1. University of Cambridge, UK
2. University of Copenhagen, Denmark

Abstract

The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [19]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids [74]. Alternative splicing results in the formation of a second peptide, [des-Gln¹⁴]ghrelin with equipotent biological activity [49]. A unique post-translational modification (octanoylation of Ser³, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) [133] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [58]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [4], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function [44]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [35, 68] inhibits ghrelin receptor-induced GH secretion and food intake [35]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [71]. In cell systems, the ghrelin receptor is constitutively active [45], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [93].

Contents

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [8].

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

References

1. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K and Toyooka S et al.. (2001) Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 86: 4753-8 [PMID:11600536]
2. Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, Malan D, Baj G, Granata R and Broglio F et al.. (2002) Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 159: 1029-37 [PMID:12486113]
3. Bedendi I, Alloatti G, Marcantoni A, Malan D, Catapano F, Ghé C, Deghenghi R, Ghigo E and Muccioli G. (2003) Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin. Eur J Pharmacol 476: 87-95 [PMID:12969753]
4. Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL, Silva MV, Warren VA, Howard AD, Van Der Ploeg LH and Heck JV. (2000) Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 43: 4370-6 [PMID:11087562]
5. Bennett KA, Langmead CJ, Wise A and Milligan G. (2009) Growth hormone secretagogues and growth hormone releasing peptides act as orthosteric super-agonists but not allosteric regulators for activation of the G protein Galpha(o1) by the Ghrelin receptor. Mol Pharmacol 76: 802-11 [PMID:19625579]
6. Bodart V, Febbraio M, Demers A, McNicoll N, Pohankova P, Perreault A, Sejlitz T, Escher E, Silverstein RL and Lamontagne D et al.. (2002) CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res 90: 844-9 [PMID:11988484]
7. Broglio F, Boutignon F, Benso A, Gottero C, Prodam F, Arvat E, Ghè C, Catapano F, Torsello A and Locatelli V et al.. (2002) EP1572: a novel peptido-mimetic GH secretagogue with potent and selective GH-releasing activity in man. J Endocrinol Invest 25: RC26-8 [PMID:12240910]
8. Buneman P, Christie G, Davies JA, Dimitrellou R, Harding SD, Pawson AJ, Sharman JL and Wu Y. (2020) Why data citation isn't working, and what to do about it Database 2020 [PMID:32367113]
9. Cassoni P, Ghé C, Marrocco T, Tarabra E, Allia E, Catapano F, Deghenghi R, Ghigo E, Papotti M and Muccioli G. (2004) Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines. Eur J Endocrinol 150: 173-84 [PMID:14763915]
10. Cassoni P, Papotti M, Catapano F, Ghè C, Deghenghi R, Ghigo E and Muccioli G. (2000) Specific binding sites for synthetic growth hormone secretagogues in non-tumoral and neoplastic human thyroid tissue. J Endocrinol 165: 139-46 [PMID:10750044]
11. Cassoni P, Papotti M, Ghè C, Catapano F, Sapino A, Graziani A, Deghenghi R, Reissmann T, Ghigo E and Muccioli G. (2001) Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines. J Clin Endocrinol Metab 86: 1738-45 [PMID:11297611]
