Ghrelin is a gastric polypeptide displaying strong GH-releasing activity by activation of the type 1a GH secretagogue receptor (GHS-R1a) located in the hypothalamus-pituitary axis. GHS-R1a is a G-protein-coupled receptor that, upon the binding of ghrelin or synthetic peptidyl and non-peptidyl ghrelin-mimetic agents known as GHS, preferentially couples to Gq, ultimately leading to increased intracellular calcium content. Beside the potent GH-releasing action, ghrelin and GHS influence food intake, gut motility, sleep, memory and behavior, glucose and lipid metabolism, cardiovascular performances, cell proliferation, immunological responses and reproduction. A growing body of evidence suggests that the cloned GHS-R1a alone cannot be the responsible for all these effects. The cloned GHS-R1b splice variant is apparently non-ghrelin/GHS-responsive, despite demonstration of expression in neoplastic tissues responsive to ghrelin not expressing GHS-R1a; GHS-R1a homologues sensitive to ghrelin are capable of interaction with GHS-R1b, forming heterodimeric species. Furthermore, GHS-R1a-deficient mice do not show evident abnormalities in growth and diet-induced obesity, suggesting the involvement of another receptor. Additional evidence of the existence of another receptor is that ghrelin and GHS do not always share the same biological activities and activate a variety of intracellular signalling systems besides Gq. The biological actions on the heart, adipose tissue, pancreas, cancer cells and brain shared by ghrelin and the non-acylated form of ghrelin (des-octanoyl ghrelin), which does not bind GHS-R1a, represent the best evidence for the existence of a still unknown, functionally active binding site for this family of molecules. Finally, located in the heart and blood vessels is the scavenger receptor CD36, involved in the endocytosis of the pro-atherogenic oxidized low-density lipoproteins, which is a pharmacologically and structurally distinct receptor for peptidyl GHS and not for ghrelin. This review highlights the most recently discovered features of GHS-R1a and the emerging evidence for a novel group of receptors that are not of the GHS1a type; these appear involved in the transduction of the multiple levels of information provided by GHS and ghrelin.

Bowers CY, Momany F, Reynolds GA, Chang D, Hong A, Chang K: Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro. Endocrinology 1980;106:663–667.
Bowers CY, Momany FA, Reynolds GA, Hong A: On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 1984;114:1537–1545.
Bowers CY, Reynolds GA, Durham D, Barrera CM, Pezzoli SS, Thorner MO: Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metabol 1990;70:975–982.
Deghenghi R, Cananzi MM, Torsello A, Battisti C, Muller EE, Locatelli V: GH-releasing activity of hexarelin, a new growth hormone-releasing peptide, in infant and adult rats. Life Sci 1994;54:1321–1328.
Camanni F, Ghigo E, Arvat E: Growth hormone-releasing peptides and their analogs. Front Neuroendocrinol 1998;9:47–72.
Isidro ML, Cordido F: Growth hormone secretagogues. Comb Chem High Throughput Screen 2006;9:175–180.
Smith RG: Development of growth hormone secretagogues. Endocr Rev 2005;26:346–360.
Smith RG, Cheng K, Schoen WR, Pong SS, Hickey G, Jacks T, Butler B, Chan WW, Chaung LY, Judith F, et al: A nonpeptidyl growth hormone secretagogue. Science 1993;260:1640–1643.
Patchett AA, Nargund RP, Tata JR, Chen MH, Barakat KJ, Johnston DB, Cheng K, Chan WW, Butler B, Hickey G, et al.: Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci USA 1995;92:7001–7005.
Chapman IM, Bach MA, Van Cauter E, Farmer M, Krupa D, Taylor AM, Schilling LM, Cole KY, Skiles EH, Pezzoli SS, Hartman ML, Veldhuis JD, Gormley GJ, Thorner MO: Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretagogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab 1996;81:4249–4257.
Smith RG, Sun Y, Betancourt L, Asnicar M: Growth hormone secretagogues: prospects and potential pitfalls. Best Pract Res Clin Endocrinol Metab 2004;18:333–347.
Smith RG, Jiang H, Sun Y: Developments in ghrelin biology and potential clinical relevance. Trends Endocrinol Metabol 2005;16:436–442.
Broglio F, Boutignon F, Benso A, Gottero C, Prodam F, Arvat E, Ghe C, Catapano F, Torsello A, Locatelli V, Muccioli G, Boeglin D, Guerlavais V, Fehrentz JA, Martinez J, Ghigo E, Deghenghi R: EP1572: a novel peptido-mimetic GH secretagogue with potent and selective GH-releasing activity in man. J Endocrinol Invest 2002;25:RC26–RC28.
Guerlavais V, Boeglin D, Mousseaux D, Oiry C, Heitz A, Deghenghi R, Locatelli V, Torsello A, Ghè C, Catapano F, Muccioli G, Galleyrand JC, Fehrentz JA, Martinez J: New active series of growth hormone secretagogues. J Med Chem 2003;46:1191–1203.
Nagamine J, Kawamura T, Tokunaga T, Hume WE, Nagata R, Nakagawa T, Taiji M: Synthesis and pharmacological profile of an orally-active growth hormone secretagogue SM-130686. Comb Chem High Throughput Screen 2006;9:187–196.
Codd EE, Yellin T, Walker RF: Binding of growth hormone-releasing hormone and enkephalin-derived growth hormone-releasing peptides to μ and δ opioid receptors in forebrain of rat. Neuropharmacology 1988;27:1019–1025.
Sethumadavan K, Veeraragavan K, Bowers CY: Demonstration and characterization of the specific binding of growth hormone-releasing peptide to rat anterior pituitary and hypothalamus. Biochem Biophys Res Commun 1991;178:31–37.
Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH: A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996;273:974–977.
Smith RG, Van der Ploeg LH, Howard AD, Feighner SD, Cheng K, Hickey GJ, Wyvratt MJ Jr, Fisher MH, Nargund RP, Patchett AA: Peptidomimetic regulation of growth hormone secretion. Endocr Rev 1997;18:621–645.
Muccioli G, Ghè C, Ghigo MC, Papotti M, Arvat E, Boghen MF, Nilsson MH, Deghenghi R, Ong H, Ghigo E: Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland. J Endocrinol 1998;157:99–106.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth hormone-releasing acylated peptide from stomach. Nature 1999;402:656–660.
Tomasetto C, Karam SM, Ribieras S, Masson R, Lefebvre O, Staub A, Alexander G, Chenard MP, Rio MC: Identification and characterization of a novel gastric peptide hormone: the motilin-related peptide. Gastroenterology 2000;119:395–405.
