Ghrelin Receptor Mutations and Human Obesity

Progress in Molecular Biology and Translational Science

Volumn 140, Issue , 2016, Pages 131-150

  Wang, W ^a   Tao, Y X ^a  

^a AUBURN UNIVERSITY   (United States)

Author keywords

growth hormone secretagogue receptor; human obesity; ligand binding; mutation; signaling

Indexed keywords

GHRELIN; GHRELIN RECEPTOR;

CARDIOVASCULAR FUNCTION; ENERGY; ENERGY EXPENDITURE; FOOD INTAKE; GENE MUTATION; GLUCOSE METABOLISM; GROWTH HORMONE RELEASE; HUMAN; LIGAND BINDING; OBESITY; PHYSIOLOGICAL PROCESS; PROTEIN EXPRESSION; SHORT STATURE; SINGLE NUCLEOTIDE POLYMORPHISM; STOMACH ACID SECRETION; ANIMAL; GENETICS; MUTATION; RAT; SIGNAL TRANSDUCTION;

ANIMALS; HUMANS; MUTATION; OBESITY; RATS; RECEPTORS, GHRELIN; SIGNAL TRANSDUCTION;

EID: 84961124779     PISSN: 18771173     EISSN: 18780814     Source Type: Book Series    
DOI: 10.1016/bs.pmbts.2016.02.001     Document Type: Chapter

References (80)

