The emerging role of heterodimerisation and interacting proteins in ghrelin receptor function

Abstract

Ghrelin is a peptide hormone secreted primarily by the stomach that acts upon the growth hormone secretagogue receptor (GHSR1), a G protein-coupled receptor whose functions include growth hormone secretion, appetite regulation, energy expenditure, regulation of adiposity, and insulin release. Following the discovery that GHSR1a stimulates food intake, receptor antagonists were developed as potential therapies to regulate appetite. However, despite reductions in signalling, the desired effects on appetite were absent. Studies in the past 15 years have demonstrated GHSR1a can interact with other transmembrane proteins, either by direct binding (i.e. heteromerisation) or via signalling cross-talk. These interactions have various effects on GHSR1a signalling including preferential coupling to one pathway (i.e. biased signalling), coupling to a unique G protein (G protein switching), suppression of GHSR1a signalling, and enhancement of signalling by both receptors. While many of these interactions have been shown in cells overexpressing the proteins of interest and remain to be verified in tissues, substantial evidence exists showing that GHSR1a and the dopamine receptor D1 (DRD1) form heteromers, which promote synaptic plasticity and formation of hippocampal memory. Additionally, a reduction in GHSR1a-DRD1 complexes in favour of establishment of GHSR1a-Aβ complexes correlates with Alzheimer's disease, indicating that GHSR1a heteromers may have pathological functions. Herein, we summarise the evidence published to date describing interactions between GHSR1a and transmembrane proteins, discuss the experimental strengths and limitations of these studies, describe the physiological evidence for each interaction, and address their potential as novel drug targets for appetite regulation, Alzheimer's disease, insulin secretion, and inflammation.

Keywords: GPCR; MRAP2; appetite; dopamine receptors; heterodimerisation; receptor cross-talk.

Figure 1

Mechanisms by which GHSR1a signalling is modified by interacting proteins. Schematic showing the different mechanisms by which GHSR1a signalling is modified by interactions with transmembrane proteins. All diagrams depict monomeric receptors, although there is evidence that heterotetramers may occur. GHSR1a is understood to primarily signal via G_q/11 pathways to activate Ca²⁺_i pathways. This involves both constitutive and agonist-mediated signalling, and association between GHSR1a and β-arrestins may increase RhoA pathways. (A) Interaction with MRAP2 impairs GHSR1a constitutive activity and β-arrestin recruitment, and biases signalling towards enhanced agonist-mediated Ca²⁺_i signalling. (B) Interactions between GHSR1a and MC3R enhance MC3R-mediated G_s-cAMP signalling and impair ghrelin-mediated increases in Ca²⁺_i. Similar mechanisms are observed for GPR83, 5-HT_2CR, and σ1R. (C) Interactions between GHSR1a and OX1R switch G protein coupling from G_q to G_S. Interactions with GHSR1b and SSTR2 also result in a switch in G protein coupling that is governed by the stoichiometry of each receptor. In the presence of high GHSR1b expression, the inactive receptor exerts a dominant-negative effect on GHSR1a-mediated signalling. When GHSR1b expression is low, as in hippocampal and striatal neurons, GHSR1a interacts with both GHSR1b and DRD1 to activate G_S-cAMP signalling. (D) Interactions between GHSR1a and DRD2 and DRD1 result in reciprocal increases in signalling by both receptors. (E) Interactions with prostanoid receptors impair GHSR1a constitutive signalling. AGRP, agouti-related peptide; Ca²⁺_i, intracellular Ca²⁺; DRD1, dopamine receptor D1; DRD2, dopamine receptor D2; EP3-I, prostaglandin E₂ receptor subtype EP_3-I; GHSR1, growth hormone secretagogue receptor; GPR83, G protein-coupled receptor-83; MC3R, melanocortin-3 receptor; MRAP2, melanocortin receptor accessory protein-2; OX1R, orexin-1 receptor; TPα, thromboxane prostanoid A2 receptor; 5-HT_2CR, serotonin (5-hydroxytryptamine) subtype-2C receptor; σ1R; neuronal sigma-1 receptor.