Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics

Pharmacology and Therapeutics

Volumn 120, Issue 2, 2008, Pages 129-148

  Tao, Ya Xiong ^a  

^a AUBURN UNIVERSITY   (United States)

Author keywords

Constitutively active mutation; Disease; G protein coupled receptor; Inverse agonist; Mechanism of activation; Transgenic model

Indexed keywords

1 [2 [(3 DIMETHYLAMINOPROPIONYL)AMINO 2 METHYLPROPYL] 6 METHYLPHENYL] 4 [METHYL 3 (4 CHLOROPHENYL)PROPIONYL]PIPERAZINE; 11 CIS RETINAL; AGOUTI RELATED PROTEIN; ALPRENOLOL; AMINE; ANASTROZOLE; ANTIANDROGEN; AROMATASE INHIBITOR; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; BICALUTAMIDE; BISOPROLOL; CETIRIZINE; CYPROTERONE ACETATE; CYTOCHROME P450 INHIBITOR; G PROTEIN COUPLED RECEPTOR; KETOCONAZOLE; LORATADINE; MELANOCORTIN 4 RECEPTOR; MELANOCORTIN 4 RECEPTOR ANTAGONIST; METOPROLOL; MUTANT PROTEIN; N ACETYL ALPHA INTERMEDIN[4-10]CYCLO[4 NORLEUCINE 5 ASPARTIC ACID 7 [3 (2 NAPHTHYL)ALANINE] 10 LYSINAMIDE]; NBI 12I; PINDOLOL; PROPRANOLOL; RHODOPSIN; SUBSTANCE P DERIVATIVE; TESTOLACTONE; TIMOLOL; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANGINA PECTORIS; ANOREXIA; CONGENITAL DISORDER; CRYSTAL STRUCTURE; DISEASE MODEL; DRUG EFFECT; ENDOCRINE DISEASE; GENETIC DISORDER; HEART ARRHYTHMIA; HUMAN; HYPERTENSION; ISCHEMIC HEART DISEASE; NONHUMAN; OVARY HYPERSTIMULATION; PATHOGENESIS; PHYSICAL DISEASE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; STRUCTURE ANALYSIS;

ANIMALS; DISEASE MODELS, ANIMAL; DRUG INVERSE AGONISM; HUMANS; MUTATION; RECEPTORS, G-PROTEIN-COUPLED; RHODOPSIN; SEQUENCE HOMOLOGY, AMINO ACID; STRUCTURAL HOMOLOGY, PROTEIN;

EID: 53949092147     PISSN: 01637258     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2008.07.005     Document Type: Review

References (301)

1. Adan R.A. Constitutive receptor activity series: endogenous inverse agonists and constitutive receptor activity in the melanocortin system. Trends Pharmacol Sci 27 (2006) 183-186
2. Adan R.A., and Kas M.J. Inverse agonism gains weight. Trends Pharmacol Sci 24 (2003) 315-321
3. Akcurin, S., Turkkahraman, D., Tysoe, C., Ellard, S., De Leener, A., Vassart, G., et al.(in press). A family with a novel TSH receptor activating germline mutation (p.Ala485Val). Eur J Pediatr.
4. al-Jandal N., Farrar G.J., Kiang A.S., Humphries M.M., Bannon N., Findlay J.B., et al. A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness. Hum Mutat 13 (1999) 75-81
5. Alberti L., Proverbio M.C., Costagliola S., Weber G., Beck-Peccoz P., Chiumello G., et al. A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism. Eur J Endocrinol 145 (2001) 249-254
6. Allan C.M., Garcia A., Spaliviero J., Jimenez M., and Handelsman D.J. Maintenance of spermatogenesis by the activated human (Asp567Gly) FSH receptor during testicular regression due to hormonal withdrawal. Biol Reprod 74 (2006) 938-944
7. Allan C.M., Garcia A., Spaliviero J., Zhang F.P., Jimenez M., Huhtaniemi I., et al. Complete Sertoli cell proliferation induced by follicle-stimulating hormone (FSH) independently of luteinizing hormone activity: evidence from genetic models of isolated FSH action. Endocrinology 145 (2004) 1587-1593
8. Almeida M.Q., Brito V.N., Lins T.S., Guerra-Junior G., de Castro M., Antonini S.R., et al. Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole. Clin Endocrinol 69 (2008) 93-98
9. Angelova K., Fanelli F., and Puett D. A model for constitutive lutropin receptor activation based on molecular simulation and engineered mutations in transmembrane helices 6 and 7. J Biol Chem 277 (2002) 32202-32213
10. Angelova K., Narayan P., Simon J.P., and Puett D. Functional role of transmembrane helix 7 in the activation of the heptahelical lutropin receptor. Mol Endocrinol 14 (2000) 459-471
11. Arseven O.K., Wilkes W.P., Jameson J.L., and Kopp P. Substitutions of tyrosine 601 in the human thyrotropin receptor result in increase or loss of basal activation of the cyclic adenosine monophosphate pathway and disrupt coupling to Gq/11. Thyroid 10 (2000) 3-10
12. Arturi F., Scarpelli D., Coco A., Sacco R., Bruno R., Filetti S., et al. Thyrotropin receptor mutations and thyroid hyperfunctioning adenomas ten years after their first discovery: unresolved questions. Thyroid 13 (2003) 341-343
13. Arvanitakis L., Geras-Raaka E., and Gershengorn M.C. Constitutively signaling G-protein-coupled receptors and human disease. Trends Endocrinol Metab 9 (1998) 27-31
14. Ascoli M. Potential Leydig cell mitogenic signals generated by the wild-type and constitutively active mutants of the lutropin/choriogonadotropin receptor (LHR). Mol Cell Endocrinol 260-262 (2007) 244-248
15. Ascoli M., Fanelli F., and Segaloff D.L. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 23 (2002) 141-174
16. Baessler A., Hasinoff M.J., Fischer M., Reinhard W., Sonnenberg G.E., Olivier M., et al. Genetic linkage and association of the growth hormone secretagogue receptor (ghrelin receptor) gene in human obesity. Diabetes 54 (2005) 259-267
17. 2-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6. J Biol Chem 276 (2001) 29171-29177
18. Ballesteros J.A., and Weinstein H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci (1995) 366-428
19. Baranski T.J., Herzmark P., Lichtarge O., Gerber B.O., Trueheart J., Meng E.C., et al. C5a receptor activation: genetic identification of critical residues in four transmembrane helices. J Biol Chem 274 (1999) 15757-15765
20. 2+-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. Hum Mol Genet 5 (1996) 601-606
21. Bastepe M., Raas-Rothschild A., Silver J., Weissman I., Wientroub S., Juppner H., et al. A form of Jansen's metaphyseal chondrodysplasia with limited metabolic and skeletal abnormalities is caused by a novel activating parathyroid hormone (PTH)/PTH-related peptide receptor mutation. J Clin Endocrinol Metab 89 (2004) 3595-3600
22. Biebermann H., Schoneberg T., Hess C., Germak J., Gudermann T., and Gruters A. The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism. J Clin Endocrinol Metab 86 (2001) 4429-4433
23. Biebermann H., Schoneberg T., Krude H., Gudermann T., and Gruters A. Constitutively activating TSH-receptor mutations as a molecular cause of non-autoimmune hyperthyroidism in childhood. Langenbecks Arch Surg 385 (2000) 390-392
24. Blakeney J.S., Reid R.C., Le G.T., and Fairlie D.P. Nonpeptidic ligands for peptide-activated G protein-coupled receptors. Chem Rev 107 (2007) 2960-3041
25. Bockaert J., and Pin J.P. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 18 (1999) 1723-1729
26. Bowers C.Y. Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci 54 (1998) 1316-1329
27. Calvi L.M., Sims N.A., Hunzelman J.L., Knight M.C., Giovannetti A., Saxton J.M., et al. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest 107 (2001) 277-286
28. Camacho P., Gordon D., Chiefari E., Yong S., DeJong S., Pitale S., et al. A Phe 486 thyrotropin receptor mutation in an autonomously functioning follicular carcinoma that was causing hyperthyroidism. Thyroid 10 (2000) 1009-1012
29. Canto P., Soderlund D., Ramon G., Nishimura E., and Mendez J.P. Mutational analysis of the luteinizing hormone receptor gene in two individuals with Leydig cell tumors. Am J Med Genet 108 (2002) 148-152
30. 2-adrendergic receptor: reconstitution of functional interactions between pure receptor and pure stimulatory nucleotide binding protein of the adenylate cyclase system. Biochemistry 23 (1984) 4519-4525