1. Callaghan, B., Furness, J.B., Novel and conventional receptors for ghrelin, desacyl-ghrelin, and pharmacologically related compounds. Pharmacol Rev 66 (2014), 984–1001.
2. Gahete, M.D., Rincon-Fernandez, D., Villa-Osaba, A., Hormaechea-Agulla, D., Ibanez-Costa, A., Martinez-Fuentes, A.J., Gracia-Navarro, F., Castano, J.P., Luque, R.M., Ghrelin gene products, receptors, and GOAT enzyme: biological and pathophysiological insight. J Endocrinol 220 (2014), R1–R24.
3. Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., Kangawa, K., Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402 (1999), 656–660.
4. 14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 275 (2000), 21995–22000.
5. Tanaka, M., Hayashida, Y., Iguchi, T., Nakao, N., Nakai, N., Nakashima, K., Organization of the mouse ghrelin gene and promoter: occurrence of a short noncoding first exon. Endocrinology 142 (2001), 3697–3700.
6. Angeloni, S.V., Glynn, N., Ambrosini, G., Garant, M.J., Higley, J.D., Suomi, S., Hansen, B.C., Characterization of the rhesus monkey ghrelin gene and factors influencing ghrelin gene expression and fasting plasma levels. Endocrinology 145 (2004), 2197–2205.
7. Ida, T., Miyazato, M., Lin, X.Z., Kaiya, H., Sato, T., Nakahara, K., Murakami, N., Kangawa, K., Kojima, M., Purification and characterization of caprine ghrelin and its effect on growth hormone release. J Mol Neurosci 42 (2010), 99–105.
8. Tomasetto, C., Wendling, C., Rio, M.C., Poitras, P., Identification of cDNA encoding motilin related peptide/ghrelin precursor from dog fundus. Peptides 22 (2001), 2055–2059.
9. Kojima, M., Ida, T., Sato, T., Structure of mammalian and nonmammalian ghrelins. Vitam Horm 77 (2008), 31–46.
10. Zhang, J.V., Ren, P.G., Avsian-Kretchmer, O., Luo, C.W., Rauch, R., Klein, C., Hsueh, A.J., Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 310 (2005), 996–999.
11. Yang, J., Brown, M.S., Liang, G., Grishin, N.V., Goldstein, J.L., Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132 (2008), 387–396.
12. Gutierrez, J.A., Solenberg, P.J., Perkins, D.R., Willency, J.A., Knierman, M.D., Jin, Z., Witcher, D.R., Luo, S., Onyia, J.E., Hale, J.E., Ghrelin, octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA 105 (2008), 6320–6325.
13. Ohgusu, H., Shirouzu, K., Nakamura, Y., Nakashima, Y., Ida, T., Sato, T., Kojima, M., Ghrelin O-acyltransferase (GOAT) has a preference for n-hexanoyl-CoA over n-octanoyl-CoA as an acyl donor. Biochem Biophys Res Commun 386 (2009), 153–158.
14. Wajnrajch, M.P., Ten, I.S., Gertner, J.M., Leibel, R.L., Genomic organization of the human GHRELIN gene. J Endocr Genet 1 (2000), 231–233.
15. Davenport, A.P., Bonner, T.I., Foord, S.M., Harmar, A.J., Neubig, R.R., Pin, J.P., Spedding, M., Kojima, M., Kangawa, K., International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev 57 (2005), 541–546.
16. Li, Z., Li, Y., Zhang, W., Ghrelin receptor in energy homeostasis and obesity pathogenesis. Prog Mol Biol Transl Sci 114 (2013), 45–87.
17. Gnanapavan, S., Kola, B., Bustin, S.A., Morris, D.G., McGee, P., Fairclough, P., Bhattacharya, S., Carpenter, R., Grossman, A.B., Korbonits, M., The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 87 (2002), 2988–2991.
18. Cowley, M.A., Smith, R.G., Diano, S., Tschop, M., Pronchuk, N., Grove, K.L., Strasburger, C.J., Bidlingmaier, M., Esterman, M., Heiman, M.L., Garcia-Segura, L.M., Nillni, E.A., Mendez, P., Low, M.J., Sotonyi, P., Friedman, J.M., Liu, H., Pinto, S., Colmers, W.F., Cone, R.D., Horvath, T.L., The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37 (2003), 649–661.
19. Kojima, M., Kangawa, K., Ghrelin: structure and function. Physiol Rev 85 (2005), 495–522.
20. Bowers, C.Y., Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci 54 (1998), 1316–1329.
21. Patchett, A.A., Nargund, R.P., Tata, J.R., Chen, M.H., Barakat, K.J., Johnston, D.B., Cheng, K., Chan, W.W., Butler, B., Hickey, G., Jacks, T., Schleim, K., Pong, S.S., Chaung, L.Y.P., Chen, H.Y., Frazier, E., Leung, K.H., Chiu, S.H.L., Smith, R.G., Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci USA 92 (1995), 7001–7005.
22. Pong, S.S., Chaung, L.Y., Dean, D.C., Nargund, R.P., Patchett, A.A., Smith, R.G., Identification of a new G-protein-linked receptor for growth hormone secretagogues. Mol Endocrinol 10 (1996), 57–61.
