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. 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. 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. Inverse agonists for the ghrelin receptor could be particularly interesting for the treatment of obesity. This activity seems to provide a tonic signal required for the development of normal height, probably through an effect on the GH axis.
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.
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.
^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. ISBN9780071481274.
^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 Endocrinology17 (11): 2201–10. doi:10.1210/me.2003-0069. PMID12907757.