31. 2-adrenergic receptor confer spontaneous activity of the receptor. Mol Pharmacol 64 (2003) 1048-1058
32. Chan C.B., Leung P.K., Wise H., and Cheng C.H. Signal transduction mechanism of the seabream growth hormone secretagogue receptor. FEBS Lett 577 (2004) 147-153
33. Chen C., Jiang W., Tucci F., Tran J.A., Fleck B.A., Hoare S.R., et al. Discovery of 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-4-methylpheny l]-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia. J Med Chem 50 (2007) 5249-5252
34. 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 β2-adrenergic G protein-coupled receptor. Science 318 (2007) 1258-1265
35. Cheung W., Yu P.X., Little B.M., Cone R.D., Marks D.L., and Mak R.H. Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest 115 (2005) 1659-1665
36. Costa T., and Cotecchia S. Historical review: negative efficacy and the constitutive activity of G-protein-coupled receptors. Trends Pharmacol Sci 26 (2005) 618-624
37. Costa T., and Herz A. Antagonists with negative intrinsic activity at δ opioid receptors coupled to GTP-binding proteins. Proc Natl Acad Sci U S A 86 (1989) 7321-7325
38. Cotecchia S., Exum S., Caron M.G., and Lefkowitz R.J. Regions of the α1-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function. Proc Natl Acad Sci U S A 87 (1990) 2896-2900
39. Cummings D.E., Purnell J.Q., Frayo R.S., Schmidova K., Wisse B.E., and Weigle D.S. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50 (2001) 1714-1719
40. Davenport A.P., Bonner T.I., Foord S.M., Harmar A.J., Neubig R.R., Pin J.P., et al. International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev 57 (2005) 541-546
41. Davies E., Bonnardeaux A., Plouin P.F., Corvol P., and Clauser E. Somatic mutations of the angiotensin II (AT1) receptor gene are not present in aldosterone-producing adenoma. J Clin Endocrinol Metab 82 (1997) 611-615
42. Davies T.F., Ando T., Lin R.Y., Tomer Y., and Latif R. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest 115 (2005) 1972-1983
43. De Leener A., Caltabiano G., Erkan S., Idil M., Vassart G., Pardo L., et al. Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome. Hum Mutat 29 (2008) 91-98
44. De Leener A., Montanelli L., Van Durme J., Chae H., Smits G., Vassart G., et al. Presence and absence of follicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology. J Clin Endocrinol Metab 91 (2006) 555-562
45. de Roux N., Polak M., Couet J., Leger J., Czernichow P., Milgrom E., et al. A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. J Clin Endocrinol Metab 81 (1996) 2023-2026
46. Deboer M.D., and Marks D.L. Cachexia: lessons from melanocortin antagonism. Trends Endocrinol Metab 17 (2006) 199-204
47. DeBoer M.D., and Marks D.L. Therapy insight: use of melanocortin antagonists in the treatment of cachexia in chronic disease. Nat Clin Pract Endocrinol Metab 2 (2006) 459-466
48. Delbaere A., Smits G., De Leener A., Costagliola S., and Vassart G. Understanding ovarian hyperstimulation syndrome. Endocrine 26 (2005) 285-290
49. Demange L., Boeglin D., Moulin A., Mousseaux D., Ryan J., Berge G., et al. Synthesis and pharmacological in vitro and in vivo evaluations of novel triazole derivatives as ligands of the ghrelin receptor. 1. J Med Chem 50 (2007) 1939-1957
50. Dezaki K., Sone H., and Yada T. Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis. Pharmacol Ther 118 (2008) 239-249
51. Donohoue P.A., Tao Y.X., Collins M., Yeo G.S.H., O'Rahilly S., and Segaloff D.L. Deletion of codons 88-92 of the melanocortin-4 receptor gene: a novel deleterious mutation in an obese female. J Clin Endocrinol Metab 88 (2003) 5841-5845
52. Dryja T.P., Berson E.L., Rao V.R., and Oprian D.D. Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. Nat Genet 4 (1993) 280-283
53. Dryja T.P., McGee T.L., Reichel E., Hahn L.B., Cowley G.S., Yandell D.W., et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 343 (1990) 364-366
54. Duprez L., Hermans J., Van Sande J., Dumont J.E., Vassart G., and Parma J. Two autonomous nodules of a patient with multinodular goiter harbor different activating mutations of the thyrotropin receptor gene. J Clin Endocrinol Metab 82 (1997) 306-308
55. Duprez L., Parma J., Costagliola S., Hermans J., Van Sande J., Dumont J.E., et al. Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain. FEBS Lett 409 (1997) 469-474
56. Duprez L., Parma J., Van Sande J., Allgeier A., Leclere J., Schvartz C., Delisle M.J., Decoulx M., Orgiazzi J., Dumont J., et al. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet 7 (1994) 396-401
57. Esapa C.T., Duprez L., Ludgate M., Mustafa M.S., Kendall-Taylor P., Vassart G., et al. A novel thyrotropin receptor mutation in an infant with severe thyrotoxicosis. Thyroid 9 (1999) 1005-1010
58. Esler W.P., Rudolph J., Claus T.H., Tang W., Barucci N., Brown S.E., et al. Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology 148 (2007) 5175-5185
59. Evans B.A.J., Bowen D.J., Smith P.J., Clayton P.E., and Gregory J.W. 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 33 (1996) 143-147
60. Fan Z.C., Sartin J.L., and Tao Y.X. Pharmacological analyses of two naturally occurring porcine melanocortin-4 receptor mutations in domestic pigs. Domest Anim Endocrinol 34 (2008) 383-390
61. Fanelli F. Theoretical study on mutation-induced activation of the luteinizing hormone receptor. J Mol Biol 296 (2000) 1333-1351
62. Fanelli F., Verhoef-Post M., Timmerman M., Zeilemaker A., Martens J.W., and Themmen A.P. Insight into mutation-induced activation of the luteinizing hormone receptor: molecular simulations predict the functional behavior of engineered mutants at M398. Mol Endocrinol 18 (2004) 1499-1508
63. Feighner S.D., Howard A.D., Prendergast K., Palyha O.C., Hreniuk D.L., Nargund R., et al. Structural requirements for the activation of the human growth hormone secretagogue receptor by peptide and nonpeptide secretagogues. Mol Endocrinol 12 (1998) 137-145
64. Feng X., Muller T., Mizrachi D., Fanelli F., and Segaloff D.L. An intracellular loop (IL2) residue confers different basal constitutive activities to the human lutropin receptor and human thyrotropin receptor through structural communication between IL2 and helix 6, via helix 3. Endocrinology 149 (2008) 1705-1717
65. Ferrari S.L., and Bisello A. Cellular distribution of constitutively active mutant parathyroid hormone (PTH)/PTH-related protein receptors and regulation of cyclic adenosine 3',5'-monophosphate signaling by beta-arrestin2. Mol Endocrinol 15 (2001) 149-163
66. Foster A.C., and Chen C. Melanocortin-4 receptor antagonists as potential therapeutics in the treatment of cachexia. Curr Top Med Chem 7 (2007) 1131-1136
67. Fournes B., Monier R., Michiels F., Milgrom E., Misrahi M., and Feunteun J. Oncogenic potential of a mutant human thyrotropin receptor expressed in FRTL-5 cells. Oncogene 16 (1998) 985-890
68. Fredriksson R., Lagerstrom M.C., Lundin L.G., and Schioth H.B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63 (2003) 1256-1272
69. Fuhrer D., Holzapfel H.P., Wonerow P., Scherbaum W.A., and Paschke R. Somatic mutations in the thyrotropin receptor gene and not in the Gsa protein gene in 31 toxic thryoid nodules. J Clin Endocrinol Metab 82 (1997) 3885-3891