12. Chen CY and Tsai CY. (2012) Ghrelin and motilin in the gastrointestinal system. Curr Pharm Des 18: 4755-65 [PMID:22632857]
13. Chu KM, Chow KB, Leung PK, Lau PN, Chan CB, Cheng CH and Wise H. (2007) Over-expression of the truncated ghrelin receptor polypeptide attenuates the constitutive activation of phosphatidylinositol-specific phospholipase C by ghrelin receptors but has no effect on ghrelin-stimulated extracellular signal-regulated kinase 1/2 activity. Int J Biochem Cell Biol 39: 752-64 [PMID:17169600]
14. Costantini VJ, Vicentini E, Sabbatini FM, Valerio E, Lepore S, Tessari M, Sartori M, Michielin F, Melotto S and Bifone A et al.. (2011) GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs. Neuroendocrinology 94: 158-68 [PMID:21778696]
15. Cummings DE, Foster-Schubert KE and Overduin J. (2005) Ghrelin and energy balance: focus on current controversies. Curr Drug Targets 6: 153-69 [PMID:15777186]
16. Damian M, Marie J, Leyris JP, Fehrentz JA, Verdié P, Martinez J, Banères JL and Mary S. (2012) 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: 3630-41 [PMID:22117076]
17. Dash PK, Karl KA, Colicos MA, Prywes R and Kandel ER. (1991) cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. Proc Natl Acad Sci USA 88: 5061-5 [PMID:1647024]
18. Date Y, Murakami N, Kojima M, Kuroiwa T, Matsukura S, Kangawa K and Nakazato M. (2000) Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. Biochem Biophys Res Commun 275: 477-80 [PMID:10964690]
19. Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, Spedding M, Kojima M and Kangawa K. (2005) International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev 57: 541-6 [PMID:16382107]
20. Delhanty PJ, Sun Y, Visser JA, van Kerkwijk A, Huisman M, van Ijcken WF, Swagemakers S, Smith RG, Themmen AP and van der Lely AJ. (2010) Unacylated ghrelin rapidly modulates lipogenic and insulin signaling pathway gene expression in metabolically active tissues of GHSR deleted mice. PLoS ONE 5: e11749 [PMID:20668691]
21. Depoortere I, De Winter B, Thijs T, De Man J, Pelckmans P and Peeters T. (2005) Comparison of the gastroprokinetic effects of ghrelin, GHRP-6 and motilin in rats in vivo and in vitro. Eur J Pharmacol 515: 160-8 [PMID:15890336]
22. Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA and Jerlhag E. (2011) The role of the central ghrelin system in reward from food and chemical drugs. Mol Cell Endocrinol 340: 80-7 [PMID:21354264]
23. Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, Lillard JW and Taub DD. (2004) Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 114: 57-66 [PMID:15232612]
24. Dixit VD, Yang H, Cooper-Jenkins A, Giri BB, Patel K and Taub DD. (2009) Reduction of T cell-derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation. Blood 113: 5202-5 [PMID:19324904]
25. Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, Ghatei MA, Small C and Bloom SR. (2005) Ghrelin increases food intake in obese as well as lean subjects. Int J Obes (Lond.) 29: 1130-6 [PMID:15917842]
26. Duxbury MS, Waseem T, Ito H, Robinson MK, Zinner MJ, Ashley SW and Whang EE. (2003) Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness. Biochem Biophys Res Commun 309: 464-8 [PMID:12951072]
27. Edholm T, Levin F, Hellström PM and Schmidt PT. (2004) Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons. Regul Pept 121: 25-30 [PMID:15256270]
28. Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown SE, Bullock W, Daly M, Decarr L and Li Y et al.. (2007) Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology 148: 5175-85 [PMID:17656463]
29. Esposito M, Pellinen J, Kapás L and Szentirmai É. (2012) Impaired wake-promoting mechanisms in ghrelin receptor-deficient mice. Eur J Neurosci 35: 233-43 [PMID:22211783]
