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AAPS PharmSci. Sep 2001; 3(3): 54–80.
Published online Jul 26, 2001. doi:  10.1208/ps030322
PMCID: PMC2751017
Genetic variations in human G protein-coupled receptors: Implications for drug therapy
Wolfgang Sadee,corresponding author1,2 Elen Hoeg,1,2 Julie Lucas,1,2 and Danxin Wang1,2
1Department of Biopharmaceutical Sciences, University of California San Francisco, 94143-0446 San Francisco, CA
2Department of Pharmaceutical Chemistry, University of California San Francisco, 94143-0446 San Francisco, CA
Wolfgang Sadee, Phone: 415-476 1947, Fax: 415-476 0464, sadee/at/cgl.ucsf.edu.
corresponding authorCorresponding author.
Received March 4, 2001; Accepted June 30, 2001.
Numerous genes encode G protein-coupled receptors (GPCRs)-a main molecular target for drug therapy. Estimates indicate that the human genome contains approximately 600 GPCR genes. This article addresses therapeutic implications of sequence variations in GPCR genes. A number of inactivating and activating receptor mutations have been shown to cause a variety of (mostly rare) genetic disorders. However, pharmacogenetic and pharmacogenomic studies on GPCRs are scarce, and therapeutic relevance of variant receptor alleles often remains unclear. Confounding factors in assessing the therapeutic relevance of variant GPCR alleles include 1) interaction of a single drug with multiple closely related receptors, 2) poorly defined binding pockets that can accommodate drug ligands in different orientations or at alternative receptor domains, 3) possibility of multiple receptor conformations with distinct functions, and 4) multiple signaling pathways engaged by a single receptor. For example, antischizophrenic drugs bind to numerous receptors, several of which might be relevant to therapeutic outcome. Without knowing accurately what role a given receptor subtype plays in clinical outcome and how a sequence variation affects drug-induced signal transduction, we cannot predict the therapeutic relevance of a receptor variant. Genome-wide association studies with single nucleotide polymorphisms could identify critical target receptors for disease susceptibility and drug efficacy or toxicity.
Keywords: G Protein-Coupled, Receptors, Drug Therapy, Pharmacogenomics, Pharmacogenetics
1. Small KM, Forbes SL, Brown KM, Liggett SB. An asn to lys polymorphism in the third intracellular loop of the human alpha 2A-adrenergic receptor imparts enhanced agonist-promoted Gi coupling. J Biol Chem. 2000;275:38518–38523. doi: 10.1074/jbc.M004550200. [PubMed] [Cross Ref]
2. Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human betal-adrenergic receptor. J Biol Chem. 1999;274:12670–12674. doi: 10.1074/jbc.274.18.12670. [PubMed] [Cross Ref]
3. Turki J, Pak J, Green S, Martin R, Liggett SB. Genetic polymorphisms of the ß2-adrenergic receptor in nocturnal and non-nocturnal asthma. Evidence that Gly 16 correlates with the nocturnal phenotype. J Clin Invest. 1995;95:1635–1641. doi: 10.1172/JCI117838. [PMC free article] [PubMed] [Cross Ref]
4. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the ß2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J. Clin. Invest. 1997;100:3184–3188. doi: 10.1172/JCI119874. [PMC free article] [PubMed] [Cross Ref]
5. Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the ß2 adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol. 1993;8:334–339. [PubMed]
6. Bray MS, Krushkal J, Li L, et al. Positional genomic analysis identifies the beta (2)-adrenergic receptor gene as a susceptibility locus for human hypertension. Circulation. 2000;101:2877–2882. [PubMed]
7. Wagoner LE, Craft LL, Singh B, et al. Polymorphisms of the beta (2)-adrenergic receptor determine exercise capacity in patients with heart failure. Circ Res. 2000;86:834–840. [PubMed]
8. Summerhill E, Leavitt SA, Gidley H, Parry R, Solway J, Ober C. Beta-2 adrenergic receptor polymorphism tied to reduced lung function. Am J Resp Crit Care Med. 2000;162:599–602. [PubMed]
9. Xu BY, Huang D, Pirskanen R, Lefvert A. Beta2-adrenergic receptor gene polymorphisms in myasthenia gravis (MG) Clin Exp Immunol. 2000;119:156–160. doi: 10.1046/j.1365-2249.2000.01111.x. [PubMed] [Cross Ref]
10. Dewar JC, Wilkinson J, Wheatley A, et al. The glutamine 27 beta2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families. J Allergy Clin Immunol. 1997;100:261–265. doi: 10.1016/S0091-6749(97)70234-3. [PubMed] [Cross Ref]
11. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of beta2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol. 1995;13:25–33. [PubMed]
12. Meirhaeghe A, Helbecque N, Cottel D, Amouyel P. Beta2-adrenoceptor gene polymorphism, body weight, and physical activity. Lancet. 1999;353:896–896. doi: 10.1016/S0140-6736(99)00251-2. [PubMed] [Cross Ref]
13. Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A polymorphism of the human ß2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem. 1993;268:23116–23121. [PubMed]
14. Birnbaumer M. Mutations and diseases of G protein coupled receptors. J Recept Signal Transduct Res. 1995;15:131–160. doi: 10.3109/10799899509045213. [PubMed] [Cross Ref]
15. Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and coding region ß2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A. 2000;97:10483–10488. doi: 10.1073/pnas.97.19.10483. [PubMed] [Cross Ref]
16. Mitchell BD, Blangero J, Comuzzie AG, et al. A paired sibling analysis of the ß-3 adrenergic receptor and obesity in Mexican Americans. J Clin Invest. 1998;101:584–587. doi: 10.1172/JCI512. [PMC free article] [PubMed] [Cross Ref]
