca2+ and other divalent cations can elicit intracellular Ca2+ signals in parathyroid cells.

    Article  CAS  PubMed  Google Scholar 

  2. Shoback, D., Thatcher, J., Leombruno, R. & Brown, E. Effects of extracellular Ca2+ and Mg2+ on cytosolic Ca2+ and PTH release in dispersed bovine parathyroid cells. Endocrinology 113, 424–426 (1983).

    Article  CAS  PubMed  Google Scholar 

  3. Shoback, D. M., Thatcher, J., Leombruno, R. & Brown, E. M. Relationship between parathyroid hormone secretion and cytosolic calcium concentration in dispersed bovine parathyroid cells. Proc. Natl Acad. Sci. USA 81, 3113–3117 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brown, E. et al. High extracellular Ca2+ and Mg2+ stimulate accumulation of inositol phosphates in bovine parathyroid cells. FEBS Lett. 218, 113–118 (1987).

    Article  CAS  PubMed  Google Scholar 

  5. Shoback, D. M., Membreno, L. A. & McGhee, J. G. High calcium and other divalent cations increase inositol trisphosphate in bovine parathyroid cells. Endocrinology 123, 382–389 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Brown, E. M. et al. Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 366, 575–580 (1993). The original article that describes the cloning of the CaR. This work paved the way for numerous subsequent studies on the CaR, allowing the identification of the receptor in a wide variety of tissues.

    Article  CAS  PubMed  Google Scholar 

  7. Brown, E. M. & MacLeod, R. J. Extracellular calcium sensing and extracellular calcium signaling. Physiol. Rev. 81, 239–297 (2001). A comprehensive review that covers all aspects of the structure, tissue distribution, signalling and physiological role of the CaR.

    Article  CAS  PubMed  Google Scholar 

  8. Kunishima, N. et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407, 971–977 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Tsuchiya, D., Kunishima, N., Kamiya, N., Jingami, H. & Morikawa, K. Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+. Proc. Natl Acad. Sci. USA 99, 2660–2665 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bai, M. et al. Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor. J. Biol. Chem. 271, 19537–19545 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Bai, M. Structure and function of the extracellular calcium-sensing receptor. Int. J. Mol. Med. 4, 115–125 (1999).

    CAS  PubMed  Google Scholar 

  12. Kubo, Y., Miyashita, T. & Murata, Y. Structural basis for a Ca2+-sensing function of the metabotropic glutamate receptors. Science 279, 1722–1725 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Wise, A. et al. Calcium sensing properties of the GABAB receptor. Neuropharmacology 38, 1647–1656 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Nash, M. S., Saunders, R., Young, K. W., Challiss, R. A. & Nahorski, S. R. Reassessment of the Ca2+ sensing property of a type I metabotropic glutamate receptor by simultaneous measurement of inositol 1,4,5-trisphosphate and Ca2+ in single cells. J. Biol. Chem. 276, 19286–19293 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Bai, M., Trivedi, S. & Brown, E. M. Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J. Biol. Chem. 273, 23605–23610 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Gama, L., Wilt, S. G. & Breitwieser, G. E. Heterodimerization of calcium sensing receptors with metabotropic glutamate receptors in neurons. J. Biol. Chem. 276, 39053–39059 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Bai, M., Trivedi, S., Kifor, O., Quinn, S. J. & Brown, E. M. Intermolecular interactions between dimeric calcium-sensing receptor monomers are important for its normal function. Proc. Natl Acad. Sci. USA 96, 2834–2839 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pace, A. J., Gama, L. & Breitwieser, G. E. 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. 274, 11629–11634 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Zhang, Z., Sun, S., Quinn, S. J., Brown, E. M. & Bai, M. The extracellular calcium-sensing receptor dimerizes through multiple types of intermolecular interactions. J. Biol. Chem. 276, 5316–5322 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Hermans, E. & Challiss, R. A. Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem. J. 359, 465–484 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jensen, A. A., Greenwood, J. R. & Brauner–Osborne, H. The dance of the clams: twists and turns in the family C GPCR homodimer. Trends Pharmacol. Sci. 23, 491–493 (2002). A succinct review that discusses how conformational movements of the CaR and other members of family C GPCRs might allow these proteins to transduce signals (on the basis of the crystal structure of the mGluR1).

