Four missense mutations in the ghrelin receptor result in distinct pharmacological abnormalities

Journal of Pharmacology and Experimental Therapeutics

Volumn 322, Issue 3, 2007, Pages 1036-1043

  Liu, Guang ^a   Fortin, Jean Philippe ^a   Beinborn, Martin ^a   Kopin, Alan S ^a,b  

^a TUFTS MEDICAL CENTER   (United States)

^b NONE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GHRELIN; GROWTH HORMONE SECRETAGOGUE RECEPTOR; INOSITOL PHOSPHATE;

ARTICLE; CELL MEMBRANE; CELL SURFACE; CONTROLLED STUDY; ENZYME LINKED IMMUNOSORBENT ASSAY; GENETIC ANALYSIS; GENETIC VARIABILITY; HUMAN; HUMAN CELL; INTRACELLULAR MEMBRANE; MISSENSE MUTATION; MUTATION RATE; PRIORITY JOURNAL; PROTEIN EXPRESSION; RECEPTOR DENSITY; SIGNAL TRANSDUCTION; SUBSTITUTION REACTION; WHOLE CELL; WILD TYPE;

HUMANS; MEMBRANE PROTEINS; MUTATION, MISSENSE; PROTEIN TRANSPORT; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; VARIATION (GENETICS);

EID: 34548093246     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.107.123141     Document Type: Article

References (30)

1. Al-Fulaij MA, Ren Y, Beinborn M, and Kopin AS (2007) Identification of amino acid determinants of dopamine 2 receptor synthetic agonist function. J Pharmacol Exp Ther 321:298-307.
2. Beinborn M, Lee YM, McBride EW, Quinn SM, and Kopin AS (1993) A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for nonpeptide antagonists. Nature 362:348-350.
3. Beinborn M, Quinn SM, and Kopin AS (1998) Minor modifications of a cholecystokinin-B/gastrin receptor non-peptide antagonist confer a broad spectrum of functional properties. J Biol Chem 273:14146-14151.
4. Beinborn M, Ren Y, Blaker M, Chen C, and Kopin AS (2004) Ligand function at constitutively active receptor mutants is affected by two distinct yet interacting mechanisms. Mol Pharmacol 65:753-760.
5. Bläker M, Ren Y, Gordon MC, Hsu JE, Beinborn M, and Kopin AS (1998) Mutations within the cholecystokinin-B/gastrin receptor ligand "pocket" interconvert the functions of nonpeptide agonists and antagonists. Mol Pharmacol 54:857-863.
6. Hearn MG, Ren Y, McBride EW, Reveillaud I, Beinborn M, and Kopin AS (2002) A Drosophila dopamine 2-like receptor: molecular characterization and identification of multiple alternatively spliced variants. Proc Natl Acad Sci U S A 99:14554-14559.
7. Holst B, Cygankiewicz A, Jensen TH, Ankersen M, and Schwartz TW (2003) High constitutive signaling of the ghrelin receptor: identification of a potent inverse agonist. Mol Endocrinol 17:2201-2210.
8. Holst B, Holliday ND, Bach A, Elling CE, Cox HM, and Schwartz TW (2004) Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem 279:53806-53817.
9. Holst B, Lang M, Brandt E, Bach A, Howard A, Frimurer TM, Beck-Sickinger A, and Schwartz TW (2006) Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Mol Pharmacol 70:936-946.
10. Holst B and Schwartz TW (2004) Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation. Trends Pharmacol Sci 25:113-117.
11. Holst B and Schwartz TW (2006) Ghrelin receptor mutations: too little height and too much hunger. J Clin Invest 116:637-641.
12. Hosoda H, Kojima M, and Kangawa K (2006) Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci 100:398-410.
13. Kojima M and Kangawa K (2005) Ghrelin: structure and function. Physiol Rev 85:495-522.
14. Lall S, Balthasar N, Carmignac D, Magoulas C, Sesay A, Houston P, Mathers K, and Robinson I (2004) Physiological studies of transgenic mice overexpressing growth hormone (GH) secretagogue receptor 1A in GH-releasing hormone neurons. Endocrinology 145:1602-1611.
15. Lefkowitz RJ, Cotecchia S, Samama P, and Costa T (1993) Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol Sci 14:303-307.
16. Li J, Chen C, Huang P, and Li-Chen LY (2001) Inverse agonist up-regulates the constitutively active D3.49(164)Q mutant of the rat mu-opioid receptor by stabilizing the structure and blocking constitutive internalization and down-regulation. Mol Pharmacol 60:1064-1075.
17. Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J, Ferron C, Froguel P, and Vaisse C (2003) Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 12:145-153.
18. MacEwan DJ and Milligan G (1996) Inverse agonist-induced up-regulation of the human beta2-adrenoceptor in transfected neuroblastoma X glioma hybrid cells. Mol Pharmacol 50:1479-1486.
19. Morello JP, Salahpour A, Laperriere A, Bernier V, Arthus MF, Lonergan M, Petaja-Repo U, Angers S, Morin D, Bichet DG, et al. (2000) Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 105:887-895.
20. Mukherjee RS, McBride EW, Beinborn M, Dunlap K, and Kopin AS (2006) Point mutations in either subunit of the GABAB receptor confer constitutive activity to the heterodimer. Mol Pharmacol 70:1406-1413.
21. Oksche A and Rosenthal W (1998) The molecular basis of nephrogenic diabetes insipidus. J Mol Med 76:326-337.
22. Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton MP, Grouselle D, de Kerdanet M, et al. (2006) Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 116:760-768.
23. Santini F, Maffei M, Ceccarini G, Pelosini C, Scartabelli G, Rosellini V, Chiellini C, Marsili A, Lisi S, Tonacchera M, et al. (2004) Genetic screening for melanocortin-4 receptor mutations in a cohort of Italian obese patients: description and functional characterization of a novel mutation. J Clin Endocrinol Metab 89:904-908.
24. Shinyama H, Masuzaki H, Fang H, and Flier JS (2003) Regulation of melanocortin-4 receptor signaling: agonist-mediated desensitization and internalization. Endocrinology 144:1301-1314.
25. Shuto Y, Shibasaki T, Otagiri A, Kuriyama H, Ohata H, Tamura H, Kamegai J, Sugihara H, Oikawa S, and Wakabayashi I (2002) Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J Clin Invest 109:1429-1436.
26. Srinivasan S, Lubrano-Berthelier C, Govaerts C, Picard F, Santiago P, Conklin BR, and Vaisse C (2004) 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 114:1158-1164.
27. Sun Y, Wang P, Zheng H, and Smith RG (2004) Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci U S A 101:4679-4684.
28. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, and Froguel P (2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106:253-262.
29. Wang HJ, Geller F, Dempfle A, Schäuble N, Friedel S, Lichtner P, Fontenla-Horro F, Wudy S, Hagemann S, Gortner L, et al. (2004) 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 89:157-162.
30. Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD, et al. (2005) Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 115:3564-3572.