Broad-spectrum amino acid-sensing class C G-protein coupled receptors: Molecular mechanisms, physiological significance and options for drug development

Pharmacology and Therapeutics

Volumn 127, Issue 3, 2010, Pages 252-260

  Conigrave, Arthur D ^a   Hampson, David R ^b  

^a UNIVERSITY OF SYDNEY   (Australia)

^b UNIVERSITY OF TORONTO   (Canada)

Author keywords

Allosteric modulators; Amino acid sensing; Calcium sensing receptor; Dimerisation; G protein coupled receptor; GPRC6A; Molecular modelling; Taste receptors; Transgenic mouse; Venus FlyTrap

Indexed keywords

4 AMINOBUTYRIC ACID B RECEPTOR; AMINO ACID; G PROTEIN COUPLED RECEPTOR; HETERODIMER; METABOTROPIC RECEPTOR 1; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR 3; METABOTROPIC RECEPTOR 4; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR 6; METABOTROPIC RECEPTOR 7; METABOTROPIC RECEPTOR 8; OLIGOMER; RECEPTOR SUBUNIT;

ANIMAL CELL; BINDING SITE; CRYSTAL STRUCTURE; HUMAN; HUMAN CELL; KNOCKOUT MOUSE; LIGAND BINDING; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DOMAIN; REVIEW; SENSOR; SIGNAL TRANSDUCTION; TASTE BUD; TASTE RECEPTOR FAMILY 1; TASTE RECEPTOR FAMILY 2; TASTE RECEPTOR FAMILY 3;

AMINO ACIDS; ANIMALS; DIMERIZATION; DRUG DESIGN; HUMANS; LIGANDS; MICE; MICE, KNOCKOUT; MODELS, MOLECULAR; PROTEIN BINDING; RECEPTORS, AMINO ACID; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 77954244300     PISSN: 01637258     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2010.04.007     Document Type: Review

References (107)