    Article  CAS  PubMed  Google Scholar 

  22. Bai, M. et al. Protein kinase C phosphorylation of threonine at position 888 in Ca2+o-sensing receptor (CaR) inhibits coupling to Ca2+ store release. J. Biol. Chem. 273, 21267–21275 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Jiang, Y. F. et al. Protein kinase C (PKC) phosphorylation of the Ca2+ o-sensing receptor (CaR) modulates functional interaction of G proteins with the CaR cytoplasmic tail. J. Biol. Chem. 277, 50543–50549 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Awata, H., Huang, C., Handlogten, M. E. & Miller, R. T. Interaction of the calcium-sensing receptor and filamin, a potential scaffolding protein. J. Biol. Chem. 276, 34871–34879 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Hjalm, G., MacLeod, R. J., Kifor, O., Chattopadhyay, N. & Brown, E. M. 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. 276, 34880–34887 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Hu, J., Hauache, O. & Spiegel, A. M. Human Ca2+ receptor cysteine-rich domain. Analysis of function of mutant and chimeric receptors. J. Biol. Chem. 275, 16382–16389 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Jensen, A. A. et al. Functional importance of the Ala(116)-Pro(136) region in the calcium-sensing receptor. Constitutive activity and inverse agonism in a family C G-protein-coupled receptor. J. Biol. Chem. 275, 29547–29555 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Brauner-Osborne, H., Jensen, A. A., Sheppard, P. O., O'Hara, P. & Krogsgaard-Larsen, P. The agonist-binding domain of the calcium-sensing receptor is located at the amino-terminal domain. J. Biol. Chem. 274, 18382–18386 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Quinn, S. J. et al. The Ca2+-sensing receptor: a target for polyamines. Am. J. Physiol. 273, C1315–C1323 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Brown, E. M., Katz, C., Butters, R. & Kifor, O. Polyarginine, polylysine, and protamine mimic the effects of high extracellular calcium concentrations on dispersed bovine parathyroid cells. J. Bone Miner. Res. 6, 1217–1225 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Ye, C. et al. Amyloid-β proteins activate Ca2+-permeable channels through calcium-sensing receptors. J. Neurosci. Res. 47, 547–554 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Handlogten, M. E., Shiraishi, N., Awata, H., Huang, C. & Miller, R. T. Extracellular Ca2+-sensing receptor is a promiscuous divalent cation sensor that responds to lead. Am. J. Physiol. Renal Physiol. 279, F1083–F1091 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Spurney, R. F., Pi, M., Flannery, P. & Quarles, L. D. Aluminum is a weak agonist for the calcium-sensing receptor. Kidney Int. 55, 1750–1758 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Brown, E. M., Butters, R., Katz, C. & Kifor, O. Neomycin mimics the effects of high extracellular calcium concentrations on parathyroid function in dispersed bovine parathyroid cells. Endocrinology 128, 3047–3054 (1991).

    Article  CAS  PubMed  Google Scholar 

  35. Katz, C. L., Butters, R. R., Chen, C. J. & Brown, E. M. Structure–function relationships for the effects of various aminoglycoside antibiotics on dispersed bovine parathyroid cells. Endocrinology 131, 903–910 (1992).