70. Fuhrer D., Lewis M.D., Alkhafaji F., Starkey K., Paschke R., Wynford-Thomas D., et al. Biological activity of activating thyroid-stimulating hormone receptor mutants depends on the cellular context. Endocrinology 144 (2003) 4018-4030
71. Fuhrer D., Tannapfel A., Sabri O., Lamesch P., and Paschke R. Two somatic TSH receptor mutations in a patient with toxic metastasising follicular thyroid carcinoma and non-functional lung metastases. Endocr Relat Cancer 10 (2003) 591-600
72. Fuhrer D., Warner J., Sequeira M., Paschke R., Gregory J., and Ludgate M. Novel TSHR germline mutation (Met463Val) masquerading as Graves' disease in a large Welsh kindred with hyperthyroidism. Thyroid 10 (2000) 1035-1041
73. Fuller P.J., Verity K., Shen Y., Mamers P., Jobling T., and Burger H.G. No evidence of a role for mutations or polymorphisms of the follicle-stimulating hormone receptor in ovarian granulosa cell tumors. J Clin Endocrinol Metab 83 (1998) 274-279
74. Galet C., and Ascoli M. A constitutively active mutant of the human lutropin receptor (hLHR-L457R) escapes lysosomal targeting and degradation. Mol Endocrinol 20 (2006) 2931-2945
75. Gether U. Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr Rev 21 (2000) 90-113
76. Giacaglia L.R., Kohek M.B.d.F., Carvalho F.M., Fragoso M.C., Mendonca B., and Latronico A.C. No evidence of somatic activating mutations on gonadotropin receptor genes in sex cord stromal tumors. Fertil Steril 74 (2000) 992-995
77. Gloriam D.E., Fredriksson R., and Schioth H.B. The G protein-coupled receptor subset of the rat genome. BMC Genomics 8 (2007) 338
78. Govardhan C.P., and Oprian D.D. Active site-directed inactivation of constitutively active mutants of rhodopsin. J Biol Chem 269 (1994) 6524-6527
79. 2+ cascade mediates TSH action on thyroid hormone synthesis. J Clin Endocrinol Metab 92 (2007) 2816-2820
80. 1b-adrenergic receptor highlight the role of the helix 3/helix 6 interface in receptor activation. Mol Pharmacol 61 (2002) 1025-1032
81. Gromoll J., Partsch C.J., Simoni M., Nordhoff V., Sippell W.G., Nieschlag E., et al. A mutation in the first transmembrane domain of the lutropin receptor causes male precocious puberty. J Clin Endocrinol Metab 83 (1998) 476-480
82. Gromoll J., Simoni M., and Nieschlag E. An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hyophysectomized man. J Clin Endocrinol Metab 81 (1996) 1367-1370
83. Gross A.K., Rao V.R., and Oprian D.D. Characterization of rhodopsin congenital night blindness mutant T94I. Biochemistry 42 (2003) 2009-2015
84. Gu W., Tu Z., Kleyn P.W., Kissebah A., Duprat L., Lee J., et al. Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 48 (1999) 635-639
85. Haskell-Luevano C., and Monck E.K. Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor. Regul Pept 99 (2001) 1-7
86. Haywood M., Tymchenko N., Spaliviero J., Koch A.E., Jimenez M., Gromoll J., et al. An activated human follicle-stimulating hormone (FSH) receptor stimulates FSH-like activity in gonadotropin-deficient transgenic mice. Mol Endocrinol 16 (2002) 2582-2591
87. Heitman, L. H., & IJzerman, A. P., (in press). G protein-coupled receptors of the hypothalamic-pituitary-gonadal axis: a case for GnRH, LH, FSH, and GPR54 receptor ligands. Med Res Rev.
88. Hinney A., Bettecken T., Tarnow P., Brumm H., Reichwald K., Lichtner P., et al. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J Clin Endocrinol Metab 91 (2006) 1761-1769
89. Hinney A., Hohmann S., Geller F., Vogel C., Hess C., Wermter A.K., et al. Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. J Clin Endocrinol Metab 88 (2003) 4258-4267
90. Hirakawa T., and Ascoli M. A constitutively active somatic mutation of the human lutropin receptor found in Leydig cell tumors activates the same families of G proteins as germ line mutations associated with Leydig cell hyperplasia. Endocrinology 144 (2003) 3872-3878
91. Hirakawa T., Galet C., and Ascoli M. MA-10 cells transfected with the human lutropin/choriogonadotropin receptor (hLHR): a novel experimental paradigm to study the functional properties of the hLHR. Endocrinology 143 (2002) 1026-1035
92. Hjorth S.A., Orskov C., and Schwartz T.W. Constitutive activity of glucagon receptor mutants. Mol Endocrinol 12 (1998) 78-86
93. Ho G., and MacKenzie R.G. Functional characterization of mutations in melanocortin-4 receptor associated with human obesity. J Biol Chem 274 (1999) 35816-35822
94. Ho S.C., Van Sande J., Lefort A., Vassart G., and Costagliola S. Effects of mutations involving the highly conserved S281HCC motif in the extracellular domain of the thyrotropin (TSH) receptor on TSH binding and constitutive activity. Endocrinology 142 (2001) 2760-2767
95. Holst B., Cygankiewicz A., Jensen T.H., Ankersen M., and Schwartz T.W. High constitutive signaling of the ghrelin receptor-identification of a potent inverse agonist. Mol Endocrinol 17 (2003) 2201-2210
96. Holst B., Holliday N.D., Bach A., Elling C.E., Cox H.M., and Schwartz T.W. Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem 279 (2004) 53806-53817
97. Holst B., and Schwartz T.W. Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation. Trends Pharmacol Sci 25 (2004) 113-117
98. Holzapfel H.P., Wonerow P., von Petrykowski W., Henschen M., Scherbaum W.A., and Paschke R. Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab 82 (1997) 3879-3884
99. Hosoda H., Kojima M., and Kangawa K. Ghrelin and the regulation of food intake and energy balance. Mol Interv 2 (2002) 494-503
100. Howard A.D., Feighner S.D., Cully D.F., Arena J.P., Liberator P.A., Rosenblum C.I., et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273 (1996) 974-977
101. Hu J., and 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 11 (2007) 908-922
102. Jeha G.S., Lowenthal E.D., Chan W.Y., Wu S.M., and Karaviti L.P. Variable presentation of precocious puberty associated with the D564G mutation of the LHCGR gene in children with testotoxicosis. J Pediatr 149 (2006) 271-274
103. Juppner H. Jansen's metaphyseal chondrodysplasia. A disorder due to a PTH/PTHrP receptor gene mutation. Trends Endocrinol Metab 7 (1996) 157-162
104. Kawate N., Kletter G.B., Wilson B.E., Netzloff M.L., and Menon K.M.J. Identification of constitutively activating mutation of the luteinising hormone receptor in a family with male limited gonadotrophin independent precocious puberty (testotoxicosis). J Med Genet 32 (1995) 553-554
105. Kaye P.V., Hapgood J., and Millar R.P. Absence of mutations in exon 3 of the GnRH receptor in human gonadotroph adenomas. Clin Endocrinol 47 (1997) 549-554
106. Keen T.J., Inglehearn C.F., Lester D.H., Bashir R., Jay M., Bird A.C., et al. Autosomal dominant retinitis pigmentosa: four new mutations in rhodopsin, one of them in the retinal attachment site. Genomics 11 (1991) 199-205
107. Kenakin T. Efficacy as a vector: the relative prevalence and paucity of inverse agonism. Mol Pharmacol 65 (2004) 2-11
108. Kenakin T. The physiological significance of constitutive receptor activity. Trends Pharmacol Sci 26 (2006) 603-605
109. Khoo D.H., Parma J., Rajasoorya C., Ho S.C., and Vassart G. A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family. J Clin Endocrinol Metab 84 (1999) 1459-1462
110. Kim J.M., Altenbach C., Kono M., Oprian D.D., Hubbell W.L., and Khorana H.G. Structural origins of constitutive activation in rhodopsin: role of the K296/E113 salt bridge. Proc Natl Acad Sci U S A 101 (2004) 12508-12513
111. 1B-adrenergic receptor by all amino acid substitutions at a single site. J Biol Chem 267 (1992) 1430-1433
