Ghrelin receptor signaling: a promising therapeutic target for metabolic syndrome and cognitive dysfunction

Abstract

The neuroendocrine hormone ghrelin is an octanoylated 28-residue peptide that exerts numerous physiological functions. Ghrelin exerts its effects on the body mainly through a highly conserved G protein-coupled receptor known as the growth hormone secretagagogue receptor subtype 1a (GHS-R1a). Ghrelin and GSH-R1a are widely expressed in both peripheral and central tissues/organs, and ghrelin signaling plays a critical role in maintaining energy balance and neuronal health. The multiple orexigenic effects of ghrelin and its receptor have been studied in great detail, and GHS-R1a-mediated ghrelin signaling has long been a promising target for the treatment of metabolic disorders, such as obesity. In addition to its well-characterized metabolic effects, there is also mounting evidence that ghrelin-mediated GHS-R1a signaling exerts neuroprotective effects on the brain. In this review, we will summarize some of the effects of ghrelin-mediated GSH-R1a signaling on peripheral energy balance and cognitive function. We will also discuss the potential pharmacotherapeutic role of GSH-R1a-mediated ghrelin signaling for the treatment of complex neuroendocrine disorders.

Figure 1. An overview of some ghrelin and GHS-R1a down-stream signaling pathways

These signaling pathways include the dominant growth hormone secretagogue-related PLC/PKC/IP3 pathway, hypothalamic ghrelin activation of NPY-containing neurons and inhibition of POMC neurons, and ghrelin augmentation of dopamine signaling, involving GHS-R1a/D1R heterodimerization, leading to a synergistic activation of AC2 via Gαs (D1Rcoupling) and βγ-subunits derived from Gαi (GHS-R1a coupling). DAG = diacylglycerol, IP3 =Inositol(1,4,5)triphosphate, POMC = pro-opiomelanocortin, D1R = dopamine receptor 1, AC2 = adenylyl cyclase-2