17. Cravchik A, Gejman PV. Functional analysis of the human D5 dopamine receptor missense and nonsense variants: differences in dopamine binding affinities. Pharmacogenetics. 1999;9:199–206. doi: 10.1097/00008571-199902000-00003. [PubMed] [Cross Ref]
18. Blum K, Sheridan PJ, Wood RC, Braverman ER, Chen TJ, Comings DE. Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behaviour. Pharmacogenetics. 1995;5:121–141. doi: 10.1097/00008571-199506000-00001. [PubMed] [Cross Ref]
19. Blum K, Braverman ER, Wood RC, et al. Increased prevalence of the Tag I A1 allele of the dopamine receptor gene (DRD2) in obesity with comorbid substance use disorder: a preliminary report. Pharmacogenetics. 1996;6:297–305. doi: 10.1097/00008571-199608000-00003. [PubMed] [Cross Ref]
20. Blum K, Noble EP, Sheridan PJ, et al. Association of the A1 allele of the D2 dopamine receptor gene with severe alcoholism. Alcohol. 1991;8:409–416. doi: 10.1016/0741-8329(91)90693-Q. [PubMed] [Cross Ref]
21. Hietala J, Pohjalainen T, Heikkila-Kallio U, West C, Salaspuro M, Syvalathi E. Allelic association between D2 but not D1 dopamine receptor gene and alcoholism in Finland. Psychiatr Genet. 1997;7:19–25. doi: 10.1097/00041444-199700710-00003. [PubMed] [Cross Ref]
22. Noble EP. The D2 dopamine receptor gene: a review of association studies in alcoholism and phenotypes. Alcohol. 1998;16:33–45. doi: 10.1016/S0741-8329(97)00175-4. [PubMed] [Cross Ref]
23. Thompson J, Thomas N, Singleton A, et al. D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the Al allele. Pharmacogenetics. 1997;7:479–84. doi: 10.1097/00008571-199712000-00006. [PubMed] [Cross Ref]
24. Comings DE, Rosenthal RJ, Lesieur HR, et al. A study of the dopamine D2 receptor gene in pathological gambling. Pharmacogenetics. 1996;6:223–232. doi: 10.1097/00008571-199606000-00004. [PubMed] [Cross Ref]
25. Chen CH, Wei FC, Koong F-J, Hsiao K. Association of Taq1 A polymorphism of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. Biol Psychiatry. 1997;41:827–829. doi: 10.1016/S0006-3223(96)00543-4. [PubMed] [Cross Ref]
26. Cravchik A, Sibley DR, Geiman PV. Analysis of neuroleptic binding affinities and potencies for the human different D2 dopamine receptor missense variants. Pharmacogenetics. 1999;9:17–23. doi: 10.1097/00008571-199902000-00003. [PubMed] [Cross Ref]
27. Klein C, Brin MF, Kramer P, et al. Association of a missense change in the D2 dopamine receptor with myoclonus dystonia. Proc Natl Acad Sci U S A. 1999;96:5173–5176. doi: 10.1073/pnas.96.9.5173. [PubMed] [Cross Ref]
28. Lannfelt L, Sokoloff P, Martres MP, et al. Amino acid substitution in the dopamine D3 receptor as a useful polymorphism for investigating psychiatric disorders. Psychiatr Genet. 1992;2:249–256. doi: 10.1097/00041444-199210000-00003. [Cross Ref]
29. Dikeos DG, Papadimitrion GN, Avramopoulos D, et al. Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder. Psychiatr Genet. 1999;9:189–195. doi: 10.1097/00041444-199912000-00005. [PubMed] [Cross Ref]
30. Hawi Z, McCabe U, Straub RE, et al. Examination of new and reported data of the DRD3/MscI polymorphism: no support for the proposed association with schizophrenia. Mol Psychiatry. 1998;3:150–155. doi: 10.1038/sj.mp.4000362. [PubMed] [Cross Ref]
31. Steen VM, Loevlie R, MacEwan T, McCreadie RG. Dopamine D3 receptor variant and susceptibility to tardive dyskinesia in schizophrenic patients. Mol Psychiatry. 1997;2:139–145. doi: 10.1038/sj.mp.4000249. [PubMed] [Cross Ref]
32. Basile VS, Masellis M, Badri F, et al. Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia. Neuropsychopharmacology. 1999;21:17–27. doi: 10.1016/S0893-133X(98)00114-6. [PubMed] [Cross Ref]
33. Sinagnanasundadaram S, Morris AG, Gaitonde EJ, McKenna PJ, Mollon JD, Hunt DM. A cluster of single nucleotide polymorphisms in the 5′-leader of the human dopamine D3 receptor gene (DRD3) and its relationship to schizophrenia. Neurosci Lett. 2000;279:13–16. doi: 10.1016/S0304-3940(99)00921-0. [PubMed] [Cross Ref]
34. Tol HHM, Wu CM, Guan HC, et al. Multiple dopamine D4 receptor variants in the human population. Nature. 1992;358:149–152. doi: 10.1038/358149a0. [PubMed] [Cross Ref]
35. Newman-Tancredi A, Audinot V, Chaput C, Verriele L, Millan MJ. [35S] Guanosine-5′o-(3-thio)triphosphate binding as a measure of efficacy at human recombinant dopamine D4.4 receptors: actions of antiparkinsonian and antipsychotic drugs. J Pharmacol Exp Ther. 1997;282:181–191. [PubMed]
36. Gilliland SL, Alper RH. Characterization of dopaminergic compounds at hD2short, hD4.2 and hD2.7 receptors in agonist stimulated [35S]-GTPgammaS binding assays. NS Arch Pharmacol. 2000;361:498–504. doi: 10.1007/s002100000224. [PubMed] [Cross Ref]
37. Perez de Castro I, Ibanez A, Torres P, Saiz-Ruiz J, Fernandez-Piqueras J. Genetic association study between pathological gambling and a functional DNA polymorphism at the D4 receptor gene. Pharmacogenetics. 1997;7:345–348. doi: 10.1097/00008571-199710000-00001. [PubMed] [Cross Ref]
38. Liu IS, Seeman P, Sanyal S, et al. Dopamine D4 receptor variant in Africans, D4 valine194glycine, is insensitive to dopamine and clozapine: report of a homozygous individual. Am J Med Genet. 1996;61:277–282. doi: 10.1002/(SICI)1096-8628(19960122)61:3<277::AID-AJMG14>3.0.CO;2-Q. [PubMed] [Cross Ref]
39. Okuyama Y, Ishiguro H, Toru M, Arinami T. A genetic polymorphism in the promoter region of DRD4 associated with expression and schizophrenia. Biochem Biophys Res Comm. 1999;258:292–295. doi: 10.1006/bbrc.1999.0630. [PubMed] [Cross Ref]
40. Holmes C, Arranz MJ, Powell JF, Collier DA, Lovestone S. 5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer’s disease. Hum Mol Genet. 1998;7:1506–1509. doi: 10.1093/hmg/7.9.1507. [PubMed] [Cross Ref]