112. Kojima M., Hosoda H., Date Y., Nakazato M., Matsuo H., and Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402 (1999) 656-660
113. Kolakowski Jr. L.F. GCRDb: a G-protein-coupled receptor database. Receptors Channels 2 (1994) 1-7
114. Kopp P. The TSH receptor and its role in thyroid disease. Cell Mol Life Sci 58 (2001) 1301-1322
115. Kopp P., Jameson J.L., and Roe T.F. Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by a sporadic germline mutation in the thyrotropin receptor gene. Thyroid 7 (1997) 765-770
116. Kopp P., Muirhead S., Jourdain N., Gu W.X., Jameson J.L., and Rodd C. Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281->isoleucine) in the extracellular domain of the thyrotropin receptor. J Clin Invest 100 (1997) 1634-1639
117. Kopp P., van Sande J., Parma J., Duprez L., Gerber H., Joss E., et al. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 332 (1995) 150-154
118. Kosugi S., Hai N., Okamoto H., Sugawa H., and Mori T. A novel activating mutation in the thyrotropin receptor gene in an autonomously functioning thyroid nodule developed by a Japanese patient. Eur J Endocrinol 143 (2000) 471-477
119. Kosugi S., Mori T., and Shenker A. The role of Asp578 in maintaining the inactive conformation of the human lutropin/choriogonadotropin receptor. J Biol Chem 271 (1996) 31813-31817
120. Kosugi S., Van Dop C., Geffner M.E., Rabl W., Carel J.C., Chaussain J.L., et al. Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in familial male precocious puberty. Hum Mol Genet 4 (1995) 183-188
121. Kotlar T., Young R.H., Albanese C., Crowley Jr. W.F., Scully R.E., and Jameson J.L. Absence of mutations in the FSH receptor in ovarian granulosa cell tumors. J Clin Endocrinol Metab 83 (1998) 3001
122. Kotlar T.J., Young R.H., Albanese C., Crowley Jr. W.F., Scully R.E., and Jameson J.L. A mutation in the follicle-stimulating hormone receptor occurs frequently in human ovarian sex cord tumors. J Clin Endocrinol Metab 82 (1997) 1020-1026
123. Kraaij R., Post M., Kremer H., Milgrom E., Epping W., Brunner H.G., et al. A missense mutation in the second transmembrane segment of the luteinizing hormone receptor causes familiar male precocious puberty. J Clin Endocrinol Metab 80 (1995) 3168-3172
124. Kremer H., Mariman E., Otten B.J., Moll Jr. G.W., Stoelinja G.B., Wit J.M., et al. Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty. Hum Mol Genet 2 (1993) 1779-1783
125. Kremer H., Martens J.W., van Reen M., Verhoef-Post M., Wit J.M., Otten B.J., et al. A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty. J Clin Endocrinol Metab 84 (1999) 1136-1140
126. Kudo M., Osuga Y., Kobilka B.K., and Hsueh A.J.W. Transmembrane regions V and VI of the human luteinizing hormone receptor are required for constitutive activation by a mutation in the third intracellular loop. J Biol Chem 271 (1996) 22470-22478
127. Kuznetsov S.A., Riminucci M., Ziran N., Tsutsui T.W., Corsi A., Calvi L., et al. The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow. J Cell Biol 167 (2004) 1113-1122
128. Latronico A., and Segaloff D. Naturally occurring mutations of the luteinizing hormone receptor: lessons learned about reproductive physiology and G protein-coupled receptors. Am J Hum Genet 65 (1999) 949-958
129. Latronico A.C., Abell A.N., Arnhold I.J.P., Liu X., Lins T.S.S., Brito V.N., et al. A unique constitutively activating mutation in the third transmembrane helix of the luteinizing hormone receptor causes sporadic male gonadotropin independent precocious puberty. J Clin Endocrinol Metab 83 (1998) 2435-2440
130. Latronico A.C., Anasti J., Arnhold I.J.P., Mendonca B.B., Domenice S., Albano M.C., et al. A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty. J. Clin. Endocrin. Metab. 80 (1995) 2490-2494
131. Latronico A.C., Reincke M., Mendonca B.B., Arai K., Mora P., Allolio B., et al. No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms. J Clin Endocrinol Metab 80 (1995) 875-877
132. Latronico A.C., Lins T.S., Brito V.N., Arnhold I.J., and Mendonca B.B. The effect of distinct activating mutations of the luteinizing hormone receptor gene on the pituitary-gonadal axis in both sexes. Clin Endocrinol 53 (2000) 609-613
133. Latronico A.C., Shinozaki H., Guerra Jr. G., Pereira M.A., Lemos Marini S.H., Baptista M.T., et al. Gonadotropin-independent precocious puberty due to luteinizing hormone receptor mutations in Brazilian boys: a novel constitutively activating mutation in the first transmembrane helix. J Clin Endocrinol Metab 85 (2000) 4799-4805
134. Latronico A.C., and Segaloff D.L. Insights learned from L457(3.43)R, an activating mutant of the human lutropin receptor. Mol Cell Endocrinol 260-262 (2007) 287-293
135. Laue L., Chan W.C., Hsueh A., Kudo M., Hsu S.Y., Wu S., et al. Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male-limited precocious puberty. Proc Natl Acad Sci U S A 92 (1995) 1906-1910
136. Laue L., Wu S.M., Kudo M., Hsueh A.J.W., Cutler G.B., Jelly D.H., et al. Heterogeneity of activating mutations of the human luteinizing hormone receptor in male-limited precocious puberty. Biochem Mol Med 58 (1996) 192-198
137. Laugwitz K.L., Allgeier A., Offermanns S., Spicher K., Van Sande J., Dumont J.E., et al. The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families. Proc Natl Acad Sci U S A 93 (1996) 116-120
138. 1B-adrenoceptor by ligands that act as inverse agonists. Biochem J 325 (1997) 733-739
139. Lei Y., Hagen G.M., Smith S.M., Liu J., Barisas G., and Roess D.A. Constitutively-active human LH receptors are self-associated and located in rafts. Mol Cell Endocrinol 260-262 (2007) 65-72
140. Lem J., and Fain G.L. Constitutive opsin signaling: night blindness or retinal degeneration?. Trends Mol Med 10 (2004) 150-157
141. Li T., Franson W.K., Gordon J.W., Berson E.L., and Dryja T.P. Constitutive activation of phototransduction by K296E opsin is not a cause of photoreceptor degeneration. Proc Natl Acad Sci U S A 92 (1995) 3551-3555
142. Light K., Jenkins P.J., Weber A., Perrett C., Grossman A., Pistorello M., et al. Are activating mutations of the adrenocorticotropin receptor involved in adrenal cortical neoplasia?. Life Sci 56 (1995) 1523-1527
143. Ligtenberg M.J., Siers M., Themmen A.P., Hanselaar T.G., Willemsen W., and Brunner H.G. Analysis of mutations in genes of the follicle-stimulating hormone receptor signaling pathway in ovarian granulosa cell tumors. J Clin Endocrinol Metab 84 (1999) 2233-2234
144. Lin Z., Shenker A., and Pearlstein R. A model of the lutropin/choriogonadotropin receptor: insights into the structural and functional effects of constitutively activating mutations. Protein Eng 10 (1997) 501-510
145. Liu B., Liu G., Xin Z., Serby M.D., Zhao H., Schaefer V.G., et al. Novel isoxazole carboxamides as growth hormone secretagogue receptor (GHS-R) antagonists. Bioorg Med Chem Lett 14 (2004) 5223-5226
146. Liu B., Liu M., Xin Z., Zhao H., Serby M.D., Kosogof C., et al. Optimization of 2,4-diaminopyrimidines as GHS-R antagonists: side chain exploration. Bioorg Med Chem Lett 16 (2006) 1864-1868
147. Liu G., Duranteau L., Carel J.C., Monroe J., Doyle D.A., and Shenker A. Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. N Engl J Med 341 (1999) 1731-1736
148. Liu G., Fortin J.P., Beinborn M., and Kopin A.S. Four missense mutations in the ghrelin receptor result in distinct pharmacological abnormalities. J Pharmacol Exp Ther 322 (2007) 1036-1043