Coulie BJ, Miller LJ: Identification of motilin-related peptide. Gastroenterology 2001;120:588–589.
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 2000;276:905–908.
Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, Kasuga M: Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 2001;120:337–345.
Mozid AM, Tringali G, Forsling ML, Hendricks MS, Ajodha S, Edwards R, Navarra P, Grossman AB, Korbonits M: Ghrelin is released from rat hypothalamic explants and stimulates corticotrophin-releasing hormone and arginine-vasopressin. Horm Metab Res 2003;35:455–459.
Schmid DA, Held K, Ising M, Weikel JC, Steiger A: Ghrelin stimulates appetite, imagination of food, GH, ACTH, and cortisol, but does not affect leptin in normal controls. Neuropsychopharmacology 2005;30:1187–1192.
Fernandez-Fernandez R, Tena-Sempere M, Navarro VM, Barreiro ML, Castellano JM, Aguilar E, Pinilla L: Effects of ghrelin upon gonadotropin-releasing hormone and gonadotropin secretion in adult female rats: in vivo and in vitro studies. Neuroendocrinology 2006;82:245–255.
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 2001;409:194–198.
Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR: Ghrelin enhances appetite and food intake in humans. J Clin Endocrinol Metab 2001;86:5992–5995.
Date Y, Nakazato M, Murakami N, Kojima M, Kangawa K, Matsukura S: Ghrelin acts in the central nervous system to stimulate gastric acid secretion. Biochem Biophys Res Commun 2001;280:904–907.
Inui A, Asakawa A, Bowers CY Mantovani G, Laviano A, Meguid MM, Fujimiya M: Ghrelin, appetite, and gastric motility: the emerging role of stomach as an endocrine organ. FASEB J 2004;18:439–456.
Date Y, Shimbara T, Koda S, Toshinai K, Ida T, Murakami N, Miyazato M, Kokame K, Ishizuka Y, Ishida Y, Kageyama H, Shioda S, Kangawa K, Nakazato M: Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway from the hindbrain to the hypothalamus. Cell Metab 2006;4:323–331.
Cumming DE: Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav 2006;89:71–84.
Tschöp M, Smiley DL, Heiman ML: Ghrelin induces adiposity in rodents. Nature 2000;407:908–913.
Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, van der Lely AJ, 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 2001;86:5083–5086.
Murata M, Okimura Y, Iida K, Matsumoto M, Sowa H, Kaji H, Kojima M, Kangawa K, Chihara K: Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. J Biol Chem 2002;277:5667–5674.
Poykko SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA, Ukkola O: Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 2003;52:2546–2553.
Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC, Wells T: Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 2004;145:234–242.
Gauna C, Delhanty PJ, Hofland L, Janssen JA, Broglio F, Ross RJ, Ghigo E, van der Lely AJ: Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. J Clin Endocrinol Metab 2005;90:1055–1060.
Heijboer AC, van den Hoek AM, Parlevliet ET, Havekes LM, Romijn JA, Pijl H, Corssmit EP: Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice. Diabetologia 2006;49:732–738.
Dezaki K, Sone H, Koizumi M, Nakata M, Kakei M, Nagai H, Hosoda H, Kangawa K, Yada T: Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance. Diabetes 2006;55:3486–3493.
Sun Y, Asnicar M, Saha PK, Chan L, Smith RG: Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab 2006;3:379–386.
Gluck EF, Stephens N, Swoap SJ: Peripheral ghrelin deepens torpor bouts in mice through the arcuate nucleus neuropeptide Y signaling pathway. Am J Physiol 2006;291:R1303–R1309.
Steiger A: Ghrelin and sleep-wake regulation. Am J Physiol 2007;292:R573–R574.
Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, Katsuura G, Makino S, Fujino MA, Kasuga M: A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 2001;74:143–147.
Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR: Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun 2004;313:635–641.
Kanehisa M, Akiyoshi J, Kitaichi T, Matsushita H, Tanaka E, Kodama K, Hanada H, Isogawa K: Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:1403–1407.
Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschöp MH, Horvath TL: Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 2006;9:381–388.
Bedendi I, Alloatti G, Marcantoni A Malan D, Catapano F, Ghè C, Deghenghi R, Ghigo E, Muccioli G: Cardiac effect of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin. Eur J Pharmacol 2003;476:87–95.
Nagaya N, Uematsu M, Kojima M Ikeda Y, Yoshihara F, Shimizu W, Hosoda H, Hirota Y, Ishida H, Mori H, Kangawa K: Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 2001;104:1430–1435.
Tritos NA, Kissinger KV, Manning WJ, Danias PJ: Association between ghrelin and cardiovascular indexes in healthy obese and lean men. Clin Endocrinol (Oxf) 2004;60:60–66.
Muccioli G, Broglio F, Tarabra E, Ghigo E: Known and unknown growth hormone secretagogue receptors and their ligands; in Ghigo E (ed): Ghrelin. Boston, Kluwer Academic, 2004, pp 27–46.
Broglio F, Prodam F, Me E, Riganti F, Lucatello B, Granata R, Benso A, Muccioli G, Ghigo E Ghrelin: Endocrine, metabolic and cardiovascular actions. J Endocrinol Invest 2005;28:23–25.
Cassoni P, Papotti M, Ghè C, Catapano F, Sapino A, Graziani A, Deghenghi R, Reissmann T, Ghigo E, Muccioli G: Identification, characterization and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues in human breast carcinomas and cell lines. J Clin Endocrinol Metab 2001;86:1738–1745.
Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, Malan D, Baj G, Granata R, Broglio F, Papotti M, Surico N, Bussolino F, Isgaard J, Deghenghi R, Sinigaglia F, Prat M, Muccioli G, Ghigo E, Graziani A: Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI3-kinase/AKT. J Cell Biol 2002;159:1029–1037.
Papotti M, Ghè C, Volante M, Muccioli G: Ghrelin and tumors; in Ghigo E (ed): Ghrelin. Boston, Kluwer Academic, 2004, pp 143–164.
Cassoni P, Ghè C, Marrocco T, Tarabra E, Allia E, Catapano F, Deghenghi R, Ghigo E, Papotti M, Muccioli G: 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 2004;150:173–184.
Nakahara K, Nakagawa M, Baba Y, Sato M, Toshinai K, Date Y, Nakazato M, Kojima M, Miyazato M, Kaiya H, Hosoda H, Kangawa K, Murakami N: Maternal ghrelin plays an important role in rat fetal development during pregnancy. Endocrinology 2006;147:1333–1342.