30. Feighner SD, Howard AD, Prendergast K, Palyha OC, Hreniuk DL, Nargund R, Underwood D, Tata JR, Dean DC and Tan CP et al.. (1998) Structural requirements for the activation of the human growth hormone secretagogue receptor by peptide and nonpeptide secretagogues. Mol Endocrinol 12: 137-45 [PMID:9440817]
31. Frascarelli S, Ghelardoni S, Ronca-Testoni S and Zucchi R. (2003) Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart. Basic Res Cardiol 98: 401-5 [PMID:14556085]
32. Fraser GL, Hoveyda HR and Tannenbaum GS. (2008) Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist. Endocrinology 149: 6280-8 [PMID:18719021]
33. Fujino K, Inui A, Asakawa A, Kihara N, Fujimura M and Fujimiya M. (2003) Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J Physiol (Lond.) 550: 227-40 [PMID:12837928]
34. Gaytan F, Morales C, Barreiro ML, Jeffery P, Chopin LK, Herington AC, Casanueva FF, Aguilar E, Dieguez C and Tena-Sempere M. (2005) Expression of growth hormone secretagogue receptor type 1a, the functional ghrelin receptor, in human ovarian surface epithelium, mullerian duct derivatives, and ovarian tumors. J Clin Endocrinol Metab 90: 1798-804 [PMID:15585554]
35. Ge X, Yang H, Bednarek MA, Galon-Tilleman H, Chen P, Chen M, Lichtman JS, Wang Y, Dalmas O and Yin Y et al.. (2018) LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor. Cell Metab 27: 461-469.e6 [PMID:29233536]
36. Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB and Korbonits M. (2002) The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 87: 2988 [PMID:12050285]
37. Gozé C, Bergé G, M'Kadmi C, Floquet N, Gagne D, Galleyrand JC, Fehrentz JA and Martinez J. (2010) Involvement of tryptophan W276 and of two surrounding amino acid residues in the high constitutive activity of the ghrelin receptor GHS-R1a. Eur J Pharmacol 643: 153-61 [PMID:20599926]
38. Gualillo O, Caminos J, Blanco M, Garcìa-Caballero T, Kojima M, Kangawa K, Dieguez C and Casanueva F. (2001) Ghrelin, a novel placental-derived hormone. Endocrinology 142: 788-94 [PMID:11159851]
39. Halem HA, Taylor JE, Dong JZ, Shen Y, Datta R, Abizaid A, Diano S, Horvath T, Zizzari P and Bluet-Pajot MT et al.. (2004) Novel analogs of ghrelin: physiological and clinical implications. Eur J Endocrinol 151 Suppl 1: S71-5 [PMID:15339248]
40. Hansen BS, Raun K, Nielsen KK, Johansen PB, Hansen TK, Peschke B, Lau J, Andersen PH and Ankersen M. (1999) Pharmacological characterisation of a new oral GH secretagogue, NN703. Eur J Endocrinol 141: 180-9 [PMID:10427162]
41. Holliday ND, Holst B, Rodionova EA, Schwartz TW and Cox HM. (2007) Importance of constitutive activity and arrestin-independent mechanisms for intracellular trafficking of the ghrelin receptor. Mol Endocrinol 21: 3100-12 [PMID:17717076]
42. Holst B, Brandt E, Bach A, Heding A and Schwartz TW. (2005) Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling. Mol Endocrinol 19: 2400-11 [PMID:15905359]
43. 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: 2201-10 [PMID:12907757]
44. Holst B, Frimurer TM, Mokrosinski J, Halkjaer T, Cullberg KB, Underwood CR and Schwartz TW. (2009) Overlapping binding site for the endogenous agonist, small-molecule agonists, and ago-allosteric modulators on the ghrelin receptor. Mol Pharmacol 75: 44-59 [PMID:18923064]
45. 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: 53806-17 [PMID:15383539]
46. 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: 936-46 [PMID:16798937]