149. Liu Z., Sun Y., Dong Q., He M., Cheng C.H., and Fan F. A novel TSHR gene mutation (Ile691Phe) in a Chinese family causing autosomal dominant non-autoimmune hyperthyroidism. J Hum Genet 53 (2008) 475-478
150. Lu Z.L., and Hulme E.C. The functional topography of transmembrane
151. Lubrano-Berthelier C., Durand E., Dubern B., Shapiro A., Dazin P., Weill J., et al. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 12 (2003) 145-153
152. Ludgate M., Gire V., Crisp M., Ajjan R., Weetman A., Ivan M., et al. Contrasting effects of activating mutations of GαS and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells. Oncogene 18 (1999) 4798-4807
153. Ludwig M., Gembruch U., Bauer O., and Diedrich K. Ovarian hyperstimulation syndrome (OHSS) in a spontaneous pregnancy with fetal and placental triploidy: information about the general pathophysiology of OHSS. Hum Reprod 13 (1998) 2082-2087
154. 2-adrenoceptor in transfected neuroblastoma X glioma hybrid cells. Mol Pharmacol 50 (1996) 1479-1786
155. Markison S., Foster A.C., Chen C., Brookhart G.B., Hesse A., Hoare S.R., et al. The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist. Endocrinology 146 (2005) 2766-2773
156. Marks D.L., Butler A.A., Turner R., Brookhart G., and Cone R.D. Differential role of melanocortin receptor subtypes in cachexia. Endocrinology 144 (2003) 1513-1523
157. Marks D.L., Ling N., and Cone R.D. Role of the central melanocortin system in cachexia. Cancer Res 61 (2001) 1432-1438
158. Martin M.M., Wu S.M., Martin A.L., Rennert O.M., and Chan W.Y. Testicular seminoma in a patient with a constitutively activating mutation of the luteinizing hormone/chorionic gonadotropin receptor. Eur J Endocrinol 139 (1998) 101-106
159. Maudsley S., Martin B., and Luttrell L.M. The origins of diversity and specificity in G protein-coupled receptor signaling. J Pharmacol Exp Ther 314 (2005) 485-494
160. Medina D.L., and Santisteban P. Thyrotropin-dependent proliferation of in vitro rat thyroid cell systems. Eur J Endocrinol 143 (2000) 161-178
161. Milligan G., and Bond R.A. Inverse agonism and the regulation of receptor number. Trends Pharmacol Sci 18 (1997) 468-474
162. Milligan G., Bond R.A., and Lee M. Inverse agonism: pharmacological curiosity or potential therapeutic strategy. Trends Pharmacol Sci 16 (1995) 10-13
163. Min L., and Ascoli M. Effect of activating and inactivating mutations on the phosphorylation and trafficking of the human lutropin/choriogonadotropin receptor. Mol Endocrinol 14 (2000) 1797-1810
164. Min L., Galet C., and Ascoli M. The association of arrestin-3 with the human lutropin/choriogonadotropin receptor depends mostly on receptor activation rather than on receptor phosphorylation. J Biol Chem 277 (2002) 702-710
165. Mirzadegan T., Benko G., Filipek S., and Palczewski K. Sequence analyses of G-protein-coupled receptors: similarities to rhodopsin. Biochemistry 42 (2003) 2759-2767
166. Montanelli L., Delbaere A., Di Carlo C., Nappi C., Smits G., Vassart G., et al. A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 89 (2004) 1255-1258
167. Montanelli L., Van Durme J.J., Smits G., Bonomi M., Rodien P., Devor E.J., et al. Modulation of ligand selectivity associated with activation of the transmembrane region of the human follitropin receptor. Mol Endocrinol 18 (2004) 2061-2073
168. Moulin A., Demange L., Berge G., Gagne D., Ryan J., Mousseaux D., et al. Toward potent ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure. 2. Synthesis and pharmacological in vitro and in vivo evaluations. J Med Chem 50 (2007) 5790-5806
169. Moulin A., Demange L., Ryan J., M'Kadmi C., Galleyrand J.C., Martinez J., et al. Trisubstituted 1,2,4-triazoles as ligands for the ghrelin receptor: on the significance of the orientation and substitution at position 3. Bioorg Med Chem Lett 18 (2008) 164-168
170. Moulin A., Demange L., Ryan J., Mousseaux D., Sanchez P., Berge G., et al. New trisubstituted 1,2,4-triazole derivatives as potent ghrelin receptor antagonists. 3. Synthesis and pharmacological in vitro and in vivo evaluations. J Med Chem 51 (2008) 689-693
171. Nakabayashi K., Kudo M., Kobilka B., and Hsueh A.J. Activation of the luteinizing hormone receptor following substitution of Ser-277 with selective hydrophobic residues in the ectodomain hinge region. J Biol Chem 275 (2000) 30264-30271
172. Nakazato M., Murakami N., Date Y., Kojima M., Matsuo H., Kangawa K., et al. A role for ghrelin in the central regulation of feeding. Nature 409 (2001) 194-198
173. Nicholson J.R., Kohler G., Schaerer F., Senn C., Weyermann P., and Hofbauer K.G. Peripheral administration of a melanocortin 4-receptor inverse agonist prevents loss of lean body mass in tumor-bearing mice. J Pharmacol Exp Ther 317 (2006) 771-777
174. Nijenhuis W.A., Garner K.M., VanRozen R.J., and Adan R.A. Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity. J Biol Chem 278 (2003) 22939-22945
175. Nijenhuis W.A., Oosterom J., and Adan R.A. AgRP(83-132) acts as an inverse agonist on the human melanocortin-4 receptor. Mol Endocrinol 15 (2001) 164-171
176. Nishihara E., Fukata S., Hishinuma A., Kudo T., Ohye H., Ito M., et al. Sporadic congenital hyperthyroidism due to a germline mutation in the thyrotropin receptor gene (Leu 512 Gln) in a Japanese patient. Endocr J 53 (2006) 735-740
177. Nishihara E., Nagayama Y., Amino N., Hishinuma A., Takano T., Yoshida H., et al. A novel thyrotropin receptor germline mutation (Asp617Tyr) causing hereditary hyperthyroidism. Endocr J 54 (2007) 927-934
178. Nogueira C.R., Kopp P., Arseven O.K., Santos C.L., Jameson J.L., and Medeiros-Neto G. Thyrotropin receptor mutations in hyperfunctioning thyroid adenomas from Brazil. Thyroid 9 (1999) 1063-1068
179. Ono N., Nakashima K., Schipani E., Hayata T., Ezura Y., Soma K., et al. Constitutively active parathyroid hormone receptor signaling in cells in osteoblastic lineage suppresses mechanical unloading-induced bone resorption. J Biol Chem 282 (2007) 25509-25516
180. 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 289 (2000) 739-745
181. Pantel J., Legendre M., Cabrol S., Hilal L., Hajaji Y., Morisset S., et al. Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 116 (2006) 760-768
182. Park J.H., Scheerer P., Hofmann K.P., Choe H.W., and Ernst O.P. Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature 454 (2008) 183-187
183. Parma J., Duprez L., Van Sande J., Cochauz P., Gervy C., Mockel J., et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365 (1993) 649-651
184. Parma J., Duprez L., Van Sande J., Hermans J., Rocmans P., Van Vliet G., et al. Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas. J Clin Endocrinol Metab 82 (1997) 2695-2701
185. 2+ cascades. Mol Endocrinol 9 (1995) 725-733
186. Parnot C., Miserey-Lenkei S., Bardin S., Corvol P., and Clauser E. Lessons from constitutively active mutants of G protein-coupled receptors. Trends Endocrinol Metab 13 (2002) 336-343
187. Paschke R., Tonacchera M., Van Sande J., Parma J., and Vassart G. Identification and functional characterization of two new somatic mutations causing constitutive activation of the thyrotropin receptor in hyperfunctioning autonomous adenomas of the thyroid. J Clin Endocrinol Metab 79 (1994) 1785-1789