    CAS  PubMed  Google Scholar 

  36. Ward, D. T., McLarnon, S. J. & Riccardi, D. Aminoglycosides increase intracellular calcium levels and ERK activity in proximal tubular OK cells expressing the extracellular calcium-sensing receptor. J. Am. Soc. Nephrol. 13, 1481–1489 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Conigrave, A. D., Quinn, S. J. & Brown, E. M. L-amino acid sensing by the extracellular Ca2+-sensing receptor. Proc. Natl Acad. Sci. USA 97, 4814–4819 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Young, S. H. & Rozengurt, E. Amino acids and Ca2+ stimulate different patterns of Ca2+ oscillations through the Ca2+-sensing receptor. Am. J. Physiol. Cell Physiol. 282, C1414–C1422 (2002). An interesting paper that indicates that the CaR might distinguish between different types of extracellular ligands by translating the information about the presence of different CaR agonists into distinct patterns of Ca2+ oscillations inside the cell.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, Z. et al. Three adjacent serines in the extracellular domains of the CaR are required for L-amino acid-mediated potentiation of receptor function. J. Biol. Chem. 277, 33727–33735 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Zhang, Z. et al. L-phenylalanine and NPS R–467 synergistically potentiate the function of the extracellular calcium-sensing receptor through distinct sites. J. Biol. Chem. 277, 33736–33741 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Frazao, J. M., Martins, P. & Coburn, J. W. The calcimimetic agents: perspectives for treatment. Kidney Int. Suppl. 80, 149–154 (2002).

    Article  Google Scholar 

  42. Nemeth, E. F. et al. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc. Natl Acad. Sci. USA 95, 4040–4045 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gowen, M. et al. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J. Clin. Invest. 105, 1595–1604 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nemeth, E. F. et al. Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J. Pharmacol. Exp. Ther. 299, 323–331 (2001).

    CAS  PubMed  Google Scholar 

  45. Quinn, S. J. et al. Sodium and ionic strength sensing by the calcium receptor. J. Biol. Chem. 273, 19579–19586 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Conigrave, A. D., Quinn, S. J. & Brown, E. M. Cooperative multi-modal sensing and therapeutic implications of the extracellular Ca2+ sensing receptor. Trends Pharmacol. Sci. 21, 401–407 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Bornefalk, E. et al. Regulation of interleukin-6 secretion from mononuclear blood cells by extracellular calcium. J. Bone Miner. Res. 12, 228–233 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. MacLeod, R. J., Chattopadhyay, N. & Brown, E. M. PTHrP stimulated by the calcium-sensing receptor requires MAP kinase activation. Am. J. Physiol. Endocrinol. Metab. 284, E435–E442 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Yamaguchi, T., Kifor, O., Chattopadhyay, N., Bai, M. & Brown, E. M. Extracellular calcium (Ca2+o)-sensing receptor in a mouse monocyte-macrophage cell line (J774): potential mediator of the actions of Ca2+o on the function of J774 cells. J. Bone Miner. Res. 13, 1390–1397 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Olszak, I. T. et al. Extracellular calcium elicits a chemokinetic response from monocytes in vitro and in vivo. J. Clin. Invest. 105, 1299–1305 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Godwin, S. L. & Soltoff, S. P. Extracellular calcium and platelet-derived growth factor promote receptor-mediated chemotaxis in osteoblasts through different signaling pathways. J. Biol. Chem. 272, 11307–11312 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Lin, K. I. et al. Elevated extracellular calcium can prevent apoptosis via the calcium-sensing receptor. Biochem. Biophys. Res. Commun. 249, 325–331 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Lorget, F. et al. High extracellular calcium concentrations directly stimulate osteoclast apoptosis. Biochem. Biophys. Res. Commun. 268, 899–903 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Mailland, M., Waelchli, R., Ruat, M., Boddeke, H. G. & Seuwen, K. Stimulation of cell proliferation by calcium and a calcimimetic compound. Endocrinology 138, 3601–3605 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Hobson, S. A., McNeil, S. E., Lee, F. & Rodland, K. D. Signal transduction mechanisms linking increased extracellular calcium to proliferation in ovarian surface epithelial cells. Exp. Cell Res. 258, 1–11 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Oda, Y., Tu, C. L., Pillai, S. & Bikle, D. D. The calcium sensing receptor and its alternatively spliced form in keratinocyte differentiation. J. Biol. Chem. 273, 23344–23352 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Komuves, L. et al. Epidermal expression of the full-length extracellular calcium-sensing receptor is required for normal keratinocyte differentiation. J. Cell. Physiol. 192, 45–54 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Bilderback, T. R., Lee, F., Auersperg, N. & Rodland, K. D. Phosphatidylinositol 3-kinase-dependent, MEK-independent proliferation in response to CaR activation. Am. J. Physiol. Cell Physiol. 283, C282–C288 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Ye, C., Kanazirska, M., Quinn, S., Brown, E. M. & Vassilev, P. M. Modulation by polycationic Ca2+-sensing receptor agonists of nonselective cation channels in rat hippocampal neurons. Biochem. Biophys. Res. Commun. 224, 271–280 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Chattopadhyay, N. et al. Extracellular calcium-sensing receptor in rat oligodendrocytes: expression and potential role in regulation of cellular proliferation and an outward K+ channel. Glia 24, 449–458 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Kifor, O., Diaz, R., Butters, R. & Brown, E. M. The Ca2+-sensing receptor (CaR) activates phospholipases C, A2, and D in bovine parathyroid and CaR-transfected, human embryonic kidney (HEK293) cells. J. Bone Miner. Res. 12, 715–725 (1997).

