Growth hormone secretagogue receptor
Growth hormone secretagogue receptor (GHSR), or ghrelin receptor, is a G protein-coupled receptor that binds ghrelin[1] and plays a role in energy homeostasis and regulation of body weight.[2] In the brain, they are located in the hypothalamic ventromedial nucleus and arcuate nucleus, as well as in ventral tegmental area dopamine neurons projecting to the nucleus accumbens.[3]
Function
Ghrelin is an appetite-regulating factor secreted from peripheral organs that is involved in regulation of energy homoeostasis via binding to the receptor resulting in the secretion of growth hormone by the pituitary gland.[4] The pathway activated by binding of ghrelin to the growth hormone secretagogue receptor, GHSR1a, regulates the activation of the downstream mitogen-activated protein kinase, Akt, nitric oxide synthase, and AMPK cascades in different cellular systems.[2] One of the important features of GHSR1a displays constitutive activity possessing basal activity in the absence of an agonist, resulting in a high degree of receptor internalization as well as of signaling activity.[2] Inverse agonists for the ghrelin receptor could be particularly interesting for the treatment of obesity.[5] This activity seems to provide a tonic signal required for the development of normal height, probably through an effect on the GH axis.[6]
Transcripts
Two identified transcript variants are expressed in several tissues and are evolutionary conserved in fish and swine. One transcript, 1a, excises an intron and encodes the functional protein; this protein is the receptor for the ghrelin ligand and defines a neuroendocrine pathway for growth hormone release. The second transcript (1b) retains the intron and does not function as a receptor for ghrelin; however, it may function to attenuate activity of isoform 1a.[7]
Selective ligands
A range of selective ligands for the GHSR receptor are now available and are being developed for several clinical applications. GHSR agonists have appetite-stimulating and growth hormone-releasing effects, and are likely to be useful for the treatment of muscle wasting and frailty associated with old-age and degenerative diseases. On the other hand, GHSR antagonists have anorectic effects and are likely to be useful for the treatment of obesity.
Agonists
- Adenosine[8]
- Alexamorelin
- Anamorelin
- Capromorelin
- CP-464709
- Cortistatin-14
- Examorelin (hexarelin)
- Ghrelin (lenomorelin)
- GHRP-1
- GHRP-3
- GHRP-4
- GHRP-5
- GHRP-6
- Ibutamoren (MK-677)
- Ipamorelin
- L-692,585
- LY-426410
- LY-444711
- Macimorelin
- Pralmorelin (GHRP-2)
- Relamorelin
- SM-130,686
- Tabimorelin
- Ulimorelin
Antagonists
- A-778,193
References
- ↑ Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, Spedding M, Kojima M, Kangawa K (Dec 2005). "International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function". Pharmacological Reviews 57 (4): 541–6. doi:10.1124/pr.57.4.1. PMID 16382107.
- 1 2 3 Pazos Y, Casanueva FF, Camiña JP (2007). "Basic aspects of ghrelin action". Vitamins and Hormones 77: 89–119. doi:10.1016/S0083-6729(06)77005-4. PMID 17983854.
- ↑ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10:Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 265–266. ISBN 9780071481274.
- ↑ Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR (Nov 2000). "The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion". Endocrinology 141 (11): 4325–8. doi:10.1210/endo.141.11.7873. PMID 11089570.
- ↑ Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW (Nov 2003). "High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist". Molecular Endocrinology 17 (11): 2201–10. doi:10.1210/me.2003-0069. PMID 12907757.
- ↑ 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 (Mar 2006). "Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature". The Journal of Clinical Investigation 116 (3): 760–8. doi:10.1172/JCI25303. PMC 1386106. PMID 16511605.
- ↑ "Entrez Gene: GHSR growth hormone secretagogue receptor".
- ↑ Kordon C, Robinson I, Hanoune J, Dantzer R (6 December 2012). Brain Somatic Cross-Talk and the Central Control of Metabolism. Springer Science & Business Media. pp. 42–. ISBN 978-3-642-18999-9.
Further reading
- Portelli J, Thielemans L, Ver Donck L, Loyens E, Coppens J, Aourz N, Aerssens J, Vermoesen K, Clinckers R, Schallier A, Michotte Y, Moechars D, Collingridge GL, Bortolotto ZA, Smolders I (2012). "Inactivation of the constitutively active ghrelin receptor attenuates limbic seizure activity in rodents". Neurotherapeutics 9 (3): 658–72. doi:10.1007/s13311-012-0125-x. PMC 3441926. PMID 22669710.
External links
- "Ghrelin Receptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- growth hormone secretagogue receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
- Ghrelin at Colorado State University
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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