188. Patchett A.A., Nargund R.P., Tata J.R., Chen M.H., Barakat K.J., Johnston D.B., et al. Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci U S A 92 (1995) 7001-7005
189. 2-adrenergic receptor is constitutively desensitized and phosphorylated. Proc Natl Acad Sci U S A 91 (1994) 2699-2702
190. Persani L., Lania A., Alberti L., Romoli R., Mantovani G., Filetti S., et al. Induction of specific phosphodiesterase isoforms by constitutive activation of the cAMP pathway in autonomous thyroid adenomas. J Clin Endocrinol Metab 85 (2000) 2872-2878
191. Pfluger P.T., Kirchner H., Gunnel S., Schrott B., Perez-Tilve D., Fu S., et al. Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. Am J Physiol 294 (2008) G610-G618
192. 2+-sensing receptor gene mutation. Nat Genet 8 (1994) 303-307
193. Porcellini A., Ciullo I., Laviola L., Amabile G., Fenzi G., and Avvedimento V.E. Novel mutations of thyrotropin receptor gene in thyroid hyperfunctioning adenomas. Rapid identification by fine needle aspiration biopsy. J Clin Endocrinol Metab 79 (1994) 657-661
194. Porcellini A., Ruggiano G., Pannain S., Ciullo I., Amabile G., Fenzi G., et al. Mutations of thyrotropin receptor isolated from thyroid autonomous functioning adenomas confer TSH-independent growth to thyroid cells. Oncogene 15 (1997) 781-789
195. Ramon E., del Valle L.J., and Garriga P. Unusual thermal and conformational properties of the rhodopsin congenital night blindness mutant Thr-94 -> Ile. J Biol Chem 278 (2003) 6427-6432
196. Rao V.R., Cohen G.B., and Oprian D.D. Rhodopsin mutation G90D and a molecular mechanism for congenital night blindness. Nature 367 (1994) 639-642
197. Rao V.R., and Oprian D.D. Activating mutations of rhodopsin and other G protein-coupled receptors. Ann Rev Biophy Biomol Struct 25 (1996) 287-314
198. Rapoport B., Chazenbalk G.D., Jaume J.C., and McLachlan S.M. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev 19 (1998) 673-716
199. 2 adrenergic G-protein-coupled receptor. Nature 450 (2007) 383-387
200. Refetoff S., Dumont J., and Vassart G. Thyroid disorders. In: Scriver C.R., Beaudet A.L., Sly W.S., Valle D., Childs B., Kinzler K.W., and Vogelstein B. (Eds). The Metabolic and Molecular Bases of Inherited Disease. 8th ed. (2001), McGraw-Hill, New York 4029-4075
201. 2-adrenergic receptor. J Biol Chem 268 (1993) 16483-16487
202. Richter-Unruh A., Wessels H.T., Menken U., Bergmann M., Schmittmann-Ohters K., Schaper J., et al. Male LH-independent sexual precocity in a 3.5-year-old boy caused by a somatic activating mutation of the LH receptor in a Leydig cell tumor. J Clin Endocrinol Metab 87 (2002) 1052-1056
203. Rim J., and Oprian D.D. Constitutive activation of opsin: interaction of mutants with rhodopsin kinase and arrestin. Biochemistry 34 (1995) 11938-11945
204. Ringkananont U., Van Durme J., Montanelli L., Ugrasbul F., Yu Y.M., Weiss R.E., et al. Repulsive separation of the cytoplasmic ends of transmembrane helices 3 and 6 is linked to receptor activation in a novel thyrotropin receptor mutant (M626I). Mol Endocrinol 20 (2006) 893-903
205. Rivas M., and Santisteban P. TSH-activated signaling pathways in thyroid tumorigenesis. Mol Cell Endocrinol 213 (2003) 31-45
206. Robbins L.S., Nadeau J.H., Johnson K.R., Kelly M.A., Roselli-Rehfuss L., Baack E., et al. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72 (1993) 827-834
207. Robinson P.R., Buczylko J., Ohguro H., and Palczewski K. Opsins with mutations at the site of chromophore attachment constitutively activate transducin but are not phosphorylated by rhodopsin kinase. Proc Natl Acad Sci U S A 91 (1994) 5411-5415
208. Robinson P.R., Cohen G.B., Zhukovsky E.A., and Oprian D.D. Constitutively active mutants of rhodopsin. Neuron 9 (1992) 719-725
209. Rodien P., Bremont C., Sanson M.L., Parma J., Van Sande J., Costagliola S., et al. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 339 (1998) 1823-1826
210. Roess D.A., Horvat R.D., Munnelly H., and Barisas B.G. Luteinizing hormone receptors are self-associated in the plasma membrane. Endocrinology 141 (2000) 4518-4523
211. Rong R., Tao Y.X., Cheung B.M., Xu A., Cheung G.C., and Lam K.S. Identification and functional characterization of three novel human melanocortin-4 receptor gene variants in an obese Chinese population. Clin Endocrinol 65 (2006) 198-205
212. 2-adrenergic receptor function. Science 318 (2007) 1266-1673
213. Rosenthal I.M., Refetoff S., Rich B., Barnes R.B., Sunthornthepvarakul T., Parma J., et al. Response to challenge with gonadotropin-releasing hormone agonist in a mother and her two sons with a constitutively activating mutation of the luteinizing hormone receptor-A clinical research center study. J Clin Endocrinol Metab 81 (1996) 3802-3806
214. Rudolph J., Esler W.P., O'Connor S., Coish P.D., Wickens P.L., Brands M., et al. Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity. J Med Chem 50 (2007) 5202-5216
215. Russo D., Arturi F., Schlumberger M., Caillou B., Monier R., Filetti S., et al. Activating mutations of the TSH receptor in differentiated thyroid carcinomas. Oncogene 11 (1995) 1907-1911
216. Russo D., Arturi F., Suarez H.G., Schlumberger M., Du Villard J.A., Crocetti U., et al. Thyrotropin receptor gene alterations in thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab 81 (1996) 1548-1551
217. Russo D., Tumino S., Arturi F., Vigneri P., Grasso G., Pontecorvi A., et al. Detection of an activating mutation of the thyrotropin receptor in a case of an autonomously hyperfunctioning thyroid insular carcinoma. J Clin Endocrinol Metab 82 (1997) 735-738
218. Russo D., Wong M.G., Costante G., Chiefari E., Treseler P.A., Arturi F., et al. A Val 677 activating mutation of the thyrotropin receptor in a Hurthle cell thyroid carcinoma associated with thyrotoxicosis. Thyroid 9 (1999) 13-17
219. 2-adrenergic receptor: extending the ternary complex model. J Biol Chem 268 (1993) 4625-4636
220. Sangkuhl K., Schulz A., Schultz G., and Schoneberg T. Structural requirements for mutational lutropin/choriogonadotropin receptor activation. J Biol Chem 277 (2002) 47748-47755
221. Schaison G., Young J., Pholsena M., Nahoul K., and Couzinet B. Failure of combined follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 77 (1993) 1545-1549
222. Schipani E., Lanske B., Hunzelman J., Luz A., Kovacs C.S., Lee K., et al. Targeted expression of constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide delays endochondral bone formation and rescues mice that lack parathyroid hormone-related peptide. Proc Natl Acad Sci U S A 94 (1997) 13689-13694
223. Schipani E., Jensen G.S., Pincus J., Nissenson R.A., Gardella T.J., and Juppner H. Constitutive activation of the cyclic adenosine 3',5'-monophosphate signaling pathway by parathyroid hormone (PTH)/PTH-related peptide receptors mutated at the two loci for Jansen's metaphyseal chondrodysplasia. Mol Endocrinol 11 (1997) 851-858
224. Schipani E., Kruse K., and Juppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268 (1995) 98-100
225. Schipani E., Langman C., Hunzelman J., Le Merrer M., Loke K.Y., Dillon M.J., et al. A novel parathyroid hormone (PTH)/PTH-related peptide receptor mutation in Jansen's metaphyseal chondrodysplasia. J Clin Endocrinol Metab 84 (1999) 3052-3057
226. Schipani E., Langman C.B., Parfitt A.M., Jensen G.S., Kikuchi S., Kooh S.W., et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. N Engl J Med 335 (1996) 708-714