23. Howard, A.D., Feighner, S.D., Cully, D.F., Arena, J.P., Liberator, P.A., Rosenblum, C.I., Hamelin, M., Hreniuk, D.L., Palyha, O.C., Anderson, J., Paress, P.S., Diaz, C., Chou, M., Liu, K.K., McKee, K.K., Pong, S.S., Chaung, L.Y., Elbrecht, A., Dashkevicz, M., Heavens, R., Rigby, M., Sirinathsinghji, D.J., Dean, D.C., Melillo, D.G., Patchett, A.A., Nargund, R., Griffin, P.R., DeMartino, J.A., Gupta, S.K., Schaeffer, J.M., Smith, R.G., Van der Ploeg, L.H., A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273 (1996), 974–977.
24. McKee, K.K., Palyha, O.C., Feighner, S.D., Hreniuk, D.L., Tan, C.P., Phillips, M.S., Smith, R.G., Van der Ploeg, L.H., Howard, A.D., Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 11 (1997), 415–423.
25. Guan, X.M., Yu, H., Palyha, O.C., McKee, K.K., Feighner, S.D., Sirinathsinghji, D.J., Smith, R.G., Van der Ploeg, L.H., Howard, A.D., Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48 (1997), 23–29.
26. Leung, P.K., Chow, K.B., Lau, P.N., Chu, K.M., Chan, C.B., Cheng, C.H., Wise, H., The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant-negative mutant of the ghrelin receptor. Cell Signal 19 (2007), 1011–1022.
27. Chow, K.B., Sun, J., Chu, K.M., Tai Cheung, W., Cheng, C.H., Wise, H., The truncated ghrelin receptor polypeptide (GHS-R1b) is localized in the endoplasmic reticulum where it forms heterodimers with ghrelin receptors (GHS-R1a) to attenuate their cell surface expression. Mol Cell Endocrinol 348 (2012), 247–254.
28. Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., Matsukura, S., A role for ghrelin in the central regulation of feeding. Nature 409 (2001), 194–198.
29. Broglio, F., Arvat, E., Benso, A., Gottero, C., Muccioli, G., Papotti, M., van der Lely, A.J., Deghenghi, R., Ghigo, E., Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 86 (2001), 5083–5086.
30. Shimizu, Y., Nagaya, N., Teranishi, Y., Imazu, M., Yamamoto, H., Shokawa, T., Kangawa, K., Kohno, N., Yoshizumi, M., Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats. Biochem Biophys Res Commun 310 (2003), 830–835.
31. Masuda, Y., Tanaka, T., Inomata, N., Ohnuma, N., Tanaka, S., Itoh, Z., Hosoda, H., Kojima, M., Kangawa, K., Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 276 (2000), 905–908.
32. Li, W.G., Gavrila, D., Liu, X., Wang, L., Gunnlaugsson, S., Stoll, L.L., McCormick, M.L., Sigmund, C.D., Tang, C., Weintraub, N.L., Ghrelin inhibits proinflammatory responses and nuclear factor-κB activation in human endothelial cells. Circulation 109 (2004), 2221–2226.
33. Cummings, D.E., Purnell, J.Q., Frayo, R.S., Schmidova, K., Wisse, B.E., Weigle, D.S., A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50 (2001), 1714–1719.
34. Holst, B., Cygankiewicz, A., Jensen, T.H., Ankersen, M., Schwartz, T.W., High constitutive signaling of the ghrelin receptor–identification of a potent inverse agonist. Mol Endocrinol 17 (2003), 2201–2210.
35. Granata, R., Settanni, F., Biancone, L., Trovato, L., Nano, R., Bertuzzi, F., Destefanis, S., Annunziata, M., Martinetti, M., Catapano, F., Ghe, C., Isgaard, J., Papotti, M., Ghigo, E., Muccioli, G., Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3’,5’-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling. Endocrinology 148 (2007), 512–529.
36. Mousseaux, D., Le Gallic, L., Ryan, J., Oiry, C., Gagne, D., Fehrentz, J.A., Galleyrand, J.C., Martinez, J., Regulation of ERK1/2 activity by ghrelin-activated growth hormone secretagogue receptor 1A involves a PLC/PKCɛ pathway. Br J Pharmacol 148 (2006), 350–365.
37. Sivertsen, B., Lang, M., Frimurer, T.M., Holliday, N.D., Bach, A., Els, S., Engelstoft, M.S., Petersen, P.S., Madsen, A.N., Schwartz, T.W., Beck-Sickinger, A.G., Holst, B., Unique interaction pattern for a functionally biased ghrelin receptor agonist. J Biol Chem 286 (2011), 20845–20860.
38. Damian, M., Marie, J., Leyris, J.P., Fehrentz, J.A., Verdie, P., Martinez, J., Baneres, J.L., Mary, S., High constitutive activity is an intrinsic feature of ghrelin receptor protein: a study with a functional monomeric GHS-R1a receptor reconstituted in lipid discs. J Biol Chem 287 (2012), 3630–3641.
39. Holst, B., Lang, M., Brandt, E., Bach, A., Howard, A., Frimurer, T.M., Beck-Sickinger, A., Schwartz, T.W., Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Mol Pharmacol 70 (2006), 936–946.
40. Lall, S., Balthasar, N., Carmignac, D., Magoulas, C., Sesay, A., Houston, P., Mathers, K., Robinson, I., Physiological studies of transgenic mice overexpressing growth hormone (GH) secretagogue receptor 1A in GH-releasing hormone neurons. Endocrinology 145 (2004), 1602–1611.