    Article  CAS  PubMed  Google Scholar 

  62. Handlogten, M. E., Huang, C., Shiraishi, N., Awata, H. & Miller, R. T. The Ca2+-sensing receptor activates cytosolic phospholipase A2 via a Gqα-dependent ERK-independent pathway. J. Biol. Chem. 276, 13941–13948 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Kifor, O. et al. Regulation of MAP kinase by calcium-sensing receptor in bovine parathyroid and CaR-transfected HEK293 cells. Am. J. Physiol. Renal Physiol. 280, F291–F302 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Huang, C., Handlogten, M. E. & Miller, R. T. Parallel activation of phosphatidylinositol 4-kinase and phospholipase C by the extracellular calcium-sensing receptor. J. Biol. Chem. 277, 20293–20300 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. de Jesus Ferreira, M. C. et al. Co-expression of a Ca2+-inhibitable adenylyl cyclase and of a Ca2+-sensing receptor in the cortical thick ascending limb cell of the rat kidney. Inhibition of hormone-dependent cAMP accumulation by extracellular Ca2+. J. Biol. Chem. 273, 15192–15202 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. McNeil, S. E., Hobson, S. A., Nipper, V. & Rodland, K. D. 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. 273, 1114–1120 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Corbetta, S. et al. Mitogen-activated protein kinase cascade in human normal and tumoral parathyroid cells. J. Clin. Endocrinol. Metab. 87, 2201–2205 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Arthur, J. M., Lawrence, M. S., Payne, C. R., Rane, M. J. & McLeish, K. R. The calcium-sensing receptor stimulates JNK in MDCK cells. Biochem. Biophys. Res. Commun. 275, 538–541 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Gama, L. & Breitwieser, G. E. A carboxyl-terminal domain controls the cooperativity for extracellular Ca2+ activation of the human calcium sensing receptor. A study with receptor–green fluorescent protein fusions. J. Biol. Chem. 273, 29712–29718 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Miki, H., Maercklein, P. B. & Fitzpatrick, L. A. Spontaneous oscillations of intracellular calcium in single bovine parathyroid cells may be associated with the inhibition of parathyroid hormone secretion. Endocrinology 136, 2954–2959 (1995).

    Article  CAS  PubMed  Google Scholar 

  71. Breitwieser, G. E. & Gama, L. Calcium-sensing receptor activation induces intracellular calcium oscillations. Am. J. Physiol. Cell Physiol. 280, C1412–C1421 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. De Luisi, A. & Hofer, A. M. Evidence that Ca2+ cycling by the plasma membrane Ca2+-ATPase increases the 'excitability' of the extracellular Ca2+-sensing receptor. J. Cell Sci. 116, 1527–1538 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. McGehee, D. S. et al. Mechanism of extracellular Ca2+ receptor-stimulated hormone release from sheep thyroid parafollicular cells. J. Physiol. 502, 31–44 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bruce, J. I. et al. Molecular and functional identification of a Ca2+ (polyvalent cation)-sensing receptor in rat pancreas. J. Biol. Chem. 274, 20561–20568 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Petrasek, D., Samtaney, R. & Cohen, D. S. Glandular regulation of interstitial diffusion: a model and simulation of a novel physiological mechanism. Am. J. Physiol. Endocrinol. Metab. 283, E195–E206 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Silver, I. A., Murrills, R. J. & Etherington, D. J. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp. Cell Res. 175, 266–276 (1988).