1. Abe H., Tateyama M., Kubo Y. Functional identification of Gd3+ binding site of metabotropic glutamate receptor 1alpha. FEBS Lett 2003, 545:233-238.
2. Blasi A.D., Conn P.J., Pin J.-P., Nicoletti F. Molecular determinants of metabotropic glutamate receptor signaling. Trends Pharmacol Sci 2001, 22:114-120.
3. Bouschet T., Martin S., Henley J.M. 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.
4. Bouschet T., Martin S., Henley J.M. Regulation of calcium-sensing-receptor trafficking and cell-surface expression by GPCRs and RAMPs. Trends Pharmacol Sci 2008, 29:633-639.
5. Breitwieser G.E., Miedlich S.U., Zhang M. Calcium sensing receptors as integrators of multiple metabolic signals. Cell Calcium 2004, 35:209-216.
6. Brock C., Oueslati N., Soler S., Boudier L., Rondard P., Pin J.P. Activation of a dimeric metabotropic glutamate receptor by intersubunit rearrangement. J Biol Chem 2007, 282:33000-33008.
7. Brown E.M. The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics. Subcell Biochem 2007, 45:139-167.
8. Brown E.M., MacLeod R.J. Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 2001, 81:239-297.
9. Buchan A., Squires P., Ring M., Meloche R. Mechanism of action of the calcium-sensing receptor in human antral gastrin cells. Gastroenterology 2001, 120:1128-1139.
10. Chandrashekar J., Hoon M.A., Ryba N.J., Zuker C.S. The receptors and cells for mammalian taste. Nature 2006, 444:288-294.
11. Chang W., Chen T.H., Pratt S., Shoback D. Amino acids in the second and third intracellular loops of the parathyroid Ca2+-sensing receptor mediate efficient coupling to phospholipase C. J Biol Chem 2000, 275:19955-19963.
12. Chang W., Tu C., Chen T.H., Bikle D., Shoback D. The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signalling 2008, 1(35). ra1.
13. Chattopadhyay N., Cheng I., Rogers K., Riccardi D., Hall A., Diaz R., et al. Identification and localization of extracellular Ca2+-sensing receptor in rat intestine. Am J Physiol 1998, 274:G122-G130.
14. Chattopadhyay N., Espinosa-Jeffrey A., Tfelt-Hansen J., Yano S., Bandyopadhyay S., Brown E., et al. Calcium receptor expression and function in oligodendrocyte commitment and lineage progression: potential impact on reduced myelin basic protein in CaR-null mice. J Neurosci Res 2008, 86:2159-2167.
15. Cherezov V., Rosenbaum D.M., Hanson M.A., Rasmussen S.G., Thian F.S., Kobilka T.S., et al. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 2007, 318:1258-1265.
16. Civelli O. An orphan receptor adopted by a family of transmitters. Mol Pharmacol 2005, 67:583-584.
17. Conigrave A.D., Brown E.M. L-amino acid-sensing by calcium-sensing receptors: implications for GI physiology. Am J Physiol 2006, 291:G753-G761.
18. Conigrave A.D., Hampson D.R. Broad-spectrum amino acid sensing by class 3 G-protein coupled receptors. Trends Endocrinol Metab 2006, 17:398-407.
19. 2+-sensing receptor. Trends Pharm Sci 2000, 21:401-407.
20. 2+-sensing receptor. Proc Natl Acad Sci U S A 2000, 97:4814-4819.
21. Conn P.J. Physiological roles and therapeutic potential of metabotropic glutamate receptors. Ann N Y Acad Sci 2003, 1003:12-21.
22. Conn P.J., Christopoulos A., Lindsley C.W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 2009, 8:41-54.
23. Damak S., Rong M., Yasumatsu K., Kokrashvili Z., Varadarajan V., Zou S., et al. Detection of sweet and umami taste in the absence of taste receptor T1r3. Science 2003, 301:850-853.
24. Ferraguti F., Shigemoto R. Metabotropic glutamate receptors. Cell Tissue Res. 2006, 326:483-504.
25. Ferry S., Traiffort E., Stinnakre J., Ruat M. Developmental and adult expression of rat calcium-sensing receptor transcripts in neurons and oligodendrocytes. Eur J Neurosci 2000, 12:872-884.
26. Finney B., del Moral P., Wilkinson W., Cayzac S., Cole M., Warburton D., et al. Regulation of mouse lung development by the extracellular calcium-sensing receptor, CaR. J Physiol 2008, 586:6007-6019.
27. Frauli M., Neuville P., Vol C., Pin J.P., Prezeau L. Among the twenty classical L-amino acids, only glutamate directly activates metabotropic glutamate receptors. Neuropharmacology 2006, 50:245-253.
28. Geibel J.P., Hebert S.C. The functions and roles of the extracellular Ca2+-sensing receptor along the gastrointestinal tract. Annu Rev Physiol 2009, 71:205-217.
29. Gerbino A., Ruder W.C., Curci S., Pozzan T., Zaccolo M., Hofer A.M. Termination of cAMP signals by Ca2+ and G(alpha)i via extracellular Ca2+ sensors: a link to intracellular Ca2+ oscillations. J Cell Biol 2005, 171:303-312.