41. Petersen, P.S., Woldbye, D.P., Madsen, A.N., Egerod, K.L., Jin, C., Lang, M., Rasmussen, M., Beck-Sickinger, A.G., Holst, B., In vivo characterization of high basal signaling from the ghrelin receptor. Endocrinology 150 (2009), 4920–4930.
42. Holst, B., Schwartz, T.W., Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation. Trends Pharmacol Sci 25 (2004), 113–117.
43. Cameron, K.O., Bhattacharya, S.K., Loomis, A.K., Small molecule ghrelin receptor inverse agonists and antagonists. J Med Chem 57 (2014), 8671–8691.
44. Tao, Y.X., Constitutive activation of G protein-coupled receptors and diseases: insights into mechanism of activation and therapeutics. Pharmacol Ther 120 (2008), 129–148.
45. Tao, Y.X., Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol 239 (2005), 1–14.
46. Tao, Y.X., Huang, H., Wang, Z.Q., Yang, F., Williams, J.N., Nikiforovich, G.V., Constitutive activity of neural melanocortin receptors. Methods Enzymol 484 (2010), 267–279.
47. Tao, Y.X., Constitutive activity in melanocortin-4 receptor: biased signaling of inverse agonists. Adv Pharmacol 70 (2014), 135–154.
48. Srinivasan, S., Lubrano-Berthelier, C., Govaerts, C., Picard, F., Santiago, P., Conklin, B.R., Vaisse, C., 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.
49. Tao, Y.X., Mutations in melanocortin-4 receptor and human obesity. Prog Mol Biol Transl Sci 88 (2009), 173–204.
50. Tao, Y.X., The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 31 (2010), 506–543.
51. Tschop, M., Smiley, D.L., Heiman, M.L., Ghrelin induces adiposity in rodents. Nature 407 (2000), 908–913.
52. Wren, A.M., Seal, L.J., Cohen, M.A., Brynes, A.E., Frost, G.S., Murphy, K.G., Dhillo, W.S., Ghatei, M.A., Bloom, S.R., Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86 (2001), 5992–5995.
53. Kroemer, N.B., Krebs, L., Kobiella, A., Grimm, O., Pilhatsch, M., Bidlingmaier, M., Zimmermann, U.S., Smolka, M.N., Fasting levels of ghrelin covary with the brain response to food pictures. Addict Biol 18 (2013), 855–862.
54. Holsen, L.M., Lawson, E.A., Christensen, K., Klibanski, A., Goldstein, J.M., Abnormal relationships between the neural response to high- and low-calorie foods and endogenous acylated ghrelin in women with active and weight-recovered anorexia nervosa. Psychiatry Res 223 (2014), 94–103.
55. Sun, Y., Wang, P., Zheng, H., Smith, R.G., Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci USA 101 (2004), 4679–4684.
56. Zigman, J.M., Nakano, Y., Coppari, R., Balthasar, N., Marcus, J.N., Lee, C.E., Jones, J.E., Deysher, A.E., Waxman, A.R., White, R.D., Williams, T.D., Lachey, J.L., Seeley, R.J., Lowell, B.B., Elmquist, J.K., Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 115 (2005), 3564–3572.
57. Chen, H.Y., Trumbauer, M.E., Chen, A.S., Weingarth, D.T., Adams, J.R., Frazier, E.G., Shen, Z., Marsh, D.J., Feighner, S.D., Guan, X.M., Ye, Z., Nargund, R.P., Smith, R.G., Van der Ploeg, L.H., Howard, A.D., MacNeil, D.J., Qian, S., Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 145 (2004), 2607–2612.
58. Kola, B., Farkas, I., Christ-Crain, M., Wittmann, G., Lolli, F., Amin, F., Harvey-White, J., Liposits, Z., Kunos, G., Grossman, A.B., Fekete, C., Korbonits, M., The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS One, 3, 2008, e1797.
59. Baessler, A., Hasinoff, M.J., Fischer, M., Reinhard, W., Sonnenberg, G.E., Olivier, M., Erdmann, J., Schunkert, H., Doering, A., Jacob, H.J., Comuzzie, A.G., Kissebah, A.H., Kwitek, A.E., Genetic linkage and association of the growth hormone secretagogue receptor (ghrelin receptor) gene in human obesity. Diabetes 54 (2005), 259–267.
60. Wang, H.J., Geller, F., Dempfle, A., Schauble, N., Friedel, S., Lichtner, P., Fontenla-Horro, F., Wudy, S., Hagemann, S., Gortner, L., Huse, K., Remschmidt, H., Bettecken, T., Meitinger, T., Schafer, H., Hebebrand, J., Hinney, A., 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.
61. Pantel, J., Legendre, M., Cabrol, S., Hilal, L., Hajaji, Y., Morisset, S., Nivot, S., Vie-Luton, M.P., Grouselle, D., de Kerdanet, M., Kadiri, A., Epelbaum, J., Le Bouc, Y., Amselem, S., Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 116 (2006), 760–768.
62. Liu, G., Fortin, J.P., Beinborn, M., Kopin, A.S., Four missense mutations in the ghrelin receptor result in distinct pharmacological abnormalities. J Pharmacol Exp Ther 322 (2007), 1036–1043.