    Article  CAS  PubMed  Google Scholar 

  77. Bosher, S. K. & Warren, R. L. Very low calcium content of cochlear endolymph, an extracellular fluid. Nature 273, 377–378 (1978).

    Article  CAS  PubMed  Google Scholar 

  78. Vassilev, P. M., Mitchel, J., Vassilev, M., Kanazirska, M. & Brown, E. M. Assessment of frequency-dependent alterations in the level of extracellular Ca2+ in the synaptic cleft. Biophys. J. 72, 2103–2116 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Egelman, D. M. & Montague, P. R. Calcium dynamics in the extracellular space of mammalian neural tissue. Biophys. J. 76, 1856–1867 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Keicher, E., Bilbaut, A., Maggio, K., Hernandez-Nicaise, M. L. & Nicaise, G. The desheathed periphery of Aplysia giant neuron. Fine structure and measurement of [Ca2+]o fluctuations with calcium-selective microelectrodes. Eur. J. Neurosci. 3, 10–17 (1991).

    Article  PubMed  Google Scholar 

  81. Rusakov, D. A. & Fine, A. Extracellular Ca2+ depletion contributes to fast activity-dependent modulation of synaptic transmission in the brain. Neuron 37, 287–297 (2003). One of the first papers to use low-affinity fluorescent indicators to monitor extracellular Ca2+ dynamics in brain tissue.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ruat, M., Molliver, M. E., Snowman, A. M. & Snyder, S. H. Calcium sensing receptor: molecular cloning in rat and localization to nerve terminals. Proc. Natl Acad. Sci. USA 92, 3161–3165 (1995). The first study to localize the CaR to nerve terminals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hofer, A. M., Landolfi, B., Debellis, L., Pozzan, T. & Curci, S. Free [Ca2+] dynamics measured in agonist-sensitive stores of single living intact cells: a new look at the refilling process. EMBO J. 17, 1986–1995 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Usachev, Y. M., DeMarco, S. J., Campbell, C., Strehler, E. E. & Thayer, S. A. Bradykinin and ATP accelerate Ca2+ efflux from rat sensory neurons via protein kinase C and the plasma membrane Ca2+ pump isoform 4. Neuron 33, 113–122 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Belan, P., Gerasimenko, O., Petersen, O. H. & Tepikin, A. V. Distribution of Ca2+ extrusion sites on the mouse pancreatic acinar cell surface. Cell Calcium 22, 5–10 (1997).

    Article  CAS  PubMed  Google Scholar 

  86. Strehler, E. E. & Zacharias, D. A. Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps. Physiol. Rev. 81, 21–50 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Penniston, J. T., Enyedi, A., Verma, A. K., Adamo, H. P. & Filoteo, A. G. Plasma membrane Ca2+ pumps. Ann. NY Acad. Sci. 834, 56–64 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Ashby, M. C. & Tepikin, A. V. Polarized calcium and calmodulin signaling in secretory epithelia. Physiol. Rev. 82, 701–734 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Caroppo, R. et al. Asymmetrical, agonist-induced fluctuations in local extracellular [Ca2+] in intact polarized epithelia. EMBO J. 20, 6316–6326 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hofer, A. M., Curci, S., Doble, M. A., Brown, E. M. & Soybel, D. I. Intercellular communication mediated by the extracellular calcium-sensing receptor. Nature Cell Biol. 2, 392–398 (2000). This paper provides evidence that intracellular Ca2+ signalling events can potentially result in extracellular [Ca2+] changes that are detected by CaRs on adjacent cells.