Granata R, Settanni F, Biancone L, Trovato L, Nano R, Bertuzzi F, Destefanis S, Annunziata M, Martinetti M, Catapano F, Ghè C, Isgaard J, Papotti M, Ghigo E, Muccioli G: Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic β cells and human islets. Involvement of cAMP/PKA, ERK1/2 and PI3K/AKT signalling. Endocrinology 2007;148:512–529.
Delhanty PJ, van der Eerden BC, van der Velde M, Gauna C, Pols HA, Jahr H, Chiba H, van der Lely AJ, van Leeuwen JP: Ghrelin and unacylated ghrelin stimulate human osteoblast growth via mitogen-activated protein kinase/phosphoinositide 3-kinase pathways in the absence of GHS-R1a. J Endocrinol 2006;188:37–47.
Dixit VD, Taub DD: Ghrelin and immunity: a young player in an old field. Exp Gerontol 2005;40:900–910.
Van der Lely AJ, Tschöp M, Heiman ML, Ghigo E: Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004;25:426–457.
Kojima M, Kangawa K: Ghrelin: structure and function. Physiol Rev 2005;85:495–522.
Ghigo E, Broglio F, Arvat E, Maccario M, Papotti M, Muccioli G: Ghrelin: more than a natural GH secretagogue and/or an orexigenic factor. Clin Endocrinol (Oxf) 2005;62:1–17.
Nogueiras R, Perez-Tilve D, Wortley KE, Tschöp M: Growth hormone secretagogue (ghrelin) receptors – a complex drug target for the regulation of body weight. CNS Neurol Disord Drug Targets 2006;5:335–343.
Gualillo O, Lago F, Casanueva FF, Dieguez C: One ancestor, several peptides post-translational modifications of preproghrelin generate several peptides with antithetical effects. Mol Cell Endocrinol 2006;256:1–8.
Zhu X, Cao Y, Voodg K, Steiner DF: On the processing of proghrelin to ghrelin. J Biol Chem 2006;281:38867–38870.
Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL, Silva MV, Warren VA, Howard AD, Van Der Ploeg LH, Heck JV: Structure-functions 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 2000;43:4370–4376.
Torsello A, Ghè C, Bresciani E, Catapano F, Ghigo E, Deghenghi R, Locatelli V, Muccioli G: Short ghrelin peptides neither displace ghrelin binding in vitro nor stimulate GH release in vivo. Endocrinology 2002;143:1968–1971.
Muccioli G, Tschöp M, Papotti M, Deghenghi R, Heiman M, Ghigo E: Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol 2002;440:235–254.
Broglio F, Prodam F, Riganti E, Muccioli G, Ghigo E: Ghrelin: From somatotrope secretion to new perspectives in the regulation of peripheral metabolic functions. Front Horm Res 2006;35:102–114.
Hosoda H, Kojima M, Kangawa K: Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci 2006;100:398–410.
Banks WA, Tschöp M, Robinson SM, Heiman ML: Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther 2002;302:822–827.
Matsumoto M, Hosoda H, Kitajima Y, Morozumi N, Minamitake Y, Tanaka S, Matsuo H, Kojima M, Hayashi Y, Kangawa K: Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides. Biochem Biophys Res Commun 2001;287:142–146.
Matsumoto M, Kitajima Y, Iwanami T, Hayashi Y, Tanaka S, Minamitake Y, Hosoda H, Kojima M, Matsuo H, Kangawa K: Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues. Biochem Biophys Res Commun 2001;284:655–659.
Tolle V, Zizzari P, Tomasetto C, Rio MC, Epelbaum J, Bluet-Pajot MT: In vivo and in vitro effects of ghrelin/motilin-related peptide on growth hormone secretion in the rat. Neuroendocrinology 2001;73:54–61.
Muccioli G, Pons N, Ghè C, Catapano F, Granata R, Ghigo E: Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor. Eur J Pharmacol 2004;498:27–35.
Hosoda H, Kojima M, Mizushima Y, Shimizu S, Kangawa K: Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem 2003;278:64–70.
Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and des-octanoyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 2000;279:909–913.
Hosoda H, Kojima M, Matsuo H, Kangawa K: Purification and characterization of rat des-Gln14-ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 2000;275:21995–22000.
Jeffery PL, Murray RE, Yeh AH, McNamara JF, Duncan RP, Francis GD, Herington AC, Chopin LK: Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and cell lines. Endocr Relat Cancer 2005;12:839–850.
Yeh AH, Jeffery PL, Duncan RP, Herington AC, Chopin LK: Ghrelin and a novel preproghrelin isoform are highly expressed in prostate cancer and ghrelin activates mitogen-activated protein kinase in prostate cancer. Clin Cancer Res 2005;11:8295–8303.
Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Hsueh AJ: Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science 2005;310:996–999.
Dun SL, Brailoiu GC, Brailoiu E, Yang J, Chang JK, Dun NJ: Distribution and biological activity of obestatin in the rat. J Endocrinol 2006;191:481–489.
Samson WK, White MM, Price C, Ferguson AV: Obestatin acts in brain to inhibit thirst. Am J Physiol 2007;292:R637–R643.
Holst B, Egerod KL, Schild E, Vickers SP, Cheetham S, Gerlach LO, Storjohann L, Stidsen CE, Jones R, Beck-Sickinger AG, Schwartz TW: GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology 2007;148:13–20.
McKee KK, Palyha OC, Feighner SD, Hreniuk DL, Tan CP, Phillips MS, Smith RG, Van der Ploeg LH, Howard AD: Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 1997;11:415–423.
Hayashida T, Nakahara K, Mondal MS, Date Y, Nakazato M, Kojima M, Kangawa K, Murakami N: Ghrelin in neonatal rats: distribution in stomach and its possible role. J Endocrinol 2002;173:239–245.
Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M: The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002;87:2988–2991.
Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, van der Ploeg LH, Howard AD: Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 1997;48:23–29.
Sun Y, Garcia JM, Smith RG: Ghrelin and growth hormone secretagogue receptor expression in mice during aging. Endocrinology 2007;148:1323–1329.
Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK: Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 2006;494:528–548.
Jaszberenyi M, Bujdoso E, Bagosi Z, Telegdy G: Mediation of the behavioral, endocrine and thermoregulatory actions of ghrelin. Horm Behav 2006;50:266–273.
Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA: Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward. Addict Biol 2006;11:45–54.
Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR, Tschöp MH, Gao XB, Horvath TL: Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 2006;116:3229–3239.