47. Holst B, Mokrosinski J, Lang M, Brandt E, Nygaard R, Frimurer TM, Beck-Sickinger AG and Schwartz TW. (2007) Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism. J Biol Chem 282: 15799-811 [PMID:17371869]
48. Holst B and Schwartz TW. (2004) Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation. Trends Pharmacol Sci 25: 113-7 [PMID:15058279]
49. Hosoda H, Kojima M, Matsuo H and Kangawa K. (2000) Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 275: 21995-2000 [PMID:10801861]
50. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC and Anderson J et al.. (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273: 974-7 [PMID:8688086]
51. Jiang H, Betancourt L and Smith RG. (2006) Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Mol Endocrinol 20: 1772-85 [PMID:16601073]
52. Kageyama H, Funahashi H, Hirayama M, Takenoya F, Kita T, Kato S, Sakurai J, Lee EY, Inoue S and Date Y et al.. (2005) Morphological analysis of ghrelin and its receptor distribution in the rat pancreas. Regul Pept 126: 67-71 [PMID:15620416]
53. Karasawa H, Pietra C, Giuliano C, Garcia-Rubio S, Xu X, Yakabi S, Taché Y and Wang L. (2014) New ghrelin agonist, HM01 alleviates constipation and L-dopa-delayed gastric emptying in 6-hydroxydopamine rat model of Parkinson's disease. Neurogastroenterol Motil 26: 1771-82 [PMID:25327342]
54. Katugampola SD, Pallikaros Z and Davenport AP. (2001) [125I-His(9)]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis. Br J Pharmacol 134: 143-9 [PMID:11522606]
55. Kern A, Albarran-Zeckler R, Walsh HE and Smith RG. (2012) Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron 73: 317-32 [PMID:22284186]
56. Kleinz MJ, Kuc RE, Maguire JJ and Davenport AP.. Endogenous vasodilator ghrelin and its growth hormone secretagogue receptor 1a (GHS-R1a) immunocytochemically localize to endothelial cells within the human vasculature.
57. Kobelt P, Tebbe JJ, Tjandra I, Stengel A, Bae HG, Andresen V, van der Voort IR, Veh RW, Werner CR and Klapp BF et al.. (2005) CCK inhibits the orexigenic effect of peripheral ghrelin. Am J Physiol Regul Integr Comp Physiol 288: R751-8 [PMID:15550621]
58. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H and Kangawa K. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656-60 [PMID:10604470]
59. Kojima M and Kangawa K. (2005) Ghrelin: structure and function. Physiol Rev 85: 495-522 [PMID:15788704]
60. Kong J, Chuddy J, Stock IA, Loria PM, Straub SV, Vage C, Cameron KO, Bhattacharya SK, Lapham K and McClure KF et al.. (2016) Pharmacological characterization of the first in class clinical candidate PF-05190457: a selective ghrelin receptor competitive antagonist with inverse agonism that increases vagal afferent firing and glucose-dependent insulin secretion ex vivo. Br J Pharmacol 173: 1452-64 [PMID:26784385]
61. Korbonits M, Kojima M, Kangawa K and Grossman AB. (2001) Presence of ghrelin in normal and adenomatous human pituitary. Endocrine 14: 101-4 [PMID:11322490]
62. Lai JK, Cheng CH, Ko WH and Leung PS. (2005) Ghrelin system in pancreatic AR42J cells: its ligand stimulation evokes calcium signalling through ghrelin receptors. Int J Biochem Cell Biol 37: 887-900 [PMID:15694847]
63. Li GZ, Jiang W, Zhao J, Pan CS, Cao J, Tang CS and Chang L. (2005) Ghrelin blunted vascular calcification in vivo and in vitro in rats. Regul Pept 129: 167-76 [PMID:15927713]
64. Li WG, Gavrila D, Liu X, Wang L, Gunnlaugsson S, Stoll LL, McCormick ML, Sigmund CD, Tang C and Weintraub NL. (2004) Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation 109: 2221-6 [PMID:15117840]
65. Lin L, Saha PK, Ma X, Henshaw IO, Shao L, Chang BH, Buras ED, Tong Q, Chan L and McGuinness OP et al.. (2011) Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell 10: 996-1010 [PMID:21895961]