    Article  CAS  PubMed  Google Scholar 

  91. Thomas, A. P. Sharing calcium opens new avenues of signalling. Nature Cell Biol. 2, E126–E127 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Kifor, O., Diaz, R., Butters, R., Kifor, I. & Brown, E. M. The calcium-sensing receptor is localized in caveolin-rich plasma membrane domains of bovine parathyroid cells. J. Biol. Chem. 273, 21708–21713 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Fujimoto, T. Calcium pump of the plasma membrane is localized in caveolae. J. Cell Biol. 120, 1147–1157 (1993).

    Article  CAS  PubMed  Google Scholar 

  94. Isshiki, M., Ying, Y. S., Fujita, T. & Anderson, R. G. A molecular sensor detects signal transduction from caveolae in living cells. J. Biol. Chem. 277, 43389–43398 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Desfleurs, E. et al. The Ca2+-sensing receptor in the rabbit cortical thick ascending limb (CTAL) is functionally not coupled to phospholipase C. Pflugers Arch. 437, 716–723 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Quist, A. P., Rhee, S. K., Lin, H. & Lal, R. Physiological role of gap-junctional hemichannels. Extracellular calcium-dependent isosmotic volume regulation. J. Cell Biol. 148, 1063–1074 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ebihara, L., Liu, X. & Pal, J. D. Effect of external magnesium and calcium on human connexin46 hemichannels. Biophys. J. 84, 277–286 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bruzzone, S., Guida, L., Zocchi, E., Franco, L. & De Flora, A. Connexin 43 hemi channels mediate Ca2+-regulated transmembrane NAD+ fluxes in intact cells. FASEB J. 15, 10–12 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Franco, L. et al. Paracrine roles of NAD+ and cyclic ADP-ribose in increasing intracellular calcium and enhancing cell proliferation of 3T3 fibroblasts. J. Biol. Chem. 276, 21642–21648 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Zanotti, S. & Charles, A. Extracellular calcium sensing by glial cells: low extracellular calcium induces intracellular calcium release and intercellular signaling. J. Neurochem. 69, 594–602 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Stout, C. E., Costantin, J. L., Naus, C. C. & Charles, A. C. Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J. Biol. Chem. 277, 10482–10488 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Babini, E., Paukert, M., Geisler, H. S. & Grunder, S. Alternative splicing and interaction with di- and polyvalent cations control the dynamic range of acid-sensing ion channel 1 (ASIC1). J. Biol. Chem. 277, 41597–41603 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Xiong, Z., Lu, W. & MacDonald, J. F. Extracellular calcium sensed by a novel cation channel in hippocampal neurons. Proc. Natl Acad. Sci. USA 94, 7012–7017 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Xiong, Z. G., Chu, X. P. & MacDonald, J. F. Effect of lamotrigine on the Ca2+-sensing cation current in cultured hippocampal neurons. J. Neurophysiol. 86, 2520–2526 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Vescovi, E. G., Ayala, Y. M., Di Cera, E. & Groisman, E. A. Characterization of the bacterial sensor protein PhoQ. Evidence for distinct binding sites for Mg2+ and Ca2+. J. Biol. Chem. 272, 1440–1443 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Zaidi, M. et al. A ryanodine receptor-like molecule expressed in the osteoclast plasma membrane functions in extracellular Ca2+ sensing. J. Clin. Invest. 96, 1582–1590 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Adebanjo, O. A., Igietseme, J., Huang, C. L. & Zaidi, M. The effect of extracellularly applied divalent cations on cytosolic Ca2+ in murine Leydig cells: evidence for a Ca2+-sensing receptor. J. Physiol. 513, 399–410 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Meldolesi, J. Rapidly exchanging Ca2+ stores in neurons: molecular, structural and functional properties. Prog. Neurobiol. 65, 309–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Mupanomunda, M. M., Ishioka, N. & Bukoski, R. D. Interstitial Ca2+ undergoes dynamic changes sufficient to stimulate nerve-dependent Ca2+-induced relaxation. Am. J. Physiol. 276, H1035–H1042 (1999).