227. Schoneberg T., Schulz A., Biebermann H., Hermsdorf T., Rompler H., and Sangkuhl K. Mutant G-protein-coupled receptors as a cause of human diseases. Pharmacol Ther 104 (2004) 173-206
228. Schoneberg T., Schulz A., and Gudermann T. The structural basis of G-protein-coupled receptor function and dysfunction in human diseases. Rev Physiol Biochem Pharmacol 144 (2002) 143-227
229. Schwab K.O., Gerlich M., Broecker M., Sohlemann P., Derwahl M., and Lohse M.J. Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism. J Pediatr 131 (1997) 899-904
230. Seifert R., and Wenzel-Seifert K. Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch Pharmacol 366 (2002) 381-416
231. Serby M.D., Zhao H., Szczepankiewicz B.G., Kosogof C., Xin Z., Liu B., et al. 2,4-diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists. J Med Chem 49 (2006) 2568-2578
232. Shenker A. G protein-coupled receptor structure and function: the impact of disease-causing mutations. Bailliere's Clin Endocrinol Metab 9 (1995) 427-451
233. Shenker A. Disorders caused by mutations of the lutropin/choriogonadotropin receptor gene. In: Spiegel A.M. (Ed). G Proteins, Receptors, and Disease (1998), Humana Press, Totowa 139-152
234. Shenker A. Activating mutations of the lutropin choriogonadotropin receptor in precocious puberty. Receptors Channels 8 (2002) 3-18
235. Shenker A., Laue L., Kosugi S., Merendino Jr. J.J., Minegishi T., and Cutler Jr. G.B. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 365 (1993) 652-654
236. Shinozaki H., Fanelli F., Liu X., Jaquette J., Nakamura K., and Segaloff D.L. Pleiotropic effects of substitutions of a highly conserved leucine in transmembrane helix III of the human lutropin/choriogonadotropin receptor with respect to constitutive activation and hormone responsiveness. Mol Endocrinol 15 (2001) 972-984
237. Shinozaki H., Butnev V., Tao Y.X., Ang K.L., Conti M., and Segaloff D.L. Desensitization of Gs-coupled receptor signaling by constitutively active mutants of the human lutropin/choriogonadotropin receptor. J Clin Endocrinol Metab 88 (2003) 1194-1204
238. Sieving P.A., Richards J.E., Naarendorp F., Bingham E.L., Scott K., and Alpern M. Dark-light: model for nightblindness from the human rhodopsin Gly-90->Asp mutation. Proc Natl Acad Sci U S A 92 (1995) 880-884
239. Simoni M., Gromoll J., and Nieschlag E. The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev 18 (1997) 739-773
240. Smit M.J., Leurs R., Alewijnse A.E., Blauw J., Van Nieuw Amerongen G.P., Van De Vrede Y., et al. Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors. Proc Natl Acad Sci U S A 93 (1996) 6802-6807
241. Smits G., Olatunbosun O., Delbaere A., Pierson R., Vassart G., and Costagliola S. Ovarian hyperstimulation syndrome due to a mutation in the follicle-stimulating hormone receptor. N Engl J Med 349 (2003) 760-766
242. Soegiarto D.W., Kiachopoulos S., Schipani E., Juppner H., Erben R.G., and Lanske B. Partial rescue of PTH/PTHrP receptor knockout mice by targeted expression of the Jansen transgene. Endocrinology 142 (2001) 5303-5310
243. Spambalg D., Sharifi N., Elisei R., Gross J.L., Medeiros-Neto G., and Fagin J.A. Structural studies of the thyrotropin receptor and Gs alpha in human thyroid cancers: low prevalence of mutations predicts infrequent involvement in malignant transformation. J Clin Endocrinol Metab 81 (1996) 3898-3901
244. Spiegel A.M. Defects in G protein-coupled signal transduction in human disease. Annu Rev Physiol 58 (1996) 143-170
245. Spiegel A.M., and Weinstein L.S. Inherited diseases involving G proteins and G protein-coupled receptors. Annu Rev Med 55 (2004) 27-39
246. Spiegel A.M., Weinstein L.S., and Shenker A. Abnormalities in G protein-coupled signal transduction pathways in human disease. J Clin Invest 92 (1993) 1119-1125
247. Srinivasan S., Lubrano-Berthelier C., Govaerts C., Picard F., Santiago P., Conklin B.R., et al. Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. J Clin Invest 114 (2004) 1158-1164
248. Stutzmann F., Vatin V., Cauchi S., Morandi A., Jouret B., Landt O., et al. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Hum Mol Genet 16 (2007) 1837-1844
249. Sullivan J.M., Scott K.M., Falls H.F., Richards J.E., and Sieving P.A. A novel rhodopsin mutation at the retinal binding site (Lys296-Met) in ADRP. Invest Ophthalmol Vis Sci. 34 (1993) 1149
250. Takeshita A., Nagayama Y., Yokoyama N., Ishikawa N., Ito K., Yamashita T., et al. Rarity of oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in Japan. J Clin Endocrinol Metab 80 (1995) 2607-2611
251. Tao Y.X. Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol 239 (2005) 1-14
252. Tao Y.X. Inactivating mutations of G protein-coupled receptors and diseases: structure-function insights and therapeutic implications. Pharmacol Ther 111 (2006) 949-973
253. Tao Y.X. Functional characterization of novel melanocortin-3 receptor mutations identified from obese subjects. Biochim Biophys Acta 1772 (2007) 1167-1174
254. Tao Y.X., Abell A.N., Liu X., Nakamura K., and Segaloff D.L. Constitutive activation of G protein-coupled receptors as a result of selective substitution of a conserved leucine residue in transmembrane helix III. Mol Endocrinol 14 (2000) 1272-1282
255. Tao Y.X., Johnson N.B., and Segaloff D.L. Constitutive and agonist-dependent self-association of the cell surface human lutropin receptor. J Biol Chem 279 (2004) 5904-5914
256. Tao Y.X., Mizrachi D., and Segaloff D.L. Chimeras of the rat and human FSH receptors (FSHRs) identify residues that permit or suppress transmembrane 6 mutation-induced constitutive activation of the FSHR via rearrangements of hydrophobic interactions between helices 6 and 7. Mol Endocrinol 16 (2002) 1881-1892
257. Tao Y.X., and Segaloff D.L. Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology 144 (2003) 4544-4551
258. Tao Y.X., and Segaloff D.L. Functional characterization of melanocortin-3 receptor variants identify a loss-of-function mutation involving an amino acid critical for G protein-coupled receptor activation. J Clin Endocrinol Metab 89 (2004) 3936-3942
259. Tao Y.X., and Segaloff D.L. Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and nonobese or obese subjects. J Clin Endocrinol Metab 90 (2005) 5632-5638
260. Tassi V., Di Cerbo A., Porcellini A., Papini E., Cisternino C., Crescenzi A., et al. Screening of thyrotropin receptor mutations by fine-needle aspiration biopsy in autonomous functioning thyroid nodules in multinodular goiters. Thyroid 9 (1999) 353-357
261. Themmen A.P.N., and Huhtaniemi I.T. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 21 (2000) 551-583
262. Tiberi M., and Caron M.G. High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype. J Biol Chem 269 (1994) 27925-27931
263. Tonacchera M., Agretti P., Rosellini V., Ceccarini G., Perri A., Zampolli M., et al. Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene. Thyroid 10 (2000) 859-863
264. Tonacchera M., Chiovato L., Pinchera A., Agretti P., Fiore E., Cetani F., et al. Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma. J Clin Endocrinol Metab 83 (1998) 492-498
265. Tonacchera M., Van Sande J., Cetani F., Swillens S., Schvartz C., Winiszewski P., et al. Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia. J Clin Endocrinol Metab 81 (1996) 547-554
266. sα mutations: in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis. J Mol Med 78 (2001) 684-691