Arvat E, Ramunni J, Bellone J, Di Vito L, Baffoni C, Broglio F, Deghenghi R, Bartolotta E, Ghigo E: The GH, prolactin, ACTH and cortisol responses to hexarelin, a synthetic hexapeptide, undergo different age-related variations. Eur J Endocrinol 1997;137:635–642.
Ghigo E, Arvat E, Camanni F: Growth hormone secretagogues as corticotrophin-releasing factors. Growth Horm IGF Res 1998;8(suppl B):145–148.
Ghigo E, Arvat E, Giordano R, Broglio F, Gianotti L, Maccario M, Bisi G, Graziani A, Papotti M, Muccioli G, Deghenghi R, Camanni F: Biologic activities of growth hormone secretagogues in humans. Endocrine 2001;14:87–93.
Popovic V, Miljic D, Micic D, Damjanovic S, Arvat E, Ghigo E, Dieguez C, Casanueva FF: Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level. J Clin Endocrinol Metab 2003;88:3450–3453.
Enomoto M, Nagaya N, Uematsu M, Okumura H, Nakagawa E, Ono F, Hosoda H, Oya H, Kojima M, Kanmatsuse K, Kangawa K: Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans. Clin Sci (Lond) 2003;105:431–435.
Rubinfeld H, Hadani M, Taylor JE, Dong JZ, Comstock J, Shen Y, DeOliveira D, Datta R, Culler MD, Shimon I: Novel ghrelin analogs with improved affinity for the GH secretagogue receptor stimulate GH and prolactin release from human pituitary cells. Eur J Endocrinol 2004;151:787–795.
Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL: The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003;37:649–661.
Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, Shen Z, Marsh DJ, Feighner SD, Guan XM, Ye Z, Nargund RP, Smith RG, Van der Ploeg LH, Howard AD, MacNeil DJ, Qian S: Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 2004;145:2607–2612.
Sun Y, Wang P, Zheng H, Smith RG: Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci USA 2004;101:4679–4684.
Murphy KG, Dhillo WS, Bloom SR: Gut peptides in the regulation of food intake and energy homeostasis. Endocr Rev 2006;27:719–727.
Sibilia V, Muccioli G, Deghenghi R, Pagani F, De Luca V, Rapetti D, Locatelli V, Netti C: Evidence for a role of the GHS-R1a receptors in ghrelin inhibition of gastric acid secretion in the rat. J Neuroendocrinol 2006;18:122–128.
Kawczynska-Drozdz A, Olszanecki R, Jawien J, Brzozowski T, Pawlik WW, Korbut R, Guzik TJ: Ghrelin inhibits vascular superoxide production in spontaneously hypertensive rats. Am J Hypertens 2006;19:764–767.
Suematsu M, Katsuki A, Sumida Y, Gabazza EC, Murashima S, Matsumoto K, Kitagawa N, Akatsuka H, Hori Y, Nakatani K, Togashi K, Yano Y, Adachi Y: Decreased circulating levels of active ghrelin are associated with increased oxidative stress in obese subjects. Eur J Endocrinol 2005;153:403–407.
Koo GC, Huang C, Camacho R, Trainor C, Blake JT, Sirotina-Meisher A, Schleim KD, Wu TJ, Cheng K, Nargund R, McKissick G: Immune enhancing effect of a growth hormone secretagogue. J Immunol 2001;166:4195–4201.
Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, Lillard JW Jr, Taub DD: Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 2004;114:57–66.
Camina JP: Cell biology of the ghrelin receptor. J Neuroendocrinol 2006;18:65–76.
Petersenn S: Structure and regulation of the growth hormone secretagogue receptor. Minerva Endocrinol 2002;27:243–256.
Bockaert J, Pin JP: Molecular tinkering of G-protein-coupled receptors: an evolutionary success. EMBO J 1999;18:1723–1729.
McKee KK, Tan CP, Palyha OC, Liu J, Feighner SD, Hreniuk DL, Smith RG, Howard AD, Van der Ploeg LH: Cloning and characterization of two human G-protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics 1997;46:426–434.
Tan CP, McKee KK, Liu Q, Palyha OC, Feighner SD, Hreniuk DL, Smith RG, Howard AD: Cloning and characterization of a human and murine T-cell orphan G-protein-coupled receptor similar to the growth hormone secretagogue and neurotensin receptors. Genomics 1998;52:223–229.
Palyha OC, Feighner SD, Tan CP, et al: Ligand activation domain of human orphan growth hormone secretagogue receptor conserved from pufferfish to humans. Mol Endocrinol 2000;14:160–169.
Muccioli G, Papotti M, Locatelli V, Ghigo E: Binding of 125I-labeled ghrelin to membranes from human hypothalamus and pituitary gland. J Endocrinol Invest 2001;24:RC7–RC9.
Tullin S, Hansen BS, Ankersen M, Moller J, Von Cappelen KA, Thim L: Adenosine is an agonist of the growth hormone secretagogue receptor. Endocrinology 2000;141:3397–3402.
Smith RG, Leonard R, Bailey AR, Palyha O, Feighner S, Tan C, Mckee KK, Pong SS, Griffin P, Howard A: Growth hormone secretagogue receptor family members and ligands. Endocrine 2001;14:9–14.
Carreira MC, Camina JP, Smith RG, Casanueva FF: Agonist-specific coupling of growth hormone secretagogue receptor type 1a to different intracellular signaling systems. Role of adenosine. Neuroendocrinology 2004;79:13–25.
Johansson S, Fredholm BB, Hjort C, Morein T, Kull B, Hu PS: Evidence against adeno-sine analogues being agonists at the growth hormone secretagogue receptor. Biochem Pharmacol 2005;70:598–605.
Carreira MC, Camina JP, Diaz-Rodriguez E, Alvear-Perez R, Llorens-Cortes C, Casanueva FF: Adenosine does not bind to the growth hormone secretagogue receptor type-1a. J Endocrinol 2006;191:147–157.
Deghenghi R, Avallone R, Torsello A, Muccioli G, Ghigo E, Locatelli V: Growth hormone-inhibiting activity of cortistatin in the rat. J Endocrinol Invest 2001;24:RC31–RC33.
Deghenghi R, Papotti M, Ghigo E, Muccioli G, Locatelli V: Somatostatin octapeptides (lanreotide, octreotide, vapreotide, and their analogs) share the growth hormone-releasing peptide receptor in the human pituitary gland. Endocrine 2001;14:29–33.