41. Arranz M, Collier D, Sodhi M, et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet. 1995;346:281–282. doi: 10.1016/S0140-6736(95)92168-0. [PubMed] [Cross Ref]
42. Joober R, Benkelfat C, Brisebois K, et al. T102C polymorphism in the 5-HT2A gene and schizophrenia: relation to phenotype drug response variability. J Psychiatry Neurosci. 1999;24:141–146. [PMC free article] [PubMed]
43. Murray MJ, Munro J, Sham P, et al. Metaanalysis of studies on genetic variation in 5HT2A receptors and clozapine response. Schiz Res. 1998;32:93–99. doi: 10.1016/S0920-9964(98)00032-2. [PubMed] [Cross Ref]
44. Arranz MJ, Munro J, Bolonna A, et al. Pharmacogenetic prediction of clozapine response. Lancet. 2000;355:1615–1616. doi: 10.1016/S0140-6736(00)02221-2. [PubMed] [Cross Ref]
45. Ozaki N, Lubierman V, Lu SJ, Lappalainen J, Rosenthal NE, Goldman D. A naturally occurring amino acid substitution of the human serotonin 5HT2A receptor influences amplitude and timing of intracellular calcium mobilization. J Neurochem. 1997;68:2186–2193. [PubMed]
46. Nacmias B, Ricca V, Tedde A, Mezzani B, Rotella CM, Sorbi S. 5-HT2A receptor gene polymorphisms in anorexia nervosa and bulimia nervosa. Neurosci Lett. 1999;277:134–136. doi: 10.1016/S0304-3940(99)00859-9. [PubMed] [Cross Ref]
47. Sodhi MS, Arranz MJ, Curtis D, et al. Association between clozapine response and allelic variation in the 5-HT2C receptor gene. Neuroreport. 1995;7:169–172. [PubMed]
48. Yuan X, Ishiyama-Shigemoto S, Koyama W, Nonaka K. Identification of polymorphic loci in the promoter region of the serotonin 5HT2C receptor and their association with obesity and type II diabetes. Diabetologica. 2000;43:373–376. doi: 10.1007/s001250050056. [PubMed] [Cross Ref]
49. Bruss M, Bonisch H, Buhlen M, Nothen MM, Propping P, Gothert M. Modified ligand binding to the naturally occurring Cys-124 variant of the human serotonin 5-HT1B receptor. Pharmacogen. 1999;9(1):95–102. [PubMed]
50. Tsai SJ, Liu HC, Liu TY, Wang YC, Hong CJ. Association analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer’s disease. Neurosci Lett. 1999;276:138–139. doi: 10.1016/S0304-3940(99)00802-2. [PubMed] [Cross Ref]
51. Sasaki Y, Ihara K, Ahmed S, et al. Lack of association between atopic asthma and polymorphisms of the histamine H1 receptor, histamine H2 receptor, and N-methyltransferase genes. Immunogenetics. 2000;51:238–240. doi: 10.1007/s002510050037. [PubMed] [Cross Ref]
52. Orange PR, Heath PR, Wright SR, Ramchand CM, Kolkeivicz L, Pearson RC. Individuals with schizophrenia have an increased incidence of the H2R649G allele for the histamine H2 receptor. Mol Psychiat. 1996;6:466–469. [PubMed]
53. Ito C, Morriset S, Krebs MO, et al. Histamine H2 gene variants: lack of association with schizophrenia. Mol Psychiat. 2000;5:159–164. doi: 10.1038/sj.mp.4000664. [PubMed] [Cross Ref]
54. Morisset S, Rouleau A, Ligneau X, et al. High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature. 2000;408:860–864. doi: 10.1038/35048583. [PubMed] [Cross Ref]
55. Rice GI, Foy CA, Grant PJ. Angiotensin converting enzyme and angiotensin II type 1-receptor gene polymorphisms and risk of ischaemic heart disease. Cardiovasc Res. 1999;41:746–753. doi: 10.1016/S0008-6363(98)00246-6. [PubMed] [Cross Ref]
56. Geel PP, Pinto YM, Zwinderman AH, et al. Increased risk for ischaemic events is related to combined RAS polymorphism. Heart. 2001;85:458–462. doi: 10.1136/heart.85.4.458. [PMC free article] [PubMed] [Cross Ref]
57. Benetos A, Cambien F, Gautier S, Ricard S, et al. Influence of the angiotensin II type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine arterial stiffness in hypertensive individuals. Hypertension. 1996;28:1081–1084. [PubMed]
58. Geel PP, Pinto YM, Buikema H, Gilst WH. Is the A1166C polymorphism of the angiotensin II type 1 receptor involved in cardiovascular disease? Eur Heart J. 1998;19:G13–G17. [PubMed]
59. Henrion D, Amant C, Benessiano J, et al. Angiotensin II type 1 receptor gene polymorphism is associated with an increased vascular reactivity in the human mammary artery in vitro. J Vasc Res. 1998;35:356–362. doi: 10.1159/000025605. [PubMed] [Cross Ref]
60. Nicaud V, Poirier O, Behague I, et al. Polymorphisms of the endothelin-A and-B receptor genes in relation to blood pressure and myocardial infarction: the Etude Cas-Temoins sur l’Infarctus du Myocarde (ECTIM) Study. Am J Hypertens. 1999;12:304–310. doi: 10.1016/S0895-7061(98)00255-6. [PubMed] [Cross Ref]
61. Puffenberger EG, Hosoda K, Washington SS, et al. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell. 1994;79:1257–1266. doi: 10.1016/0092-8674(94)90016-7. [PubMed] [Cross Ref]
62. Osuga Y, Hayashi M, Kudo M, Conti M, Kobilka B, Hsueh AJ. Co-expression of defective luteinizing hormone receptor fragments partially reconstitutes ligand-induced signal generation. J Biol Chem. 1997;272:25006–25012. doi: 10.1074/jbc.272.40.25006. [PubMed] [Cross Ref]
63. Shenker A, Laue L, Kosugi S, Merendino JJ, Minegishi T, Cutler GB. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature. 1993;365:652–654. doi: 10.1038/365652a0. [PubMed] [Cross Ref]
64. Evans BA, Bowen DJ, Smith PJ, Clayton PE, Gregory JW. A new point mutation in the luteinising hormone receptor gene in familial and sporadic male limited precocious puberty: genotype does not always correlate with phenotype. J Med Genet. 1996;33:143–147. [PMC free article] [PubMed]
65. Gromoll J, Simoni M, Norhoff V, Behre HM, Geyter C, Nieschlag E. Functional and clinical consequences of mutations in the FSH receptor. Mol Cell Endocrin. 1996;125:177–182. doi: 10.1016/S0303-7207(96)03949-4. [PubMed] [Cross Ref]