66. Lin Y, Matsumura K, Fukuhara M, Kagiyama S, Fujii K and Iida M. (2004) Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats. Hypertension 43: 977-82 [PMID:14993197]
67. Longo KA, Charoenthongtrakul S, Giuliana DJ, Govek EK, McDonagh T, Qi Y, DiStefano PS and Geddes BJ. (2008) Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice. Regul Pept 150: 55-61 [PMID:18453014]
68. M'Kadmi C, Cabral A, Barrile F, Giribaldi J, Cantel S, Damian M, Mary S, Denoyelle S, Dutertre S and Péraldi-Roux S et al.. (2019) N-Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor. J Med Chem 62: 965-973 [PMID:30543423]
69. Ma X, Lin Y, Lin L, Qin G, Pereira FA, Haymond MW, Butte NF and Sun Y. (2012) Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice. Am J Physiol Endocrinol Metab 303: E422-31 [PMID:22669248]
70. Malcolm JA and Sutherland DC. (1991) HIV and nutrition. Lancet 338: 760 [PMID:1679893]
71. Mani BK, Puzziferri N, He Z, Rodriguez JA, Osborne-Lawrence S, Metzger NP, Chhina N, Gaylinn B, Thorner MO and Thomas EL et al.. (2019) LEAP2 changes with body mass and food intake in humans and mice. J Clin Invest 129: 3909-3923 [PMID:31424424]
72. Mary S, Damian M, Louet M, Floquet N, Fehrentz JA, Marie J, Martinez J and Banères JL. (2012) Ligands and signaling proteins govern the conformational landscape explored by a G protein-coupled receptor. Proc Natl Acad Sci USA 109: 8304-9 [PMID:22573814]
73. Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, Hosoda H, Kojima M and Kangawa K. (2000) Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 276: 905-8 [PMID:11027567]
74. Matsumoto M, Hosoda H, Kitajima Y, Morozumi N, Minamitake Y, Tanaka S, Matsuo H, Kojima M, Hayashi Y and Kangawa K. (2001) Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides. Biochem Biophys Res Commun 287: 142-6 [PMID:11549267]
75. McKee KK, Palyha OC, Feighner SD, Hreniuk DL, Tan CP, Phillips MS, Smith RG, Van der Ploeg LH and Howard AD. (1997) Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 11: 415-23 [PMID:9092793]
76. Mende F, Hundahl C, Plouffe B, Skov LJ, Sivertsen B, Madsen AN, Lückmann M, Diep TA, Offermanns S and Frimurer TM et al.. (2018) Translating biased signaling in the ghrelin receptor system into differential in vivo functions. Proc Natl Acad Sci U S A 115: E10255-E10264 [PMID:30301804]
77. Mokrosiński J, Frimurer TM, Sivertsen B, Schwartz TW and Holst B. (2012) Modulation of constitutive activity and signaling bias of the ghrelin receptor by conformational constraint in the second extracellular loop. J Biol Chem 287: 33488-502 [PMID:22846991]
78. Mondal MS, Date Y, Yamaguchi H, Toshinai K, Tsuruta T, Kangawa K and Nakazato M. (2005) Identification of ghrelin and its receptor in neurons of the rat arcuate nucleus. Regul Pept 126: 55-9 [PMID:15620414]
79. Moulin A, Brunel L, Boeglin D, Demange L, Ryan J, M'Kadmi C, Denoyelle S, Martinez J and Fehrentz JA. (2013) The 1,2,4-triazole as a scaffold for the design of ghrelin receptor ligands: development of JMV 2959, a potent antagonist. Amino Acids 44: 301-14 [PMID:22798076]
80. Moulin A, Demange L, Bergé G, Gagne D, Ryan J, Mousseaux D, Heitz A, Perrissoud D, Locatelli V and Torsello A et al.. (2007) 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: 5790-806 [PMID:17927165]
81. Mousseaux D, Le Gallic L, Ryan J, Oiry C, Gagne D, Fehrentz JA, Galleyrand JC and Martinez J. (2006) Regulation of ERK1/2 activity by ghrelin-activated growth hormone secretagogue receptor 1A involves a PLC/PKCvarepsilon pathway. Br J Pharmacol 148: 350-65 [PMID:16582936]