Luque RM, Peinado JR, Gracia-Navarro F, Broglio F, Ghigo E, Kineman RD, Malagon MM, Castano JP: Cortistatin mimics somatostatin by inducing a dose-dependent stimulatory and inhibitory effect on growth hormone secretion in somatotrope. J Mol Endocrinol 2006;36:547–555.
Ma JN, Schiffer HH, Knapp AE, Wang J, Wong KK, Currier EA, Owens M, Nash NR, Gardell LR, Brann MR, Olsson R, Brurstein ES. Identification of the atypical L-type Ca2+ channel blocker diltiazem and its metabolites as ghrelin receptor agonists; Mol Pharmacol 2007; [Epub ahead of print].
Broglio F, van Koetsveld P, Benso A, Gottero C, Prodam F, Papotti M, Muccioli G, Gauna C, Hofland L, Deghenghi R, Arvat E, Van Der Lely AJ, Ghigo E: Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans. J Clin Endocrinol Metab 2002;87:4829–4832.
Woll PJ, Rozengurt E: [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, a potent bombesin antagonist in murine Swiss 3T3 cells, inhibits the growth of human small cell lung cancer cells in vitro. Proc Natl Acad Sci USA 1988;85:1859–1863.
Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW: High constitutive signaling of the ghrelin receptor – identification of a potent inverse agonist. Mol Endocrinol 2003;17:2201–2210.
Holst B, Lang M, Brandt E, Bach A, Howard A, Frimurer TM, Beck-Sickinger A, Schwartz TW: Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor. Mol Pharmacol 2006;70:936–946.
Xin Z, Zhao H, Serby MD, Liu B, Schaefer VG, Falls DH, Kaszubska W, Colins CA, Sham HL, Liu G: Synthesis and structure-activity relationships of isoxazole carboxamides as growth hormone secretagogue receptor antagonists. Bioorg Med Chem Lett 2005;15:1201–1204.
Serby MD, Zhao H, Szczepankiewicz BG, Kosogof C, Xin Z, Liu B, Liu M, Nelson LT, Kaszubska W, Falls HD, Schaefer V, Bush EN, Shapiro R, Droz BA, Knourek-Segel VE, Fey TA, Brune ME, Beno DW, Turner TM, Collins CA, Jacobson PB, Sham HL, Liu G: 2,4-Diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists. J Med Chem 2006;49:2568–2578.
Demange L, Boeglin D, Moulin A, Mousseaux D, Ryan J, Berge G, Gagne D, Heitz A, Perrissoud D, Locatelli V, Torsello A, Galleyrand JC, Fehrentz JA, Martinez J: Synthesis and pharmacological in vitro and in vivo evaluation of novel triazole derivatives as ligands of the ghrelin receptor. 1. J Med Chem 2007;50:1939–1957.
Hornby PJ: Designing Spiegelmers to antagonise ghrelin. Gut 2006;55:754–755.
Helmling S, Maasch C, Eulberg D, Buchner K, Schroder W, Lange C, Vonhoff S, Wlotzka B, Tschöp MH, Rosewicz S, Klussmann S: Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer. Proc Natl Acad Sci USA 2004;101:13174–13179.
Schwartz TW, Frimurer TM, Holst B, Rosenkilde MM, Elling CE: Molecular mechanism of 7TM receptor activation – a global toggle switch model. Annu Rev Pharmacol Toxicol 2006;46:481–519.
Pedretti A, Villa M, Pallavicini M, Valoti E, Vistoli G: Construction of human ghrelin receptor (hGHS-R1a) model using a fragmental prediction approach and validation through docking analysis. J Med Chem 2006;49:3077–3085.
Feighner SD, Howard AD, Prendergast K, Palyha OC, Hreniuk DL, Nargund R, Underwood D, Tata JR, Dean DC, Tan CP, McKee KK, Woods JW, Patchett AA, Smith RG, Van der Ploeg LH: Structural requirements for the activation of the human growth hormone secretagogue receptor by peptide and non-peptide secretagogues. Mol Endocrinol 1998;12:137–145.
Falls HD, Dayton BD, Fry DG, Ogiela CA, Schaefer VG, Brodjian S, Reilly RM, Collins CA, Kaszubska W: Characterization of ghrelin receptor activity in a rat pituitary cell line RC-4B/C. J Mol Endocrinol 2006;37:51–62.
Chen C: Growth hormone secretagogue actions on the pituitary gland: multiple receptors for multiple ligands? Clin Exp Pharmacol Physiol 2000;27:323–329.
Malagon MM, Luque RM, Ruiz-Guerrero E, Rodriguez-Pacheco F, Garcia-Navarro S, Casanueva FF, Gracia-Navarro F, Castano JP: Intracellular signaling mechanisms mediating ghrelin-stimulated growth hormone release in somatotropes. Endocrinology 2003;144:5372–5380.
Glavaski-Joksimovic A, Jeftinija K, Scanes CG, Anderson LL, Jeftinija S: Stimulatory effect of ghrelin on isolated porcine somatotropes. Neuroendocrinology 2003;77:367–379.
Rodriguez-Pacheco F, Luque RM, Garcia-Navarro S, Gracia-Navarro F, Castano JP, Malagon MM: Ghrelin induces growth hormone secretion via nitric oxide/cGMP signaling. Ann NY Acad Sci 2005;1040:452–453.
Han XF, Zhu YL, Hernandez M, Keating DJ, Chen C: Ghrelin reduces voltage-gated potassium currents in GH3 cells via cyclic GMP pathways. Endocrine 2005;28:217–224.
Kato M, Sakuma Y: The effect of GHRP-6 on the intracellular Na+ concentration of rat pituitary cells in primary culture. J Neuroendocrinol 1999;11:795–800.
Kohno D, Gao HZ, Muroya S, Kikuyama S, Yada T: Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 2003;52:948–956.
Amar S, Mazella J, Checler F, Kitabgi P, Vincent JP: Regulation of cyclic GMP levels by neurotensin in neuroblastoma clone N1E115. Biochem Biophys Res Commun 1985;129:117–125.
Bozou JC, Rochet N, Magnaldo I, Vincent JP, Kitabgi P: Neurotensin stimulates inositol trisphosphate-mediated calcium mobilization but not protein kinase C activation in HT29 cells. Involvement of a G-protein. Biochem J 1989;264:871–878.
Bozou JC, de Nadai F, Vincent JP, Kitabgi P: Neurotensin, bradykinin and somatostatin inhibit cAMP production in neuroblastoma N1E115 cells via both pertussis toxin sensitive and insensitive mechanisms. Biochem Biophys Res Commun 1989;161:1144–1150.