66. Valverde P, Healy E, Jackson I, Rees JL, Thody AJ. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nature Gen. 1995;11:328–330. doi: 10.1038/ng1195-328. [PubMed] [Cross Ref]
67. Valverde P, Healy E, Sikkink S, et al. The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Hum Mol Gen. 1996;5:1665–1666. [PubMed]
68. Xu X, Thornwall M, Lundin LG, Chhajlani V. Val92Met variant of the melanocyte stimulating hormone receptor gene. Nat Genet. 1996;14:384–384. doi: 10.1038/ng1296-384. [PubMed] [Cross Ref]
69. Koppula SV, Robbins LS, Lu D, et al. Identification of a common polymorphism in the coding sequence of the human MSH receptor (MC1R) with possible biological effects. Hum Mutat. 1997;9:30–36. doi: 10.1002/(SICI)1098-1004(1997)9:1<30::AID-HUMU5>3.0.CO;2-T. [PubMed] [Cross Ref]
70. Vaisse C, Clement K, Durant E, Hercberg S, Guy-Grand B, Froguel P. Melanocortin-4 mutations are frequent and heterogeneous cause of morbid obesity. J Clin Invest. 2000;106:253–262. doi: 10.1172/JCI9238. [PMC free article] [PubMed] [Cross Ref]
71. Hinney A, Schmidt A, Nottebom K, et al. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly associated obesity in humans. J Clin Endocrinol Metab. 1999;84:1483–1486. doi: 10.1210/jc.84.4.1483. [PubMed] [Cross Ref]
72. Tsigos C, Arai K, Hung W, Chrousos GP. Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene. J Clin Invest. 1993;92:2458–2461. doi: 10.1172/JCI116853. [PMC free article] [PubMed] [Cross Ref]
73. Clark AJ, McLoughlin L, Grossman A. Familial glucocorticoid deficiency associated with point mutation in the adrenocorticoid receptor. Lancet. 1993;341:461–462. doi: 10.1016/0140-6736(93)90208-X. [PubMed] [Cross Ref]
74. Weber A, Kapas S, Hinson J, Grant DB, Grossman A, Clark AJ. Functional characterization of the cloned human ACTH receptor: impaired responsiveness of a mutant receptor in familial glucocorticoid deficiency. Biochem Biophys Res Comm. 1993;197:172–178. doi: 10.1006/bbrc.1993.2456. [PubMed] [Cross Ref]
75. Tsigos C, Arai K, Latronico AC, DiGeorge AM, Rapaport R, Chrousos GP. A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome. J Clin Endocrinol Metab. 1995;80:2186–2189. doi: 10.1210/jc.80.7.2186. [PubMed] [Cross Ref]
76. Reincke M, Mora P, Beuschlein F, Arlt W, Chrousos GP, Allolio B. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis. J Clin Endocrinol Metab. 1997;82:3054–3058. doi: 10.1210/jc.82.9.3054. [PubMed] [Cross Ref]
77. Schipani E, Kruse K, Juppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science. 1995;268:98–100. doi: 10.1126/science.7701349. [PubMed] [Cross Ref]
78. Schipani E, Langman CB, Parfitt AM, et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen’s metaphysical chondrodysplasia. N Engl J Med. 1996;335:708–714. doi: 10.1056/NEJM199609053351004. [PubMed] [Cross Ref]
79. Schipani E, Langman C, Hunzelman J, et al. A novel parathyroid hormone (PTH)/PTH-related peptide receptor mutation in Jansen’s metaphyseal chondrodysplasia. J Clin Endocrinol Metab. 1999;84:3052–3057. doi: 10.1210/jc.84.9.3052. [PubMed] [Cross Ref]
80. Karaplis AC, He B, Nguyen MT, et al. Inactivating mutation in the human parathyroid hormone receptor 1 gene in Blomstrand chondrodysplasia. Endocrinology. 1998;139:5255–5258. doi: 10.1210/en.139.12.5255. [PubMed] [Cross Ref]
81. Karperien M, Harten HJ, Schooten R, et al. A fiame-shift mutation in the type I parathyroid hormone (PTH)/PTH-related peptide receptor causing Blomstrand lethal osteochondrodysplasia. J Clin Endocrinol Metab. 1999;84:3713–3720. doi: 10.1210/jc.84.10.3713. [PubMed] [Cross Ref]
82. Jobert AS, Zhang P, Couvineau A, et al. Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand Chondrodysplasia. J Clin Invest. 1998;102:34–40. doi: 10.1172/JCI2918. [PMC free article] [PubMed] [Cross Ref]
83. Cuddihy RM, Dutton CM, Bahn RS. A polymorphism in the extracellular domain of the thyrotropin receptor is highly associated with autoimmune thyroid disease in females. Thyroid. 1995;5:89–95. [PubMed]
84. Cuddihy RM, Schaid DS, Bahn RS. Multivariate analysis of HLA loci in conjunction with a thyrotropin receptor codon 52 polymorphism in conferring risk of Graves’ disease. Thyroid. 1996;6:261–265. [PubMed]
85. Kaczur V, Szalai C, Falus A, Nagy Z, Krajczar G, Balazs C. Polymorphism of the 52 triplet gene (nucleotide 253) of the TSH receptor in Basedow-Graves patients and in healthy controls. Orv Hetil. 1997;138:1625–1628. [PubMed]
86. Gabriel EM, Bergert ER, Grant CS, Heerden JA, Thompson GB, Morris JC. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. J Clin Endocrinol Metab. 1999;84:3328–3335. doi: 10.1210/jc.84.9.3328. [PubMed] [Cross Ref]
87. Parma J, Duprez L, Sande J, Cochaux P, Gervy C, Mockel J, Dumont J, Vassart G. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature. 1993;365:649–651. doi: 10.1038/365649a0. [PubMed] [Cross Ref]
88. Rosenthal W, Seibold A, Antaramian A, et al. Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature. 1992;359:233–235. doi: 10.1038/359233a0. [PubMed] [Cross Ref]
89. Schoneberg T, Yun J, Wenkert D, Wess J. Functional rescue of mutant V2 vasopressin receptors causing nephrogenic diabetes insipidus by a co-expressed receptor polypeptide. EMBO J. 1996;15:1283–1291. [PubMed]
90. Birnbaumer M, Gilbert S, Rosenthal W. An extracellular congenital nephrogenic diabetes insipidus mutation of the vasopressin receptor reduces cell surface expression, affinity for ligand, and coupling to the Gs/adenylyl cyclase system. Mol Endocrin. 1994;8:886–894. doi: 10.1210/me.8.7.886. [PubMed] [Cross Ref]