    CAS  PubMed  Google Scholar 

  110. Bukoski, R. D. Dietary Ca2+ and blood pressure: evidence that Ca2+-sensing receptor activated, sensory nerve dilator activity couples changes in interstitial Ca2+ with vascular tone. Nephrol. Dial. Transplant 16, 218–221 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Bukoski, R. D. The perivascular sensory nerve Ca2+ receptor and blood pressure regulation: a hypothesis. Am. J. Hypertens. 11, 1117–1123 (1998). An interesting hypothesis paper that suggested a potential role for the CaR in regulating vascular tone. This paper was followed up several years later with experimental evidence for such a mechanism.

    Article  CAS  PubMed  Google Scholar 

  112. Kallay, E. et al. Dietary calcium and growth modulation of human colon cancer cells: role of the extracellular calcium-sensing receptor. Cancer Detect. Prev. 24, 127–136 (2000).

    CAS  PubMed  Google Scholar 

  113. Diaz, R. et al. Cloning, expression, and tissue localization of the calcium-sensing receptor in chicken (Gallus domesticus). Am. J. Physiol. 273, R1008–R1016 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Cima, R. R. et al. Identification and functional assay of an extracellular calcium-sensing receptor in Necturus gastric mucosa. Am. J. Physiol. 273, G1051–G1060 (1997).

    CAS  PubMed  Google Scholar 

  115. Fellner, S. K. & Parker, L. A Ca2+-sensing receptor modulates shark rectal gland function. J. Exp. Biol. 205, 1889–1897 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Radman, D. P., McCudden, C., James, K., Nemeth, E. M. & Wagner, G. F. Evidence for calcium-sensing receptor mediated stanniocalcin secretion in fish. Mol. Cell. Endocrinol. 186, 111–119 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Nearing, J. et al. Polyvalent cation receptor proteins (CaRs) are salinity sensors in fish. Proc. Natl Acad. Sci. USA 99, 9231–9236 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Naito, T. et al. Putative pheromone receptors related to the Ca2+-sensing receptor in Fugu. Proc. Natl Acad. Sci. USA 95, 5178–5181 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cao, Y., Oh, B. C. & Stryer, L. Cloning and localization of two multigene receptor families in goldfish olfactory epithelium. Proc. Natl Acad. Sci. USA 95, 11987–11992 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Speca, D. J. et al. Functional identification of a goldfish odorant receptor. Neuron 23, 487–498 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Hubbard, P. C., Barata, E. N. & Canario, A. V. Olfactory sensitivity to changes in environmental [Ca2+] in the marine teleost Sparus aurata. J. Exp. Biol. 203, 3821–3829 (2000). This paper showed that there were electrophysiological responses in the living sea bream after changes in the ambient [Ca2+], indicating that these fish can 'smell' Ca2+ in their environments.

    Article  CAS  PubMed  Google Scholar 

  122. Ingleton, P. M., Bendell, L. A., Flanagan, J. A., Teitsma, C. & Balment, R. J. Calcium-sensing receptors and parathyroid hormone-related protein in the caudal neurosecretory system of the flounder (Platichthys flesus). J. Anat. 200, 487–497 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Thakker, R. V. Disorders of the calcium-sensing receptor. Biochim. Biophys. Acta 1448, 166–170 (1998).

    Article  CAS  PubMed  Google Scholar 

  124. Pollak, M. R. et al. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75, 1297–1303 (1993).

    Article  CAS  PubMed  Google Scholar 

  125. Ho, C. et al. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nature Genet. 11, 389–394 (1995).

    Article  CAS  PubMed  Google Scholar 

  126. Pollak, M. R. et al. Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation. Nature Genet. 8, 303–307 (1994). References 124–126 are groundbreaking papers (the second of which uses a knockout mouse model) that provided definitive evidence for a crucial role for the CaR in maintaining systemic Ca2+ homeostasis and that supplied the link between CaR mutations and inherited disorders of Ca2+ metabolism in humans.