30. Hampson D.R., Huang X.P., Pekhletski R., Peltekova V., Hornby G., Thomsen C., et al. Probing the ligand-binding domain of the mGluR4 subtype of metabotropic glutamate receptor. J Biol Chem 1999, 274:33488-33495.
31. Hampson D.R., Rose E., Antflick J. The structures of metabotropic glutamate receptors. The Glutamate Receptors 2008, 363-386. Humana Press, New York Heidelberg. R.W. Gereau-IV, G.T. Swanson (Eds.).
32. Harno E., Edwards G., Geraghty A.R., Ward D.T., Dodd R.H., Dauban P., et al. Evidence for the presence of GPRC6A receptors in rat mesenteric arteries. Cell Calcium 2008, 44:210-219.
33. Hauache O.M., Hu J., Ray K., Xie R., Jacobson K.A., Spiegel A.M. 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.
34. Havlickova M., Blahos J., Brabet I., Liu J., Hruskova B., Prézeau L., et al. The second intracellular loop of metabotropic glutamate receptors recognizes C termini of G-protein alpha-subunits. J Biol Chem 2003, 278:35063-35070.
35. Hay D.L., Poyner D.R., Sexton P.M. GPCR modulation by RAMPs. Pharmacol Ther 2006, 109:173-197.
36. Hermit M.B., Greenwood J.R., Bräuner-Osborne H. Mutation-induced quisqualic acid and ibotenic acid affinity at the metabotropic glutamate receptor subtype 4: ligand selectivity results from a synergy of several amino acid residues. J Biol Chem 2004, 279:34811-34817.
37. Hira T., Nakajima S., Eto Y., Hara H. Calcium-sensing receptor mediates phenylalanine-induced cholecystokinin secretion in enteroendocrine STC-1 cells. FEBS J 2008, 275:4620-4626.
38. Hlavackova V., Goudet C., Kniazeff J., Zikova A., Maurel D., Vol C., et al. Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR. EMBO J 2005, 24:499-509.
39. Ho C., Conner D.A., Pollak M.R., Ladd D.J., Kifor O., Warren H.B., et al. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 1995, 11:389-394.
40. Hofer A.M., Brown E.M. Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol 2003, 4(7):530-538.
41. 2+ receptor cysteine-rich domain. Analysis of function of mutant and chimeric receptors. J Biol Chem 2000, 275(21):16382-16389.
42. Hu J., Reyes-Cruz G., Goldsmith P.K., Spiegel A.M. The Venus's-flytrap and cysteine-rich domains of the human Ca2+ receptor are not linked by disulfide bonds. J Biol Chem 2001, 276:6901-6904.
43. Hu J., Spiegel A.M. 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.
44. Huang Y., Zhou Y., Castiblanco A., Yang W., Brown E.M., Yang J.J. 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.
45. Huang Y., Zhou Y., Yang W., Butters R., Lee H.-W., Li S., et al. Identification and dissection of Ca(2+)-binding sites in the extracellular domain of Ca(2+)-sensing receptor. J Biol Chem 2007, 282:19000-19010.
46. Jang H.J., Kokrashvili Z., Theodorakis M.J., Carlson O.D., Kim B.J., Zhou J., et al. Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc Natl Acad Sci U S A 2007, 104:15069-15074.
47. Jiang P., Ji Q., Liu Z., Snyder L.A., Benard L.M., Margolskee R.F., et al. The cysteine-rich region of T1R3 determines responses to intensely sweet proteins. J Biol Chem 2004, 279:45068-45075.
48. Jiang Y., Minet E., Zhang Z., Silver P.A., Bai M. Modulation of interprotomer relationships is important for activation of dimeric calcium-sensing receptor. J Biol Chem 2004, 279:14147-14156.
49. Jones K.A., Borowsky B., Tamm J.A., Craig D.A., Durkin M.M., Dai M., et al. GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature 1998, 396(6712):674-679.
50. Kaupmann K., Malitschek B., Schuler V., Heid J., Froestl W., Beck P., et al. GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature 1998, 396(6712):683-687.
51. Kim M.R., Kusakabe Y., Miura H., Shindo Y., Ninomiya Y., Hino A. Regional expression patterns of taste receptors and gustducin in the mouse tongue. Biochem Biophys Res Commun 2003, 312:500-506.
52. Kos C.H., Karaplis A.C., Peng J.B., Hediger M.A., Goltzman D., Mohammad K.S., et al. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J Clin Invest 2003, 117:1021-1028.
53. Kuang D., Yao Y., Lam J., Tsushima R.G., Hampson D.R. Cloning and characterization of a family C orphan G-protein coupled receptor. J Neurochem 2005, 93:383-391.
54. Kuang D., Yao Y., Maclean D., Wang M., Hampson D.R., Chang B.S. Ancestral reconstruction of the ligand-binding pocket of Family C G protein-coupled receptors. Proc Natl Acad Sci U S A 2006, 103:14050-14055.