63. Mager, U., Degenhardt, T., Pulkkinen, L., Kolehmainen, M., Tolppanen, A.M., Lindstrom, J., Eriksson, J.G., Carlberg, C., Tuomilehto, J., Uusitupa, M., Finnish Diabetes Prevention Study Group. Variations in the ghrelin receptor gene associate with obesity and glucose metabolism in individuals with impaired glucose tolerance. PLoS One, 3, 2008, e2941.
64. Dossus, L., McKay, J.D., Canzian, F., Wilkening, S., Rinaldi, S., Biessy, C., Olsen, A., Tjonneland, A., Jakobsen, M.U., Overvad, K., Clavel-Chapelon, F., Boutron-Ruault, M.C., Fournier, A., Linseisen, J., Lukanova, A., Boeing, H., Fisher, E., Trichopoulou, A., Georgila, C., Trichopoulos, D., Palli, D., Krogh, V., Tumino, R., Vineis, P., Quiros, J.R., Sala, N., Martinez-Garcia, C., Dorronsoro, M., Chirlaque, M.D., Barricarte, A., van Duijnhoven, F.J., Bueno-de-Mesquita, H.B., van Gils, C.H., Peeters, P.H., Hallmans, G., Lenner, P., Bingham, S., Khaw, K.T., Key, T.J., Travis, R.C., Ferrari, P., Jenab, M., Riboli, E., Kaaks, R., Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk: a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Carcinogenesis 29 (2008), 1360–1366.
65. Pantel, J., Legendre, M., Nivot, S., Morisset, S., Vie-Luton, M.P., le Bouc, Y., Epelbaum, J., Amselem, S., Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. J Clin Endocrinol Metab 94 (2009), 4334–4341.
66. Gjesing, A.P., Larsen, L.H., Torekov, S.S., Hainerova, I.A., Kapur, R., Johansen, A., Albrechtsen, A., Boj, S., Holst, B., Harper, A., Urhammer, S.A., Borch-Johnsen, K., Pisinger, C., Echwald, S.M., Eiberg, H., Astrup, A., Lebl, J., Ferrer, J., Schwartz, T.W., Hansen, T., Pedersen, O., Family and population-based studies of variation within the ghrelin receptor locus in relation to measures of obesity. PLoS One, 5, 2010, e10084.
67. Inoue, H., Kangawa, N., Kinouchi, A., Sakamoto, Y., Kimura, C., Horikawa, R., Shigematsu, Y., Itakura, M., Ogata, T., Fujieda, K., Japan Growth Genome Consortium. Identification and functional analysis of novel human growth hormone secretagogue receptor (GHSR) gene mutations in Japanese subjects with short stature. J Clin Endocrinol Metab 96 (2011), E373–E378.
68. Pugliese-Pires, P.N., Fortin, J.P., Arthur, T., Latronico, A.C., Mendonca, B.B., Villares, S.M., Arnhold, I.J., Kopin, A.S., Jorge, A.A., Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty. Eur J Endocrinol 165 (2011), 233–241.
69. Garcia, E.A., King, P., Sidhu, K., Ohgusu, H., Walley, A., Lecoeur, C., Gueorguiev, M., Khalaf, S., Davies, D., Grossman, A.B., Kojima, M., Petersenn, S., Froguel, P., Korbonits, M., The role of ghrelin and ghrelin-receptor gene variants and promoter activity in type 2 diabetes. Eur J Endocrinol 161 (2009), 307–315.
70. Gueorguiev, M., Lecoeur, C., Meyre, D., Benzinou, M., Mein, C.A., Hinney, A., Vatin, V., Weill, J., Heude, B., Hebebrand, J., Grossman, A.B., Korbonits, M., Froguel, P., Association studies on ghrelin and ghrelin receptor gene polymorphisms with obesity. Obesity (Silver Spring) 17 (2009), 745–754.
71. Liu, B., Garcia, E.A., Korbonits, M., Genetic studies on the ghrelin, growth hormone secretagogue receptor (GHSR) and ghrelin O-acyl transferase (GOAT) genes. Peptides 32 (2011), 2191–2207.
72. Tao, Y.X., Inactivating mutations of G protein-coupled receptors and diseases: structure-function insights and therapeutic implications. Pharmacol Ther 111 (2006), 949–973.
73. Tao, Y.X., Conn, P.M., Chaperoning G protein-coupled receptors: from cell biology to therapeutics. Endocr Rev 35 (2014), 602–647.
74. Holst, B., Holliday, N.D., Bach, A., Elling, C.E., Cox, H.M., Schwartz, T.W., Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem 279 (2004), 53806–53817.
75. Tao, Y.X., Segaloff, D.L., Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology 144 (2003), 4544–4551.
76. Wortley, K.E., del Rincon, J.P., Murray, J.D., Garcia, K., Iida, K., Thorner, M.O., Sleeman, M.W., Absence of ghrelin protects against early-onset obesity. J Clin Invest 115 (2005), 3573–3578.
77. Mo, X.L., Tao, Y.X., Activation of MAPK by inverse agonists in six naturally occurring constitutively active mutant human melanocortin-4 receptors. Biochim Biophys Acta 1832 (2013), 1939–1948.
78. Fan, Z.C., Tao, Y.X., Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients. J Cell Mol Med 13 (2009), 3268–3282.
79. Tao, Y.X., Huang, H., Ipsen 5i is a novel potent pharmacoperone for intracellularly retained melanocortin-4 receptor mutants. Front Endocrinol (Lausanne), 5, 2014, 131.
80. Huang, H., Tao, Y.X., A small molecule agonist THIQ as a novel pharmacoperone for intracellularly retained melanocortin-4 receptor mutants. Int J Biol Sci 10 (2014), 817–824.