    Article  CAS  PubMed  Google Scholar 

  127. De Luca, F. et al. Sporadic hypoparathyroidism caused by de novo gain-of-function mutations of the Ca2+-sensing receptor. J. Clin. Endocrinol. Metab. 82, 2710–2715 (1997).

    CAS  PubMed  Google Scholar 

  128. Li, Y. et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J. Clin. Invest. 97, 910–914 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kifor, O. et al. A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. J. Clin. Endocrinol. Metab. 88, 60–72 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Nagai, T., Sawano, A., Park, E. S. & Miyawaki, A. Circularly permuted green fluorescent proteins engineered to sense Ca2+. Proc. Natl Acad. Sci. USA 98, 3197–3202 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Support for work in the laboratory of E.M.B. is provided by grants from the St. Giles Foundation and the United States Public Health Service. A.M.H. is supported by grants from the Medical Research Service of the Veteran's Administration and a Harvard Digestive Diseases Center Grant. We thank A. Miyawaki and E. Nemeth for generously providing us with the ratiometric pericam probe and NPS-R-467, respectively, which were used to produce figure 3.

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Authors and Affiliations

  1. Department of Surgery, West Roxbury Veterans Affairs Medical Center and Brigham and Women's Hospital, Harvard Medical School, Room 2B111, 1400 VFW Parkway, West Roxbury, 02132, Massachusetts, USA

    Aldebaran M. Hofer

  2. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Edward M. Brown

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DATABASES

LocusLink

GABAB receptors

OMIM

autosomal dominant hypocalcemia

familial hypocalciuric hypercalcemia

neonatal severe hyperparathyroidism

Protein Data Bank

mGluR1

rhodopsin

Swiss-Prot

CaR

JNK

Glossary

POLYCATION

A molecule that carries numerous positive charges.

METABOTROPIC

Requiring metabolic action. Metabotropic receptors are generally coupled to signalling cascades through heterotrimeric G proteins and are distinct from ionotropic receptors, which are ligand-gated ion channels that are activated without intervening metabolic steps.

FAMILY C GCPRs

One of the five principal families of the G-protein-coupled receptor (GPCR) superfamily, the members of which are classified according to their amino-acid sequence similarity.

CAVEOLAE

Specialized, flask-shaped microdomains in the plasma membrane of cells that are enriched in signal-transducing molecules and other plasma-membrane proteins. Caveolae are characterized by the presence of the marker protein caveolin-1.

HILL COEFFICIENT

A numerical value that reflects the degree of cooperativity in a ligand–protein interaction; it is derived from the slope of the portion of a Hill plot that corresponds to the cooperative transition. A non-cooperative enzyme would produce a slope of 1, positive cooperativity a slope >1 and negative cooperativity a slope <1.

EC50

The effective concentration of an agonist that provokes a response that is halfway between the baseline and maximum responses.

CALCIMIMETIC

A pharmacological agent that mimics or potentiates the stimulatory action of Ca2+ on the extracellular calcium-sensing receptor.

HYPERPARATHYROIDISM

A condition in which there is excessive secretion of the parathyroid hormone from the parathyroid gland, one cause of which can be defective Ca2+ sensing by the extracellular calcium-sensing receptor.

CALCILYTIC

A pharmacological antagonist of the extracellular calcium-sensing receptor. One of the principal actions of such a compound is to increase secretion of the parathyroid hormone, which results in the elevation of the serum Ca2+ concentration owing to the mobilization of skeletal Ca2+ and enhanced renal tubular Ca2+ reabsorption.

IC50

The concentration at which an agent inhibits a reaction or enzyme by 50% of the maximum value.

TIGHT JUNCTION

A junctional element that connects adjacent epithelial cells, and helps to maintain polarity and epithelial-barrier function.

HEMICHANNEL

A free-floating connexon in the non-junctional plasma membrane. When it is paired with a connexon from a neighbouring cell, a functional gap-junction channel is formed.

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Hofer, A., Brown, E. Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol 4, 530–538 (2003). https://doi.org/10.1038/nrm1154

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