Heterogeneity of Ghrelin/Growth Hormone Secretagogue Receptors

Abstract

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 G_q, 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 G_q. 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.

Unraveling the role of the ghrelin gene peptides in the endocrine pancreas

“…Furthermore, in human pancreatic islets, GHS-R1a immunoreactivity partially overlaps with insulin-positive b-cells, as demonstrated by double immunofluorescence staining for both GHS-R1a and insulin (Granata et al 2007), indicating that human b-cells might also be responsive to ghrelin stimulation. Like the two forms of ghrelin, GHS-R1a expression was shown in human and rat developing pancreatic islets, from early gestation to adult (Date et al 2002, Chanoine & Wong 2004, Granata et al 2007, Ueberberg et al 2009). …”

“…Only one study reported b-cell restricted ghrelin expression in the human pancreas (Volante et al 2002). Ghrelin expression in insulin-producing cells was, however, also demonstrated in rodent-derived b-cell lines (Granata et al 2007). Interestingly, AG and UAG were found expressed both in the adult and perinatal rat pancreas (Date et al 2002, Chanoine et al 2006, suggesting autocrine/paracrine effects throughout the organ's development.…”

“…Similarly, GHS-R1a is expressed in a variety of tissues (suggesting that AG may target them) besides the hypothalamus and pituitary (Kojima et al 1999, Gnanapavan et al 2002, van der Lely et al 2004. Indeed, AG was demonstrated to act as an autocrine/paracrine factor, regulating cell proliferation and survival, apoptosis, inflammation, cardiovascular and gastric functions, metabolism, angiogenesis, development, and reproduction (Muccioli et al 2007, Dezaki et al 2008, Chanoine et al 2009, van der Lely 2009.…”

“…UAG, which circulates in amounts far greater than AG, does not bind to GHS-R1a, and is devoid of effects on GH release (van der Lely et al 2004, Muccioli et al 2007. Initially thought to be nonfunctional, UAG was subsequently proven to exert specific biological activities, some of which are similar to and others opposed to or independent of AG.…”

Differential effects of GH and GH-releasing peptide-6 on astrocytes

“…Upon binding to the GHS receptor, which has been renamed ghrelin receptor (GRLN-R1a; Davenport et al 2005), GHSs activate pathways that regulate the activation of downstream MAPK, protein kinase B (PKB/Akt), nitric oxide synthase and adenosine monophosphate-activated protein kinase cascades in different cellular systems (Petersenn 2002). GRLN-R1a activation leads to an increase in intracellular levels of Ca 2C via phosphatidylinositol-specific phospholipase C (Camiña et al 2003, Muccioli et al 2007). Ghrelin and GHRP-6 stimulate proliferation of different cell types (Dieguez & Casanueva 2000, Pettersson et al 2002, Thompson et al 2004, Rossi et al 2009) and may also affect the CNS by protecting neurons from apoptosis (Frago et al 2002, 2011, Delgado-Rubin de Célix et al 2006, Delgado-Rubin et al 2009).…”