91. Birnbaumer M, Gilbert S, Rosenthal W. Nephrogenic diabetes insipidus. A V2 vasopressin receptor unable to stimulate adenylyl cyclase. J Biol Chem. 1993;268:13030–13033. [PubMed]
92. Bond C, LaForge KS, Tian M, Melia D, Zhang S, et al. Single-nucleotide polymorphism in the human μ opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Nat Acad Sci U S A. 1998;95:9608–9613. doi: 10.1073/pnas.95.16.9608. [PubMed] [Cross Ref]
93. Sander T, Berlin W, Gscheidel N, Wendel B, Janz D, Hoehe MR. Genetic variation of the human μ-opioid receptor and susceptibility to idiopathic absence epilepsy. Epilepsy Res. 2000;39:57–61. doi: 10.1016/S0920-1211(99)00109-6. [PubMed] [Cross Ref]
93a. Single nucleotide polymorphisms in the human μ opioid receptor gene alter G protein coupling and calmodulin binding. Wang D, Quillan JM, Winans K, Lucas JL, Sadee W. J. Biol. Chem., 2001, in press. [PubMed]
94. Koch T, Kroslak T, Mayer P, Raulf E, Hoellt V. Site mutation in the rat μ-opioid receptor demonstrates the involvement of calcium/calmodulin-dependent protein kinase II in agonist-mediated desensitization. J Neurochem. 1997;69:1767–1770. [PubMed]
95. Befort K, Filliol D, Decaillot FM, Gaveriaux-Ruff C, Hoehe MR, Kieffer BL. A single nucleotide polymorphic mutation in the human μ-opioid receptor severely impairs receptor signaling. J Biol Chem. 2001;276:3130–3137. doi: 10.1074/jbc.M006352200. [PubMed] [Cross Ref]
96. Hoehe J, Koepke K, Wendel B, et al. Sequence variability and candidate gene analysis in complex disease: association of μ opioid receptor gene variation with substance dependence. Human Mol Gen. 2000;9:2895–2908. doi: 10.1093/hmg/9.19.2895. [PubMed] [Cross Ref]
97. Mayer P, Rochlitz H, Rauch E, et al. Association between d-opioidreceptor gene polymorphism and heroin dependence in man. Neuroreport. 1997;8:2547–2550. doi: 10.1097/00001756-199707280-00025. [PubMed] [Cross Ref]
98. Franke P, Nothen M, Wang T, et al. Human d-opioidreceptor gene and susceptibility to heroin and alcohol dependence. Am J Med Genet. 1999;88:462–464. doi: 10.1002/(SICI)1096-8628(19991015)88:5<462::AID-AJMG4>3.0.CO;2-S. [PubMed] [Cross Ref]
99. compton SJ, Cairns JA, Palmer KJ, Al-Ani B, Hollenberg MD, Walls AF. A polymorphic protease-activated receptor 2 (PAR2) displaying reduced sensitivity to trypsin and differential responses to PAR agonists. J Biol Chem. 2000;275:39207–39212. doi: 10.1074/jbc.M007215200. [PubMed] [Cross Ref]
100. Gwinn MR, Sharma A, Nardin E. Single nucleotide polymorphisms of the N-formyl peptide receptor in localized juvenile periodontitis. J Periodontol. 1999;70:1194–1201. doi: 10.1902/jop.1999.70.10.1194. [PubMed] [Cross Ref]
101. Smith MV, Dean M, Carrington M, et al. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Science. 1997;277:959–965. doi: 10.1126/science.277.5328.959. [PubMed] [Cross Ref]
102. O’Brien TR, McDermott DH, Ioannidis JP, et al. Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy. AIDS. 2000;14:821–826. doi: 10.1097/00002030-200005050-00008. [PubMed] [Cross Ref]
103. Hizawa N, Yamaguchi E, Furuya K, Jinushi E, Ito A, Kawakami Y. The role of the C-C chemokine receptor 2 gene polymorphism V64I (CCR2-64I) in sarcoidosis in a Japanese population. Am J Respir Crit Care Med. 1999;159:2021–2023. [PubMed]
104. Mellado M, Rodriguez-Frade JM, Vila-Coro AJ, Ana AM, Martinez-A C. Chemokine control of HIV-1 infection. Nature. 1999;400:723–724. doi: 10.1038/23382. [PubMed] [Cross Ref]
105. Szalai C, Csaszar A, Czinner A, Szabo T, Panczel P, Madacsy L, Falus A. Chemokine receptor CCR2 and CCR5 polymorphisms in children with insulin-dependent diabetes mellitus. Pediatr Res. 1999;46:82–84. doi: 10.1203/00006450-199907000-00014. [PubMed] [Cross Ref]
106. Zimmermann N, Bernstein JA, Rothenberg ME. Polymorphisms in the human CC chemokine receptor-3 gene. Biochim Biophys Acta. 1998;1442:170–6107. [PubMed]
107. Bream JH, Young HA, Rice N, et al. CCR5 promoter alleles and specific DNA binding factors. Science. 1999;284:223a–223a. doi: 10.1126/science.284.5412.223a. [PubMed] [Cross Ref]
108. Martin MP, Dean M, Smith MW, et al. Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science. 1998;282:1907–1910. doi: 10.1126/science.282.5395.1907. [PubMed] [Cross Ref]
109. McDermott DH, Zimmermann PA, Guignard F, Kleeberger CA, Leitman SF, the Multicenter AIDS Cohort Study (MACS) Murphy PM. CCR5 promoter polymorphism and HIV-1 disease progression. Lancet. 1998;352:866–870. doi: 10.1016/S0140-6736(98)04158-0. [PubMed] [Cross Ref]
110. Samson M, Libert F, Doranz BJ, et al. Resistance to HIV infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996;382:722–725. doi: 10.1038/382722a0. [PubMed] [Cross Ref]
111. Rabkin CS, Yang Q, Goedert JJ, Nguyen G, Mitsuya H, Sei S. Chemokine and chemokine receptor gene variants and risk of non-Hodgkin’s lymphoma in human immunodeficiency virus-1-infected individuals. Blood. 1999;93:1838–1842. [PubMed]
112. Faure S, Meyer L, Costagliola D, et al. Rapid progression to AIDS in HIV—individuals with a structural variant of the chemokine receptor CX3CR1. Science. 2000;287:2274–2277. doi: 10.1126/science.287.5461.2274. [PubMed] [Cross Ref]
113. Birkenbach M, Josefsen Kyalamanchili R, Lenoir G, Kieff E. Epstein-Barr virus induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J Virol. 1993;67:2209–2220. [PMC free article] [PubMed]
114. Gao JL, Murphy PM. Human cytomegalovirus open reading frame US28 encodes a functional b-chemokine receptor. J Biol Chem. 1994;269:28539–28542. [PubMed]