Watson MA, Yamada M, Yamada M, Cusack B, Veverka K, Bolden-Watson C, Richelson E: The rat neurotensin receptor expressed in Chinese hamster ovary cells mediates the release of inositol phosphates. J Neurochem 1992;59:1967–1970.
Herrington J, Hille B: Growth hormone-releasing hexapeptide elevates intracellular calcium in rat somatotropes by two mechanisms. Endocrinology 1994;135:1100–1108.
Adams EF, Lei T, Buchfelder M, Bowers CY, Fahlbusch R: Protein kinase C-dependent growth hormone-releasing peptides stimulate cyclic adenosine 3,5-monophosphate production by human pituitary somatotropinomas expressing gsp oncogenes: evidence for cross-talk between transduction pathways. Mol Endocrinol 1996;10:432–438.
Maudsley S, Martin B, Luttrell LM: The origins of diversity and specificity in G-protein-coupled receptor signaling. J Pharmacol Exp Ther 2005;314:485–494.
Mousseaux D, Le Gallic L, Ryan J, Oiry C, Gagne D, Fehrentz JA, Galleyrand JC, Martinez J: Regulation of ERK1/2 activity by ghrelin-activated growth hormone secretagogue receptor 1A involves a PLC/PKCvarepsilon pathway. Br J Pharmacol 2006;148:350–365.
Holst B, Holliday ND, Bach A, Elling CE, Cox HM, Schwartz TW: Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem 2004;279:53806–53817.
Nanzer AM, Khalaf S, Mozid AM, Fowkes RC, Patel MV, Burrin JM, Grossman AB, Korbonits M: Ghrelin exerts a proliferative effect on a rat pituitary somatotroph cell line via the mitogen-activated protein kinase pathway. Eur J Endocrinol 2004;151:233–240.
Granata R, Settanni F, Trovato L, Destefanis S, Gallo D, Martinetti M, Ghigo E, Muccioli G: Unacylated as well as acylated ghrelin promotes cell survival and inhibit apoptosis in HIT-T15 pancreatic β-cells. J Endocrinol Invest 2006;29:RC19–RC22.
Bond RA, Ijzerman AP: Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery. Trends Pharmacol Sci 2006;27:92–96.
Wang HJ, 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 2004;89:157–162.
Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton MP, 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 2006;116:760–768.
Holst B, Schwartz TW: Ghrelin receptor mutations – too little height and too much hunger. J Clin Invest 2006;116:637–641.
Holst B, Brandt E, Bach A, Heding A, Schwartz TW: Non-peptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling. Mol Endocrinol 2005;19:2400–2411.
Binet V, Brajon C, Le Corre L, Acher F, Pin JP, Prezeau L: The heptahelical domain of GABAB2 is activated directly by CGP7930, a positive allosteric modulator of the GABAB receptor. J Biol Chem 2004;279:29085–29091.
Holst B, Elling CE, Schwartz TW: Metal ion-mediated agonism and agonist enhancement in melanocortin MC1 and MC4 receptors. J Biol Chem 2002;277:47662–47670.
Schwartz TW, Holst B: Ago-allosteric modulation and other types of allostery in dimeric 7TM receptors. J Recept Signal Transduct Res 2006;26:107–128.
Hataya Y, Akamizu T, Takaya K, Kanamoto N, Ariyasu H, Saijo M, Moriyama K, Shimatsu A, Kojima M, Kangawa K, Nakao K: A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab 2001;86:4552–4255.
Bowers CY, Sartor AO, Reynolds GA, Badger TM: On the actions of the growth hormone-releasing hexapeptide, GHRP. Endocrinology 1991;128:2027–2035.
Wu D, Chen C, Katoh K, Zhang J, Clarke IJ: The effect of GH-releasing peptide-2 (GHRP-2 or KP-102) on GH secretion from primary cultured ovine pituitary cells can be abolished by a specific GH-releasing factor receptor antagonist. J Endocrinol 1994;140:R9–R13.
Pandya N, DeMott-Friberg R, Bowers CY, Barkan AL, Jaffe CA: Growth hormone (GH)-releasing peptide-6 requires endogenous hypothalamic GH-releasing hormone for maximal GH stimulation. J Clin Endocrinol Metab 1998;83:1186–1189.
Bennett PA, Thomas GB, Howard AD, Feighner SD, van der Ploeg LH, Smith RG, Robinson IC: Hypothalamic growth hormone secretagogue-receptor expression is regulated by growth hormone in the rat. Endocrinology 1997;138:4552–4557.
Kamegai J, Wakabayashi I, Miyamoto K, Unterman TG, Kineman RD, Frohman LA: Growth hormone-dependent regulation of pituitary GH secretagogue receptor mRNA levels in the spontaneous dwarf Rat. Neuroendocrinology 1998;68:312–318.
Kineman RD, Kamegai J, Frohman LA: Growth hormone (GH)-releasing hormone (GHRH) and the GH secretagogue (GHS), L-692,585, differentially modulate rat pituitary GHS receptor and GHRH receptor messenger ribonucleic acid levels. Endocrinology 1999;140:3581–3586.
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 2004;145:1602–1611.
Mano-Otagiri A, Nemoto T, Sekino A, Yamauchi N, Shuto Y, Sugihara H, Oikawa S, Shibasaki T: Growth hormone-releasing hormone (GHRH) neurons in the arcuate nucleus (Arc) of the hypothalamus are decreased in transgenic rats whose expression of ghrelin receptor is attenuated: evidence that ghrelin receptor is involved in the upregulation of GHRH expression in the Arc. Endocrinology 2006;147:4093–4103.
Maggio R, Novi F, Scarselli M, Corsini GU: The impact of G-protein-coupled receptor hetero-oligomerization on function and pharmacology. FEBS J 2005;272:2939–2946.
Cunha SR, Mayo KE: Ghrelin and growth hormone (GH) secretagogues potentiate GH-releasing hormone (GHRH)-induced cyclic adenosine 3′,5′-monophosphate production in cells expressing transfected GHRH and GH secretagogue receptors. Endocrinology 2002;143:4570–4582.
Jiang H, Betancourt L, Smith RG: Ghrelin amplifies dopamine signaling by cross-talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype-1 heterodimers. Endocrinology 2006;20:1772–1785.
Ferguson SS: Evolving concepts in G-protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 2001;53:1–24.
Camina JP, Carreira MC, El Messari S, Llorens-Cortes C, Smith RG, Casanueva FF: Desensitization and endocytosis mechanisms of ghrelin-activated growth hormone secretagogue receptor 1a. Endocrinology 2004;145:930–940.