55. Kunishima N., Shimada Y., Tsuji Y., Sato T., Yamamoto M., Kumasaka T., et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 2000, 407:971-977.
56. Li X., Staszewski L., Xu H., Durick K., Zoller M., Adler E. Human receptors for sweet and umami taste. Proc Natl Acad Sci U S A 2002, 99:4692-4696.
57. Mace O.J., Lister N., Morgan E., Shepherd E., Affleck J., Helliwell P., et al. An energy supply network of nutrient absorption coordinated by calcium and T1R taste receptors in rat small intestine. J Physiol 2009, 587:195-210.
58. Marquis R.W., Lago A.M., Callahan J.F., Trout R.E., Gowen M., DelMar E.G., et al. Antagonists of the calcium receptor I. Amino alcohol-based parathyroid hormone secretagogues. J Med Chem 2009, 52:3982-3993.
59. Maruyama Y., Pereira E., Margolskee R.F., Chaudhari N., Roper S.D. Umami responses in mouse taste cells indicate more than one receptor. J Neurosci 2006, 26:2227-2234.
60. Miedlich S.U., Gama L., Seuwen K., Wolf R.M., Breitwieser G.E. 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.
61. Mun H., Culverston E., Franks A., Collyer C., Clifton-Bligh R., Conigrave A. A double mutation in the extracellular Ca2+-sensing receptor's Venus fly trap domain that selectively disables L-amino acid sensing. J Biol Chem 2005, 280:29067-29072.
62. Mun H., Franks A., Culverston E., Krapcho K., Nemeth E., Conigrave A. 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.
63. Muto T., Tsuchiya D., Morikawa K., Jingami H. Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci U S A 2007, 104:3759-3764.
64. Naismith J.H., Devine T.Q., Kohno T., Sprang S.R. Structures of the extracellular domain of the type I tumor necrosis factor receptor. Structure 1996, 4:1251-1262.
65. Nelson G., Chandrashekar J., Hoon M.A., Feng L., Zhao G., Ryba N.J.P., et al. An amino-acid taste receptor. Nature 2002, 416:199-202.
66. Nemeth E.F. Misconceptions about calcimimetics. Ann N Y Acad Sci 2006, 1068:471-476.
67. Oda Y., Tu C.L., Chang W., Crumrine D., Komuves L., Mauro T., et al. The calcium sensing receptor and its alternatively spliced form in murine epidermal differentiation. J Biol Chem 2000, 275:1183-1190.
68. 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 1998, 273:23344-23352.
69. Ohsu T., Amino Y., Nagasaki H., Yamanaka T., Takeshita S., Hatanaka T., et al. Involvement of the calcium-sensing receptor in human taste perception. J Biol Chem 2010, 285:1016-1022.
70. Palczewski K., Kumasaka T., Hori T., Behnke C.A., Motoshima H., Fox B.A., et al. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 2000, 289:739-745.
71. Palmer R.K. The pharmacology and signaling of bitter, sweet, and umami taste sensing. Mol Interv 2007, 7:87-98.
72. Phillips C.G., Harnett M.T., Chen W., Smith S.M. Calcium-sensing receptor activation depresses synaptic transmission. J Neurosci 2008, 28:12062-12070.
73. Pi M., Chen L., Huang M.Z., Zhu W., Ringhofer B., Luo J., et al. GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PLoS ONE 2008, 3:e3858.
74. Pi M., Faber P., Ekema G., Jackson P.D., Ting A., Wang N., et al. Identification of a novel extracellular cation sensing G-protein coupled receptor. J Biol Chem 2005, 280:40201-40209.
75. Pi M., Luo Q., Hunag M., Zybko M., Ringhofer B., Brunden K.R., et al. Evidence that GPRC6A is a novel cation-sensing receptor regulating bone formation. J Bone Miner Res 2006, 21:1007.
76. Pin J.-P., Comps-Agrar L., Maurel D., Monnier C., Rives M.L., Trinquet E., et al. G-protein coupled receptor oligomers: two or more for what? Lessons from mGlu and GABAB receptors. J Physiol 2009, 587:5337-5344.
77. Pin J.-P., Kniazeff J., Goudet C., Bessis A.S., Liu J., Galvez T., et al. The activation mechanism of class-C G-protein coupled receptors. Biol Cell 2004, 96:335-342.
78. Rasmussen S.G., Choi H.J., Rosenbaum D.M., Kobilka T.S., Thian F.S., Edwards P.C., et al. Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 2007, 450:383-387.
79. Ray K., Adipietro K.A., Chen C., Northup J.K. Elucidation of the role of peptide linker in calcium-sensing receptor activation process. J Biol Chem 2007, 282:5310-5317.
80. Ray K., Hauschild B.C., Steinbach P.J., Goldsmith P.K., Hauache O., Spiegel A.M. 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(39):27642-27650.
81. Ray K., Northup J. Evidence for distinct cation and calcimimetic compound (NPS 568) recognition domains in the transmembrane regions of the human Ca2+ receptor. J Biol Chem 2002, 277:18908-18913.