115. Pleskoff O, Treboute C, Brelot A, Heveker N, Seman M, Alozon M. Identification of a chemokine receptor encode by human cytomegalovirus as a cofactor for HIV-1 entry. Science. 1997;276:1874–1878. doi: 10.1126/science.276.5320.1874. [PubMed] [Cross Ref]
116. Bais C, Santomasso B, Coso O, et al. G protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature. 1998;391:86–89. doi: 10.1038/34193. [PubMed] [Cross Ref]
117. Lam CW, Xie J, To KF, et al. A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene. 1999;18:833–836. doi: 10.1038/sj.onc.1202360. [PubMed] [Cross Ref]
118. Xie J, Murone M, Luoh SM, et al. Activating smoothened mutations in sporadic basal cell carcinma. Nature. 1998;391:90–92. doi: 10.1038/34201. [PubMed] [Cross Ref]
119. Talpale J, Chen JK, Cooper MK, et al. Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature. 2000;406:1005–1009. doi: 10.1038/35023008. [PubMed] [Cross Ref]
120. Hirata T, Kakizuka A, Ushikubi F, Fuse I, Okuma M, Narumiya S. Arg60-to-leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder. J Clin Invest. 1994;94:1662–1667. doi: 10.1172/JCI117510. [PMC free article] [PubMed] [Cross Ref]
121. Hirata T, Ushikubi F, Kakizuka A, Okuma M, Narumiya S. Two thromboxane A(2) receptor isoforms in human platelets: opposite coupling to adenylyl cyclase with different sensitivity to arg60-to-leu mutation. J Clin Invest. 1996;97:949–956. doi: 10.1172/JCI118518. [PMC free article] [PubMed] [Cross Ref]
122. Hollopeter G, Jantzen H-M, Vincent D, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 2001;409:202–207. doi: 10.1038/35051599. [PubMed] [Cross Ref]
123. Ward BK, Stuckey BG, Gutteridge DH, Laing NG, Pullan PT, Ratajczak T. A novel mutation (L174R) in the Ca2+-sensing receptor gene associated with familial hypocalciuric hypercalcemia. Hum Mutat. 1997;10:233–235. doi: 10.1002/(SICI)1098-1004(1997)10:3<233::AID-HUMU9>3.0.CO;2-J. [PubMed] [Cross Ref]
124. Aida K, Koishi S, Inoue M, Nakazato M, Tawata M, Onaya T. Familial hypocalciuric hypercalcemia associated with mutation in the human Ca (2+)-sensing receptor gene. J Clin Endocrinol Metab. 1995;80:2594–2598. doi: 10.1210/jc.80.9.2594. [PubMed] [Cross Ref]
125. Chou Yh, Pollak MR, Brandi ML, et al. Mutations in the human Ca (2+)-sensing receptor gene that cause familial hypocalciuric hypercalcemia. Am J Hum Genet. 1995;56:1075–1079. [PubMed]
126. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciurie hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993;75:1297–1303. doi: 10.1016/0092-8674(93)90617-Y. [PubMed] [Cross Ref]
127. Pollak MR, Brown EM, Estep HL, et al. Autosomal dominant hypocalcemia caused by a Ca (2+)-sensing receptor gene mutation. Nat Genet. 1994;8:303–307. doi: 10.1038/ng1194-303. [PubMed] [Cross Ref]
128. Pearce SH, Williamson C, Kifor O, et al. A familial syndrome of hypocalcemia with hypocalciuria due to mutations in the calcium-sensing receptor. N Engl J Med. 1996;335:1115–1122. doi: 10.1056/NEJM199610103351505. [PubMed] [Cross Ref]
129. Rao VR, Cohen GB, Oprian DD. Rhodopsin mutation G90D and a molecular mechanism for congenital night blindness. Nature. 1994;367:639–642. doi: 10.1038/367639a0. [PubMed] [Cross Ref]
130. Dryja TP, Berson EL, Rao VR, Oprian DD. Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. Nat Genet. 1993;4:280–283. doi: 10.1038/ng0793-280. [PubMed] [Cross Ref]
131. Robinson PR, Cohen GB, Zhukovsky EA, Oprian DD. Constitutively active mutants of rhodopsin. Neuron. 1992;9:719–725. doi: 10.1016/0896-6273(92)90034-B. [PubMed] [Cross Ref]
132. Robinson PR, Cohen GB, Zhukovsky EA, Oprian DD. Constitutive activation of opsin: influence of charge at position 134 and size at position 296. Biochemistry. 1993;32:6111–6115. doi: 10.1021/bi00065a016. [PubMed] [Cross Ref]
133. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291:1304–1350. doi: 10.1126/science.1058040. [PubMed] [Cross Ref]
134. Lander ES, Linton LM, Birren B, et al. International sequencing consortium. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921. doi: 10.1038/35057062. [PubMed] [Cross Ref]
135. Graul RC, Sadee W. Evolutionary relationships among G protein-coupled receptors using a clustered database approach. AAPS PharmSci. 2001; 2001; 3 (2) article 12 (http://www.pharmsci.org/scientificjournals/pharmsci/journal/01_12.html). [PMC free article] [PubMed]
136. Namba T, Sugimoto Y, Negishi M, et al. Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity. Nature. 1993;365:166–169. doi: 10.1038/365166a0. [PubMed] [Cross Ref]
137. Gudermann T, Kalkbrenner F, Schultz G. Diversity and selectivity of receptor-G protein interaction. Ann Rev Pharmacol Toxicol. 1996;36:429–459. [PubMed]
138. Migeon JC, Nathanson NM. Differential regulation of cAMP-mediated gene transcription by m1 and m4 muscarinic acetylcholine receptors. J Biol Chem. 1994;269:9767–9773. [PubMed]
139. Moro O, Lameh J, Högger P, Sadee W. Hydrophobic amino acid in the il loop plays a key role in receptor-G protein coupling. J Biol Chem. 1993;268:22273–22276. [PubMed]
140. Moro O, Shockley MS, Lameh J, Sadee W. Overlapping multisite domains of the muscarinic cholinergic Hm1 receptor involved in signal transduction and sequestration. J Biol Chem. 1994;269:6651–6655. [PubMed]
141. Burstein ES, Spalding TA, Brann MR. The second intracellular loop of the m5 muscarinic receptor is the switch which enables G-protein coupling. J Biol Chem. 1998;273:24322–24327. doi: 10.1074/jbc.273.38.24322. [PubMed] [Cross Ref]
142. Heuss C, Gerber U. G-protein-independent signaling by G-protein-coupled receptors. TiNS. 2000;23:469–475. [PubMed]
143. Wang D, Sadee W, Quillan JM. Calmodulin binding to G protein-coupling domain of opioid receptors. J Biol Chem. 1999;274:22081–22088. doi: 10.1074/jbc.274.31.22081. [PubMed] [Cross Ref]