Parnot C, Miserey-Lenkei S, Bardin S, Corvol P, Clauser E: Lessons from constitutively active mutants of G-protein-coupled receptors. Trends Endocrinol Metab 2002;13:336–343.
Wilbanks AM, Laporte SA, Bohn LM, Barak LS, Caron MG: Apparent loss-of-function mutant GPCRs revealed as constitutively desensitized receptors. Biochemistry 2002;41:11981–11989.
Miserey-Lenkei S, Parnot C, Bardin S, Corvol P, Clauser E: Constitutive internalization of constitutively active agiotensin II AT(1A) receptor mutants is blocked by inverse agonists. J Biol Chem 2002;277:5891–5901.
Leterrier C, Bonnard D, Carrel D, Rossier J, Lenkei Z: Constitutive endocytic cycle of the CB1 cannabinoid receptor. J Biol Chem 2004;279:36013–36021.
Kim MS, Yoon CY, Park KH, Shin CS, Park KS, Kim SY, Cho BY, Lee HK: Changes in ghrelin and ghrelin receptor expression according to feeding status. Neuroreport 2003;14:1317–1320.
Tups A, Helwig M, Khorooshi RM, Archer ZA, Klingenspor M, Mercer JG: Circulating ghrelin levels and central ghrelin receptor expression are elevated in response to food deprivation in a seasonal mammal (Phodopus sungorus). J Neuroendocrinol 2004;16:922–928.
Wu R, Zhou M, Cui X, Simms HH, Wang P: Upregulation of cardiovascular ghrelin receptor occurs in the hyperdynamic phase of sepsis. Am J Physiol 2004;287:H1296–H1302.
Ong H, McNicoll N, Escher E, Collu R, Deghenghi R, Locatelli V, Ghigo E, Muccioli G, Boghen M, Nilsson M: Identification of a pituitary growth hormone-releasing peptide receptor subtype by photoaffinity labeling. Endocrinology 1998;139:432–435.
Ong H, Bodart V, McNicoll N, Lamontagne D, Bouchard JF: Binding sites for growth hormone-releasing peptide. Growth Hormone IGF Res 1998;8:137–140.
Papotti M, Ghè C, Cassoni P, Catapano F, Deghenghi R, Ghigo E, Muccioli G: Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab 2000;85:3803–3807.
Muccioli G, Broglio F, Valetto MR, Ghè C, Catapano F, Graziani A, Papotti M, Bisi G, Deghenghi R, Ghigo E: Growth hormone-releasing peptides and the cardiovascular system. Ann Endocrinol (Paris)2000;61:27–31.
Bodart V, Bouchard JF, McNicoll N, Escher E, Carriere P, Ghigo E, Sejlitz T, Sirois MG, Lamontagne D, Ong H: Identification and characterization of a new growth hormone-releasing peptide receptor in the heart. Circ Res 1999;85:796–808.
Huang J, Zhou H, Mahavadi S, Sriwai W, Lyall V, Murthy KS: Signaling pathways mediating gastrointestinal smooth muscle contraction and MLC20 phosphorylation by motilin receptors. Am J Physiol 2005;288:G23–G31.
Tremblay F, Perreault M, Klaman LD, Tobin JF, Smith E, Gimeno RE: Normal food intake and body weight in mice lacking the G-protein-coupled receptor GPR39. Endocrinology 2007;148:501–506.
Lauwers E, Landuyt B, Arckens L, Schoofs L, Luyten W: Obestatin does not activate orphan G-protein-coupled receptor GPR39. Biochem Biophys Res Commun 2006;351:21–25.
Bresciani E, Rapetti D, Dona F, Bulgarelli I, Tamiazzo L, Locatelli V, Torsello A: Obestatin inhibits feeding but does not modulate GH and corticosterone secretion in the rat. J Endocrinol Invest 2006;29:RC16–RC18.
Seoane LM, Al-Massadi O, Pazos Y, Pagotto U, Casanueva FF: Central obestatin administration does not modify either spontaneous or ghrelin-induced food intake in rats. J Endocrinol Invest 2006;29:RC13–RC15.
Morello JP, Bouvier M: Palmitoylation: a post-translational modification that regulates signalling from G-protein-coupled receptors. Biochem Cell Biol 1996;74:449–457.
Brighton PJ, Szekeres PG, Willars GB: Neuromedin U and its receptors: structure, function, and physiological roles. Pharmacol Rev 2004;56:231–248.
Jethwa PH, Smith KL, Small CJ, Abbott CR, Darch SJ, Murphy KG, Seth A, Semjonous NM, Patel SR, Todd JF, Ghatei MA, Bloom SR: Neuromedin U partially mediates leptin-induced hypothalamo-pituitary adrenal (HPA) stimulation and has a physiological role in the regulation of the HPA axis in the rat. Endocrinology 2006;147:2886–2892.
Nogueiras R, Tovar S, Mitchell SE, Barrett P, Rayner DV, Dieguez C, Williams LM: Negative energy balance and leptin regulate neuromedin-U expression in the rat pars tuberalis. J Endocrinol 2006;190:545–553.
Alevizos I, Mahadevappa M, Zhang X, Ohyama H, Kohno Y, Posner M, Gallagher GT, Varvares M, Cohen D, Kim D, Kent R, Donoff RB, Todd R, Yung CM, Warrington JA, Wong DT: Oral cancer in vivo gene expression profiling assisted by laser capture microdissection and microarray analysis. Oncogene2001;20:6196–6204.
Yamashita K, Upadhyay S, Osada M, Hoque MO, Xiao Y, Mori M, Sato F, Meltzer SJ, Sidransky D: Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell 2002;2:485–495.
Takahashi K, Furukawa C, Takano A, Ishikawa N, Kato T, Hayama S, Suzuki C, Yasui W, Inai K, Sone S, Ito T, Nishimura H, Tsuchiya E, Nakamura Y, Daigo Y: The neuromedin U-growth hormone secretagogue receptor 1b/neurotensin receptor 1 oncogenic signaling pathway as a therapeutic target for lung cancer. Cancer Res 2006;66:9408–9419.
Vincent JP, Mazella J, Kitabgi P: Neurotensin and neurotensin receptors. Trends Pharmacol Sci 1999;20:302–309.
Poinot-Chazel C, Portier M, Bouaboula M, Vita N, Pecceu F, Gully D, Monroe JG, Maffrand JP, Le Fur G, Casellas P: Activation of mitogen-activated protein kinase couples neurotensin receptor stimulation to induction of the primary response gene Krox-24. Biochem J 1996;320:145–151.