82. Muccioli G, Papotti M, Locatelli V, Ghigo E and Deghenghi R. (2001) Binding of 125I-labeled ghrelin to membranes from human hypothalamus and pituitary gland. J Endocrinol Invest 24: RC7-9 [PMID:11314756]
83. Nagaya N and Kangawa K. (2003) Ghrelin, a novel growth hormone-releasing peptide, in the treatment of chronic heart failure. Regul Pept 114: 71-7 [PMID:12832093]
84. Nagaya N and Kangawa K. (2003) Ghrelin improves left ventricular dysfunction and cardiac cachexia in heart failure. Curr Opin Pharmacol 3: 146-51 [PMID:12681236]
85. Nagaya N, Kojima M and Kangawa K. (2006) Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia. Intern Med 45: 127-34 [PMID:16508225]
86. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, Hayashi Y and Kangawa K. (2001) Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol 280: R1483-7 [PMID:11294772]
87. Nagaya N, Miyatake K, Uematsu M, Oya H, Shimizu W, Hosoda H, Kojima M, Nakanishi N, Mori H and Kangawa K. (2001) Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J Clin Endocrinol Metab 86: 5854-9 [PMID:11739451]
88. Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu W, Hosoda H, Hirota Y, Ishida H and Mori H et al.. (2001) Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 104: 1430-5 [PMID:11560861]
89. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K and Matsukura S. (2001) A role for ghrelin in the central regulation of feeding. Nature 409: 194-8 [PMID:11196643]
90. Okumura H, Nagaya N, Enomoto M, Nakagawa E, Oya H and Kangawa K. (2002) Vasodilatory effect of ghrelin, an endogenous peptide from the stomach. J Cardiovasc Pharmacol 39: 779-783 [PMID:12021570]
91. Palus S, Schur R, Akashi YJ, Bockmeyer B, Datta R, Halem H, Dong J, Culler MD, Adams V and Anker SD et al.. (2011) Ghrelin and its analogues, BIM-28131 and BIM-28125, improve body weight and regulate the expression of MuRF-1 and MAFbx in a rat heart failure model. PLoS ONE 6: e26865 [PMID:22102869]
92. Palyha OC, Feighner SD, Tan CP, McKee KK, Hreniuk DL, Gao YD, Schleim KD, Yang L, Morriello GJ and Nargund R et al.. (2000) Ligand activation domain of human orphan growth hormone (GH) secretagogue receptor (GHS-R) conserved from Pufferfish to humans. Mol Endocrinol 14: 160-9 [PMID:10628755]
93. Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton MP, Grouselle D and de Kerdanet M et al.. (2006) Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 116: 760-8 [PMID:16511605]
94. Papotti M, Ghè C, Cassoni P, Catapano F, Deghenghi R, Ghigo E and Muccioli G. (2000) Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab 85: 3803-7 [PMID:11061542]
95. Pawson AJ, Faccenda E, Maudsley S, Lu ZL, Naor Z and Millar RP. (2008) Mammalian type I gonadotropin-releasing hormone receptors undergo slow, constitutive, agonist-independent internalization. Endocrinology 149: 1415-22 [PMID:18039780]
96. Peeters TL. (2003) Central and peripheral mechanisms by which ghrelin regulates gut motility. J Physiol Pharmacol 54 Suppl 4: 95-103 [PMID:15075452]
97. Peino R, Baldelli R, Rodriguez-Garcia J, Rodriguez-Segade S, Kojima M, Kangawa K, Arvat E, Ghigo E, Dieguez C and Casanueva FF. (2000) Ghrelin-induced growth hormone secretion in humans. Eur J Endocrinol 143: R11-4 [PMID:11124868]
98. Perdonà E, Faggioni F, Buson A, Sabbatini FM, Corti C and Corsi M. (2011) Pharmacological characterization of the ghrelin receptor antagonist, GSK1614343 in rat RC-4B/C cells natively expressing GHS type 1a receptors. Eur J Pharmacol 650: 178-83 [PMID:21034740]
99. Pettersson I, Muccioli G, Granata R, Deghenghi R, Ghigo E, Ohlsson C and Isgaard J. (2002) Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation. J Endocrinol 175: 201-9 [PMID:12379504]