144. Wang D, Surratt CK, Sadee W. Calmodulin regulation of basal and agonist-stimulated G protein coupling by μ opioid receptors (OP3) in morphine pretreated cells. J Neurochem. 2000;75:763–771. doi: 10.1046/j.1471-4159.2000.0750763.x. [PubMed] [Cross Ref]
145. Wang D, Tolbert LM, Carlson KW, Sadee W. Nuclear Ca2+/calmodulin translocation activated by μ opioid (OP3) receptor. J Neurochem. 2000;74:1418–1425. doi: 10.1046/j.1471-4159.2000.0741418.x. [PubMed] [Cross Ref]
146. Coughlin SR. Expanding horizons for receptors coupled to G proteins: diversity and disease. Curr Op Cell Biol. 1994;6:191–197. doi: 10.1016/0955-0674(94)90135-X. [PubMed] [Cross Ref]
147. Felder CB, Graul RC, Lee AY, Merkle HP, Sadee W. Venus flytrap of periplasmic binding proteins: an ancient protein module present in multiple drug receptors. AAPS PharmSci. 1999;1(2): article 2 http://www.pharmsci.org/scientificjournals/pharmsci/journal/venus/index.html. [PMC free article] [PubMed]
148. Chen J, Ishii M, Wang L, Ishii K, Coughlin SR. Thrombin receptor activation. Confirmation of the intramolecular tethered liganding hypothesis and discovery of an alternative intermolecular liganding mode. J Biol Chem. 1994;269:16041–16045. [PubMed]
149. Law PY, Wong YH, Loh HH. Mutational analysis of the structure and function of opioid receptors. Biopolymers. 1999;51:440–455. doi: 10.1002/(SICI)1097-0282(1999)51:6<440::AID-BIP6>3.0.CO;2-T. [PubMed] [Cross Ref]
150. Befort K, Tabbara L, Kling D, Maigret B, Kieffer BL. Role of aromatic transmembrane residues of the delta-opioid receptor in ligand recognition. J Biol Chem. 1996;271:10161–10168. doi: 10.1074/jbc.271.17.10161. [PubMed] [Cross Ref]
151. Lefkowitz RJ, Cotecchia S, Samama P, Costa T. Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. TiPS. 1993;14:303–307. [PubMed]
152. Leff P. The two-state model of receptor activation. TiPS. 1995;16:89–97. [PubMed]
153. Milligan P, Bond RA. Inverse agonism and the regulation of receptor number. TiPS. 1997;18:468–474. [PubMed]
154. Chidiac P, Hebert TE, Valiquette M, Dennis M, Bouvier M. Inverse agonist activity of beta-adrenergic antagonists. Mol Pharmacol. 1994;45:490–499. [PubMed]
155. Barker EL, Westphal RS, Schmidt D, Sanders-Bush E. Constitutively active 5-hydroxytryptamine2C receptors reveal novel inverse agonist activity of receptor ligands. J Biol Chem. 1994;269:11687–11690. [PubMed]
156. Brys R, Josson K, Castelli MP, et al. Reconstituting the human 5-HT1D receptor-G protein coupling: evidence for constitutive activity and multiple receptor conformations. Mol Pharmacol. 2000;57:1132–1141. [PubMed]
157. Leeb-Lundberg LM, Mathis SA, Herzig MC. Antagonists of bradykinin that stabilize a G-protein-uncoupled state of the B2 receptor act as inverse agonists in rat myometrial cells. J Biol Chem. 1994;269:25970–25973. [PubMed]
158. Costa T, Herz A. Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins. Proc Natl Acad Sci U S A. 1989;86:7321–7325. doi: 10.1073/pnas.86.19.7321. [PubMed] [Cross Ref]
159. Jakubik J, Bacakova L, el-Fakahany EE, Tucek S. Constitutive activity of the M1–M4 subtypes of muscarinic receptors in transfected CHO cells and of muscarinic receptors in the heart cells revealed by negative antagonists. FEBS Lett. 1995;377:275–279. doi: 10.1016/0014-5793(95)01360-1. [PubMed] [Cross Ref]
160. Burford NT, Wang D, Sadee W. G protein coupling of μopioid receptors (OP3): elevated basal signaling activity. Biochem J. 2000;348:531–537. doi: 10.1042/0264-6021:3480531. [PubMed] [Cross Ref]
161. Wang Z, Bilsky EJ, Porreca F, Sadee W. Constitutive μ receptor activation as a regulatory mechanism underlying narcotic tolerance and dependence. Life Sci. 1994;54:339–350. [PubMed]
162. Högger P, Shockley MS, Lameh J, Sadee W. Activating and inactivating mutations in N- and C-terminal loop junctions of muscarinic acetylcholine Hm1 receptors. J Biol Chem. 1995;270:7405–7410. doi: 10.1074/jbc.270.13.7405. [PubMed] [Cross Ref]
163. Rao VR, Oprian DD. Activating mutations of rhodopsin and other G protein-coupled receptors. Ann Rev Biophys Biomol Struct. 1996;25:287–314. [PubMed]
164. Claeysen S, Sebben M, Becamel C, et al. Pharmacological properties of 5-hydroxytryptamine(4) receptor antagonists on constitutively active wild-type and mutated receptors. Mol Pharmacol. 2000;58:136–144. [PubMed]
165. Wang D, Raehal KM, Bilsky EJ, Sadee W. Inverse agonists and neutral antagonists at μ opioid receptor (MOR): possible role of basal receptor signaling in narcotic dependence. J Neurochem. 2001;77:1590–1600. doi: 10.1046/j.1471-4159.2001.00362.x. [PubMed] [Cross Ref]
166. Allen LF, Lefkowitz RJ, Caron MG, Cotecchia S. G-protein-coupled receptor genes as protooncogenes: constitutively activating mutations of the al B-adrenergic receptor enhances mitogenesis and tumorigenicity. Proc Natl Acad Sci U S A. 1991;88:11354–11358. doi: 10.1073/pnas.88.24.11354. [PubMed] [Cross Ref]
167. Robb S, Cheek TR, Hannan FL, Hall LM, Midgley JM, Evans PD. Agonist-specific coupling of a cloned Drosophila octopamine/tyramine receptor to multiple second messenger systems. EMBO J. 1994;13:1325–1330. [PubMed]
168. Perez DM, Hwa J, Gaivin R, Mathur M, Brown F, Graham RM. Constitutive activation of a single effector pathway: evidence for multiple activation states of a G protein-coupled receptor. Mol Pharmacol. 1996;49:112–122. [PubMed]
169. Houston DB, Howlett AC. Differential receptor-G protein coupling evoked by dissimilar cannabinoid receptor agonists. Cell Signal. 1998;10:667–674. doi: 10.1016/S0898-6568(98)00013-8. [PubMed] [Cross Ref]