82. Rodriguez L., Tu C., Cheng Z., Chen T.-H., Bikle D., Shoback D., et al. Expression and functional assessment of an alternatively spliced extracellular Ca2+-sensing receptor in growth plate chondrocytes. Endocrinology 2005, 146:5294-5303.
83. Rogers K.V., Dunn C.K., Hebert S.C., Brown E.M. Localization of calcium receptor mRNA in the adult rat central nervous system by in situ hybridization. Brain Res 1997, 744(1):47-56.
84. Rondard P., Liu J., Huang S., Malhaire F., Vol C., Pinault A., et al. Coupling of agonist binding to effector domain activation in metabotropic glutamate-like receptors. J Biol Chem 2006, 281:24653-24661.
85. Rosemond E., Wang M., Yao Y., Storjohann L., Stormann T., Johnson E.C., et al. Molecular basis for the differential agonist affinities of group III metabotropic glutamate receptors. Mol Pharmacol 2004, 66:834-842.
86. 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 U S A 1995, 92:3161-3165.
87. Sato T., Shimada Y., Nagasawa N., Nakanishi S., Jingami H. Amino acid mutagenesis of the ligand binding site and the dimer interface of the metabotropic glutamate receptor 1. J Biol Chem 2003, 278:4314-4321.
88. Speca D., Lin D., Sorensen P., Isacoff E., Ngai J., Dittman A. Functional identification of a goldfish odorant receptor. Neuron 1999, 23:487-498.
89. 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 U S A 2002, 99:2660-2665.
90. Tu Q., Pi M., Karsenty G., Simpson L., Liu S., Quarles L.D. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J Clin Invest 2003, 111:1029-1037.
91. Vezzoli G., Soldati L., G.G.G. Roles of calcium-sensing receptor (CaSR) in renal mineral ion transport. Curr Pharm Biotechnol 2009, 10:302-310.
92. Vizard T.N., O'Keeffe G.W., Gutierrez H., Kos C.H., Riccardi D., Davies A.M. Regulation of axonal and dendritic growth by the extracellular calcium-sensing receptor. Nat Neurosci 2008, 11:285-291.
93. Wang M., Hampson D.R. An evaluation of automated in silico ligand docking of amino acid ligands to Family C G-protein coupled receptors. Bioorg Med Chem 2006, 14:2032-2039.
94. Wang M., Yao Y., Kuang D., Hampson D.R. Activation of family C G-protein-coupled receptors by the tripeptide glutathione. J Biol Chem 2006, 281:8864-8870.
95. Ward D.T., Riccardi D. Renal physiology of the extracellular calcium-sensing receptor. Pflugers Arch 2002, 445:169-176.
96. Warne T., Serrano-Vega M.J., Baker J.G., Moukhametzianov R., Edwards P.C., Henderson R., et al. Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 2008, 454:486-491.
97. Wellendorph P., Bräuner-Osborne H. Molecular basis for amino acid sensing by family C G-protein-coupled receptors. Br J Pharmacol 2009, 156:869-894.
98. Wellendorph P., Burhenne N., Christiansen B., Walter B., Schmale H., Bräuner-Osborne H. The rat GPRC6A: cloning and characterization. Gene 2007, 396:257-267.
99. Wellendorph P., Hansen K.B., Balsgaard A., Greenwood J.R., Egebjerg J., Brauner-Osborne H. Deorphanization of GPRC6A: a promiscuous L-{alpha}-amino acid receptor with preference for basic amino acids. Mol Pharmacol 2005, 67:589-597.
100. Wellendorph P., Johansen L.D., Brauner-Osborne H. Molecular pharmacology of promiscuous 7TM receptors sensing organic nutrients. Mol Pharmacol 2009, 76:453-465.
101. Wellendorph P., Johansen L.D., Jensen A.A., Casanova E., Gassmann M., Deprez P., et al. No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions. J Mol Endocrinol 2009, 42:215-223.
102. White J.H., Wise A., Main M.J., Green A., Fraser N.J., Disney G.H., et al. Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature 1998, 396(6712):679-682.
103. Yao Y., Pattabiraman N., Michne W.F., Huang X.P., Hampson D.R. Molecular modeling and mutagenesis of the ligand-binding pocket of the mGlu3 subtype of metabotropic glutamate receptor. J Neurochem 2003, 86:947-957.
104. Zhang F., Klebansky B., Fine R.M., Xu H., Pronin A., Liu H., et al. Molecular mechanism for the umami taste synergism. Proc Natl Acad Sci U S A 2008, 105:20930-20934.
105. Zhang Z., Qiu W., Quinn S.J., Conigrave A.D., Brown E.M., 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.
106. 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 2001, 276:5316-5322.
107. Zhao G.Q., Zhang Y., Hoon M.A., Chandrashekar J., Erlenbach I., Ryba N.J., et al. The receptors for mammalian sweet and umami taste. Cell 2003, 115:255-266.