267. Urizar E., Montanelli L., Loy T., Bonomi M., Swillens S., Gales C., et al. Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity. EMBO J 24 (2005) 1954-1964
268. Vaisse C., Clement K., Durand E., Hercberg S., Guy-Grand B., and Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106 (2000) 253-262
269. Valli-Jaakola K., Lipsanen-Nyman M., Oksanen L., Hollenberg A.N., Kontula K., Bjorbaek C., et al. Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese Finnish children and adults. J Clin Endocrinol Metab 89 (2004) 940-945
270. Van Sande J., Parma J., Tonacchera M., Swillens S., Dumont J., and Vassart G. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endocrinol Metab 80 (1995) 2577-2585
271. VanLeeuwen D., Steffey M.E., Donahue C., Ho G., and MacKenzie R.G. Cell surface expression of the melanocortin-4 receptor is dependent on a C-terminal di-isoleucine sequence at codons 316/317. J Biol Chem 278 (2003) 15935-15940
272. Vasseur C., Rodien P., Beau I., Desroches A., Gerard C., de Poncheville L., et al. A chorionic gonadotropin-sensitive mutation in the follicle-stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyperstimulation syndrome. N Engl J Med 349 (2003) 753-759
273. Vlaeminck-Guillem V., Ho S.C., Rodien P., Vassart G., and Costagliola S. Activation of the cAMP pathway by the TSH receptor involves switching of the ectodomain from a tethered inverse agonist to an agonist. Mol Endocrinol 16 (2002) 736-746
274. Vos T.J., Caracoti A., Che J.L., Dai M., Farrer C.A., Forsyth N.E., et al. Identification of 2-[2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorophenyl]-4,5-dihydro-1H- imidazole (ML00253764), a small molecule melanocortin 4 receptor antagonist that effectively reduces tumor-induced weight loss in a mouse model. J Med Chem 47 (2004) 1602-1604
275. Wang H.J., Geller F., Dempfle A., Schauble N., Friedel S., Lichtner P., et al. Ghrelin receptor gene: identification of several sequence variants in extremely obese children and adolescents, healthy normal-weight and underweight students, and children with short normal stature. J Clin Endocrinol Metab 89 (2004) 157-162
276. 1-adrenergic G-protein-coupled receptor. Nature 454, 486-491.
277. Watson S.G., Radford A.D., Kipar A., Ibarrola P., and Blackwood L. Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism. J Endocrinol 186 (2005) 523-537
278. Weiss J.M., Morgan P.H., Lutz M.W., and Kenakin T.P. The cubic ternary complex receptor-occupancy model. III. Resurrecting efficacy. J Theor Biol 181 (1996) 381-397
279. Whistler J.L., Gerber B.O., Meng E.C., Baranski T.J., von Zastrow M., and Bourne H.R. Constitutive activation and endocytosis of the complement factor 5a receptor: evidence for multiple activated conformations of a G protein-coupled receptor. Traffic 3 (2002) 866-877
280. Wisse B.E., Frayo R.S., Schwartz M.W., and Cummings D.E. Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology 142 (2001) 3292-3301
281. Wonerow P., Chey S., Fuhrer D., Holzapfel H.P., and Paschke R. Functional characterization of five constitutively activating thyrotrophin receptor mutations. Clin Endocrinol (Oxf) 53 (2000) 461-468
282. Wonerow P., Schoneberg T., Schultz G., Gudermann T., and Paschke R. Deletions in the third intracellular loop of the thyrotropin receptor. A new mechanism for constitutive activation. J Biol Chem 273 (1998) 7900-7905
283. Woodruff M.L., Wang Z., Chung H.Y., Redmond T.M., Fain G.L., and Lem J. Spontaneous activity of opsin apoprotein is a cause of Leber congenital amaurosis. Nat Genet 35 (2003) 158-164
284. Wortley K.E., del Rincon J.P., Murray J.D., Garcia K., Iida K., Thorner M.O., et al. Absence of ghrelin protects against early-onset obesity. J Clin Invest 115 (2005) 3573-3578
285. Wu S.M., Leschek E.W., Brain C., and Chan W.Y. A novel luteinizing hormone receptor mutation in a patient with familial male-limited precocious puberty: effect of the size of a critical amino acid on receptor activity. Mol Genet Metab 66 (1999) 68-73
286. Xiang Z., Litherland S.A., Sorensen N.B., Proneth B., Wood M.S., Shaw A.M., et al. Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. Biochemistry 45 (2006) 7277-7288
287. Xin Z., Serby M.D., Zhao H., Kosogof C., Szczepankiewicz B.G., Liu M., et al. Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists. J Med Chem 49 (2006) 4459-4469
288. Xin Z., Zhao H., Serby M.D., Liu B., Schaefer V.G., Falls D.H., et al. Synthesis and structure-activity relationships of isoxazole carboxamides as growth hormone secretagogue receptor antagonists. Bioorg Med Chem Lett 15 (2005) 1201-1204
289. Yang T., Snider B.B., and Oprian D.D. Synthesis and characterization of a novel retinylamine analog inhibitor of constitutively active rhodopsin mutants found in patients with autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A 94 (1997) 13559-13564
290. Yano K., Hidaka A., Saji M., Polymeropoulos M.H., Okuno A., Kohn L.D., et al. A sporadic case of male-limited precocious puberty has the same consitutively activating point mutation in luteinizing hormone/choriogonadotropin receptor gene as familial cases. J Clin Endocrinol Metab 79 (1994) 1818-1823
291. Yano K., Kohn L.D., Saji M., Kataoka N., Okuno A., and Cutler Jr. G.B. A case of male-limited precocious puberty caused by a point mutation in the second transmembrane domain of the luteinizing hormone choriogonadotropin receptor gene. Biochem Biophys Res Commun 220 (1996) 1036-1042
292. Yano K., Saji M., Hidaka A., Moriya N., Okuno A., Kohn L.D., et al. A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty. J Clin Endocrinol Metab 80 (1995) 1162-1168
293. Yeo G.S., Lank E.J., Farooqi I.S., Keogh J., Challis B.G., and O'Rahilly S. Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 12 (2003) 561-574
294. Young E.H., Wareham N.J., Farooqi S., Hinney A., Hebebrand J., Scherag A., et al. The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals. Int J Obes (Lond) 31 (2007) 1437-1441
295. Zhang M., Mizrachi D., Fanelli F., and Segaloff D.L. The formation of a salt bridge between helices 3 and 6 is responsible for the constitutive activity and lack of hormone responsiveness of the naturally occurring L457R mutation of the human lutropin receptor. J Biol Chem 280 (2005) 26169-26176
296. Zhang M., Tao Y.X., Ryan G.L., Feng X., Fanelli F., and Segaloff D.L. Intrinsic differences in the response of the human lutropin receptor versus the human follitropin receptor to activating mutations. J Biol Chem 282 (2007) 25527-25539
297. Zhao H., Xin Z., Liu G., Schaefer V.G., Falls H.D., Kaszubska W., et al. Discovery of tetralin carboxamide growth hormone secretagogue receptor antagonists via scaffold manipulation. J Med Chem 47 (2004) 6655-6657
298. Zhao H., Xin Z., Patel J.R., Nelson L.T., Liu B., Szczepankiewicz B.G., et al. Structure-activity relationship studies on tetralin carboxamide growth hormone secretagogue receptor antagonists. Bioorg Med Chem Lett 15 (2005) 1825-1828
299. 2+ receptor. FEBS Lett 448 (1999) 180-184
300. Zigman J.M., Nakano Y., Coppari R., Balthasar N., Marcus J.N., Lee C.E., et al. Mice lacking ghrelin receptors resist the development of
301. Zvyaga T.A., Fahmy K., and Sakmar T.P. Characterization of rhodopsin-transducin interaction: a mutant rhodopsin photoproduct with a protonated Schiff base activates transducin. Biochemistry 33 (1994) 9753-9761