Botto JM, Guillemare E, Vincent JP, Mazella J: Effects of SR 48692 on neurotensin-induced calcium-activated chloride currents in the Xenopus oocyte expression system: agonist-like activity on the levocabastine-sensitive neurotensin receptor and absence of antagonist effect on the levocabastine insensitive neurotensin receptor. Neurosci Lett 1997;223:193–196.
Sarret P, Gendron L, Kilian P, Nguyen HM, Gallo-Payet N, Payet MD, Beaudet A: Pharmacology and functional properties of NTS2 neurotensin receptors in cerebellar granule cells. J Biol Chem 2002;277:36233–36243.
Gendron L, Perron A, Payet MD, Gallo-Payet N, Sarret P, Beaudet A: Low-affinity neurotensin receptor (NTS2) signaling: internalization-dependent activation of extracellular signal-regulated kinases 1/2. Mol Pharmacol 2004;66:1421–1430.
Perron A, Sarret P, Gendron L, Stroh T, Beaudet A: Identification and functional characterization of a 5-transmembrane domain variant isoform of the NTS2 neurotensin receptor in rat central nervous system. J Biol Chem 2005;280:10219–10227.
Chu KM, Chow KB, Leung PK, Lau PN, Chan CB, Cheng CH, Wise H: Overexpression 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 2007;39:752–764.
Jeffery PL, Herington AC, Chopin LK: Expression and action of the growth hormone-releasing peptide ghrelin and its receptor in prostate cancer cell lines. J Endocrinol 2002;172:R7–R11.
De Vriese C, Gregoire F, De Neef P, Robberecht P, Delporte C: Ghrelin is produced by the human erythroleukemic HEL cell line and involved in an autocrine pathway leading to cell proliferation. Endocrinology 2005;146:1514–1522.
Barzon L, Pacenti M, Masi G, Stefani AL, Fincati K, Palu G: Loss of growth hormone secretagogue receptor 1a and overexpression of type 1b receptor transcripts in human adrenocortical tumors. Oncology 2005;68:414–421.
Sato M, Nakahara K, Goto S, Kalya H, Miyazato M, Date Y, Nakazato M, Kangawa K, Murakami N: Effects of ghrelin and des-acyl ghrelin on neurogenesis of the rat fetal spinal cord. Biochem Biophys Res Commun 2006;350:598–603.
Gauna C, Meyler FM, Janssen JA, Delhanty PJ, Abribat T, van Koetsveld P, Hofland LJ, Broglio F, Ghigo E, van der Lely AJ: Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. J Clin Endocrinol Metab 2004;89:5035–5042.
Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, Abribat T, Van Der Lely AJ, Ghigo E: Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab 2004;89:3062–3065.
Gauna C, Delhanty PJ, van Aken MO, Janssen JA, Themmen AP, Hofland LJ, Culler M, Broglio F, Ghigo E, van der Lely AJ: Unacylated ghrelin is active on the INS-1E rat insulinoma cell line independently of the growth hormone secretagogue receptor type 1a and the corticotropin-releasing factor-2 receptor. Mol Cell Endocrinol 2006;251:103–111.
Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T, Murakami N, Miyazato M, Kangawa K, Nakazato M: Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology 2006;147:2306–2314.
Matsuda K, Miura T, Kaiya H, Maruyama K, Shimakura S, Uchiyama M, Kangawa K, Shioda S: Regulation of food intake by acyl and des-acyl ghrelins in the goldfish. Peptides 2006;27:2321–2325.
Ghè C, Cassoni P, Catapano F, Marrocco T, Deghenghi R, Ghigo E, Muccioli G, Papotti M: The antiproliferative effect of synthetic peptidyl GH secretagogues in human CALU-1 lung carcinoma cells. Endocrinology 2002;143:484–491.
Torsello A, Bresciani E, Rossoni G, Avallone R, Tulipano G, Cocchi D, Bulgarelli I, Deghenghi R, Berti F, Locatelli V: Ghrelin plays a minor role in the physiological control of cardiac function in the rat. Endocrinology 2003;136:1146–1152.
Deghenghi R: Structural requirements of growth hormone secretagogues; in Bercu BB, Walker RF (eds): Growth Hormone Secretagogues in Clinical Practice. New York, Dekker, 1998, pp 27–33.
Febbraio M, Haijar DP, Silverstein RL: CD36: A class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest 2001;108:785–791.
Bodart V, Febbraio M, Demers A, McNicoll N, Pohankova P, Perreault A, Sejlitz T, Escher E, Silverstein RL, Lamontagne D, Ong H: CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res 2002;90:844–849.
Pettersson I, Muccioli G, Granata R, Deghenghi R, Ghigo E, Ohlsson C, Isgaard J: Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation. J Endocrinol 2002;175:201–209.
Frascarelli S, Ghelardoni S, Ronca-Testoni S, Zucchi R: Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart. Basic Res Cardiol 2003;98:401–405.
Demers A, McNicoll N, Febbraio M, Servant M, Marleau S, Silverstein R, Ong H: Identification of the growth hormone-releasing peptide binding site in CD36: a photoaffinity cross-linking study. Biochem J 2004;382:417–424.
Avallone R, Demers A, Rodrigue-Way A, Bujold K, Harb D, Anghel S, Wahli W, Marleau S, Ong H, Tremblay A: A growth hormone-releasing peptide that binds scavenger receptor CD36 and ghrelin receptor upregulates sterol transporters and cholesterol efflux in macrophages through a peroxisome proliferator-activated receptor-γ-dependent pathway. Mol Endocrinol 2006;20:3165–3178.
Marleau S, Harb D, Bujold K, Avallone R, Iken K, Wang Y, Demers A, Sirois MG, Febbraio M, Silverstein RL, Tremblay A, Ong H: EP-80317, a ligand of the CD36 scavenger receptor, protects apolipoprotein E-deficient mice from developing atherosclerotic lesions. FASEB J 2005;19:1869–1871.
Cummings DE, Foster-Shubert KE, Overduin J: Ghrelin and energy balance: focus on current controversies. Current Drug Targets 2006;6:153–169.
Wortley KE, del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO, Sleeman MW: Absence of ghrelin protects against early-onset obesity. J Clin Invest 2005;115:3573–3578.
Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD, Williams TD, Lachey JL, Seeley RJ, Lowell BB, Elmquist JK: Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 2005;115:3564–3572.
Bowers CY: Historical milestones; in Ghigo E (ed): Ghrelin. Boston, Kluwer Academic, 2004, pp 1–13.
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