100. Pfluger PT, Kirchner H, Günnel S, Schrott B, Perez-Tilve D, Fu S, Benoit SC, Horvath T, Joost HG and Wortley KE et al.. (2008) Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. Am J Physiol Gastrointest Liver Physiol 294: G610-8 [PMID:18048479]
101. Poitras P and Peeters TL. (2008) Motilin. Curr Opin Endocrinol Diabetes Obes 15: 54-7 [PMID:18185063]
102. Rediger A, Piechowski CL, Habegger K, Grüters A, Krude H, Tschöp MH, Kleinau G and Biebermann H. (2012) MC4R dimerization in the paraventricular nucleus and GHSR/MC3R heterodimerization in the arcuate nucleus: is there relevance for body weight regulation? Neuroendocrinology 95: 277-88 [PMID:22327910]
103. Rudolph J, Esler WP, O'connor S, Coish PD, Wickens PL, Brands M, Bierer DE, Bloomquist BT, Bondar G and Chen L et al.. (2007) Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity. J Med Chem 50: 5202-16 [PMID:17887659]
104. Sabbatini FM, Di Fabio R, Corsi M, Cavanni P, Bromidge SM, St-Denis Y, D'Adamo L, Contini S, Rinaldi M and Guery S et al.. (2010) Discovery process and characterization of novel carbohydrazide derivatives as potent and selective GHSR1a antagonists. ChemMedChem 5: 1450-5 [PMID:20593439]
105. Schellekens H, van Oeffelen WE, Dinan TG and Cryan JF. (2013) Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling. J Biol Chem 288: 181-91 [PMID:23161547]
106. Shin YK, Martin B, Kim W, White CM, Ji S, Sun Y, Smith RG, Sévigny J, Tschöp MH and Maudsley S et al.. (2010) Ghrelin is produced in taste cells and ghrelin receptor null mice show reduced taste responsivity to salty (NaCl) and sour (citric acid) tastants. PLoS ONE 5: e12729 [PMID:20856820]
107. 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: 1429-36 [PMID:12045256]
108. Sivertsen B, Holliday N, Madsen AN and Holst B. (2013) Functionally biased signalling properties of 7TM receptors - opportunities for drug development for the ghrelin receptor. Br J Pharmacol 170: 1349-62 [PMID:24032557]
109. Sivertsen B, Lang M, Frimurer TM, Holliday ND, Bach A, Els S, Engelstoft MS, Petersen PS, Madsen AN and Schwartz TW et al.. (2011) Unique interaction pattern for a functionally biased ghrelin receptor agonist. J Biol Chem 286: 20845-60 [PMID:21402696]
110. Smith RG, Cheng K, Schoen WR, Pong SS, Hickey G, Jacks T, Butler B, Chan WW, Chaung LY and Judith F et al.. (1993) A nonpeptidyl growth hormone secretagogue. Science 260: 1640-3 [PMID:8503009]
111. Stevens T and Parsi MA. (2010) Endoscopic ultrasound for the diagnosis of chronic pancreatitis. World J Gastroenterol 16: 2841-50 [PMID:20556829]
112. Sun Y, Butte NF, Garcia JM and Smith RG. (2008) Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. Endocrinology 149: 843-50 [PMID:18006636]
113. 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 USA 101: 4679-84 [PMID:15070777]
114. Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T and Shimatsu A et al.. (2000) Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 85: 4908-11 [PMID:11134161]
115. Tanaka M, Hayashida Y, Iguchi T, Nakao N, Nakai N and Nakashima K. (2001) Organization of the mouse ghrelin gene and promoter: occurrence of a short noncoding first exon. Endocrinology 142: 3697-700 [PMID:11459820]
116. Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, Castaneda TR, Muzzin P, Schürmann A and Szanto I et al.. (2006) Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 116: 1983-93 [PMID:16767221]
117. Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC and Wells T. (2004) Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 145: 234-42 [PMID:14551228]