170. Arden JR, Segredo V, Wang Z, Lameh J, Sadee W. Phosphorylation and agonist specific intracellular trafficking of an epitope-tagged μ opioid receptor expressed in HEK293 cells. J Neurochem. 1995;65:1636–1641. [PubMed]
171. Keith DE, Murray SR, Zaki PA, et al. Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem. 1996;271:19021–19024. doi: 10.1074/jbc.271.46.29279. [PubMed] [Cross Ref]
172. Thomas WG, Alan H, Chang C-S, Karnik S. Agonist induced phosphorylation of the angiotensin II (AT1A) receptor requires generation of a conformation that is distinct from the inositol phosphate signaling state. J Biol Chem. 2000;275:2893–2900. doi: 10.1074/jbc.275.4.2893. [PubMed] [Cross Ref]
173. Standifer KM, Clark JA, Pasternak GW. Modulation of μ1 opioid binding by magnesium: evidence for multiple receptor conformations. J Pharmacol Exp Ther. 1993;266:106–1. [PubMed]
174. Wreggett KA, Wells JW. Cooperativity in the binding properties of purified cardiac muscarinic receptors. J Biol Chem. 1995;270:22499–22499. [PubMed]
175. Ostrom RS, Post SR, Insel PA. Stoichiometry and compartmentation in G protein-coupled receptor signaling: implications for therapeutic interventions involving Gs. J Pharmacol Exp Ther. 2000;294:407–4. [PubMed]
176. Rodbell M. The role of GTP-binding proteins in signal transduction: from the sublimely simple to the conceptually complex. Curr Top Cell Regul. 1992;32:1–47. [PubMed]
177. Jordan BA, Devi LA. G-protein-coupled receptor heterodimerization modulates receptor function. Nature. 1999;399:697–700. doi: 10.1038/21441. [PMC free article] [PubMed] [Cross Ref]
178. George SR, Fan T, Xie Z, et al. Oligomerization of μ and d-opioidreceptors. Generation of novel functional properties. J Biol Chem. 2000;275:26128–26135. doi: 10.1074/jbc.M000345200. [PubMed] [Cross Ref]
179. Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Pate YC. Recpetors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science. 2000;288:154–157. doi: 10.1126/science.288.5463.154. [PubMed] [Cross Ref]
180. Jones KA, Borowsky B, Tamm JA, et al. GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2. Nature. 1998;396:674–679. doi: 10.1038/25348. [PubMed] [Cross Ref]
181. Liu F, Wan Q, Pristupa ZD, Yu XM, Wang YT, Niznik HB. Direct protein-protein coupling enables cross-talk between dopamine D5 and? acid A receptors. Nature. 2000;403:274–280. doi: 10.1038/35001232. [PubMed] [Cross Ref]
182. Shenker A. G protein-coupled receptor structure and function: the impact of disease-causing mutations. Baillieres Clin Endocrinol Metab. 1995;9:427–451. doi: 10.1016/S0950-351X(95)80519-2. [PubMed] [Cross Ref]
183. Spiegel AM. Defects in G protein-coupled signal transduction in human disease. Annu Rev Physiol. 1996;58:143–170. doi: 10.1146/annurev.ph.58.030196.001043. [PubMed] [Cross Ref]
184. Kamsteeg EJ, Deen PM, Os CH. Defective processing and trafficking of water channels in nephrogenic diabetes insipidus. Exp Nephrol. 2000;8:326–331. doi: 10.1159/000020686. [PubMed] [Cross Ref]
185. Kopin AS, McBride EW, Schaffer K, Beinborn M. CCK receptor polymorphisms: an illustration of emerging themes in pharmacogenomics. TiPS. 2002;21:346–353. [PubMed]
186. Feng Y, Broder CC, Kennedy PA, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996;272:872–877. doi: 10.1126/science.272.5263.872. [PubMed] [Cross Ref]
187. Alkhatib G, Combadiere C, Broder CC, et al. CC CKR5: A RANTES, MIP-1aa, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996;272:1955–1958. doi: 10.1126/science.272.5270.1955. [PubMed] [Cross Ref]
188. Bleul CC, Farzan M, Choe H, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV entry. Nature. 1996;382:829–833. doi: 10.1038/382829a0. [PubMed] [Cross Ref]
189. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1aa, and MIP-1β as the major HIV-suppressive factors produced by CD8+T cells. Science. 1995;270:1811–1815. doi: 10.1126/science.270.5243.1811. [PubMed] [Cross Ref]
190. Moore PS, Boshoff C, Weiss RA, Chang Y. Molecular minicry of human cytokine and cytokine response pathway genes by KSWHV. Science. 1996;274:1739–1743. doi: 10.1126/science.274.5293.1739. [PubMed] [Cross Ref]
191. Quillan JM, Sadee W. Dynorphin peptides: antagonists at melanocortin receptors. Pharm Res. 1997;14:713–719. doi: 10.1023/A:1012185919153. [PubMed] [Cross Ref]
192. Pickar D. Pharmacogenomics of psychiatric disorders. TiPS. 2001;22:75–83. [PubMed]
193. Lahti RA, Evans DL, Stratman NC, Figur LM. Dopamine D4 versus D2 receptor selectivity of dopamine receptor antagonists: possible therapeutic implications. Eur J Pharmacol. 1993;236:483–486. doi: 10.1016/0014-2999(93)90488-4. [PubMed] [Cross Ref]
194. Phillips ST, Paulis T, Baron BM, et al. Binding of 5H-dibenzo[b,e][1.4]diazepine and chiral 5Hdibenzo[a,d]cycloheptene analogues of clozapine to dopamine and serotonin receptors. J Med Chem. 1994;37:2686–2696. doi: 10.1021/jm00043a008. [PubMed] [Cross Ref]
195. Olianas MC, Maullu C, Onali P. Mixed agonist-antagonist properties of clozapine at different human cloned muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Neuropsychopharmacology. 1999;20:263–270. doi: 10.1016/S0893-133X(98)00048-7. [PubMed] [Cross Ref]
196. Korpi ER, Wong G, Lueddens H. Subtype specificity of gamma-aminobutyric acid type A receptor antagonism by clozapine. NS Arch Pharmacol. 1995;352:365–373. [PubMed]
197. Gelernter J, Kranzler H, Cubells J. Genetics of two μopioid receptor gene (OPRM1) exon I polymorphisms: population studies and allele frequencies in alcohol- and drug-dependent subjects. Mol Psychiatr. 1999;4:476–483. doi: 10.1038/sj.mp.4000556. [PubMed] [Cross Ref]
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