118. Tokunaga T, Hume WE, Umezome T, Okazaki K, Ueki Y, Kumagai K, Hourai S, Nagamine J, Seki H and Taiji M et al.. (2001) Oxindole derivatives as orally active potent growth hormone secretagogues. J Med Chem 44: 4641-9 [PMID:11741481]
119. Tolle V, Zizzari P, Tomasetto C, Rio MC, Epelbaum J and Bluet-Pajot MT. (2001) In vivo and in vitro effects of ghrelin/motilin-related peptide on growth hormone secretion in the rat. Neuroendocrinology 73: 54-61 [PMID:11174017]
120. Tschöp M, Smiley DL and Heiman ML. (2000) Ghrelin induces adiposity in rodents. Nature 407: 908-13 [PMID:11057670]
121. Tsubota Y, Owada-Makabe K, Yukawa K and Maeda M. (2005) Hypotensive effect of des-acyl ghrelin at nucleus tractus solitarii of rat. Neuroreport 16: 163-6 [PMID:15671869]
122. Valentin-Hansen L, Holst B, Frimurer TM and Schwartz TW. (2012) PheVI:09 (Phe6.44) as a sliding microswitch in seven-transmembrane (7TM) G protein-coupled receptor activation. J Biol Chem 287: 43516-26 [PMID:23135271]
123. van der Lely AJ, Tschöp M, Heiman ML and Ghigo E. (2004) Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25: 426-57 [PMID:15180951]
124. Verhulst PJ, De Smet B, Saels I, Thijs T, Ver Donck L, Moechars D, Peeters TL and Depoortere I. (2008) Role of ghrelin in the relationship between hyperphagia and accelerated gastric emptying in diabetic mice. Gastroenterology 135: 1267-76 [PMID:18657539]
125. Volante M, Allia E, Fulcheri E, Cassoni P, Ghigo E, Muccioli G and Papotti M. (2003) Ghrelin in fetal thyroid and follicular tumors and cell lines: expression and effects on tumor growth. Am J Pathol 162: 645-54 [PMID:12547722]
126. Weber J, Staerz E, Mettang T, Machleidt C and Kuhlmann U. (1989) Treatment of peritonitis in continuous ambulatory peritoneal dialysis (CAPD) with intraperitoneal cefazolin and gentamicin. Perit Dial Int 9: 191-5 [PMID:2488364]
127. Wierup N, Svensson H, Mulder H and Sundler F. (2002) The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas. Regul Pept 107: 63-9 [PMID:12137967]
128. Wiley KE and Davenport AP. (2002) Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol 136: 1146-52 [PMID:12163347]
129. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA and Bloom SR. (2001) Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86: 5992 [PMID:11739476]
130. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG and Ghatei MA et al.. (2000) The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141: 4325-8 [PMID:11089570]
131. Xin Z, Serby MD, Zhao H, Kosogof C, Szczepankiewicz BG, Liu M, Liu B, Hutchins CW, Sarris KA and Hoff ED et al.. (2006) Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists. J Med Chem 49: 4459-69 [PMID:16854051]
132. Xu L, Depoortere I, Tomasetto C, Zandecki M, Tang M, Timmermans JP and Peeters TL. (2005) Evidence for the presence of motilin, ghrelin, and the motilin and ghrelin receptor in neurons of the myenteric plexus. Regul Pept 124: 119-25 [PMID:15544849]
133. Yang J, Brown MS, Liang G, Grishin NV and Goldstein JL. (2008) Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132: 387-96 [PMID:18267071]
134. Yasuda T, Masaki T, Kakuma T and Yoshimatsu H. (2003) Centrally administered ghrelin suppresses sympathetic nerve activity in brown adipose tissue of rats. Neurosci Lett 349: 75-8 [PMID:12946556]
135. Zigman JM, Jones JE, Lee CE, Saper CB and Elmquist JK. (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 494: 528-48 [PMID:16320257]
136. Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR and White RD et al.. (2005) Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 115: 3564-72 [PMID:16322794]