Dimerization of G‐protein coupled Receptors (GPCRs) in Appetite Regulation and Food Reward

Abstract

Heterodimerization of GPCRs involved in appetite signalling may explain functional crosstalk observed between neuropeptide systems. The ghrelin (GHSR1a) and the serotonin 2C receptor (5‐ HT2C) have been implicated in homeostatic control of appetite and satiety and in neurocircuits involved in the rewarding aspects of food. Interestingly, serotonin has been shown to effectively block ghrelin's orexigenic actions and the 5‐HT2C receptor exerts a tonic inhibitory influence over dopamine neurotransmission. Moreover, ghrelin mediates rewarding effects of palatable foods via neuronal dopamine secretion. Thus, investigations into how such interactions occur at the molecular level are warranted and under investigation in this study. We show, to our knowledge for the first time, compelling evidence for the existence of a novel 5‐HT2C/D1 and 5‐HT2C/GHS‐R1a receptor heterodimer in vitro and ex vivo. Colocalization and agonist‐mediated co‐internalization was demonstrated in lentivirally‐transduced cells and endogenously in hypothalamic rat neurons. Interestingly, dimerization of the unedited 5‐HT2C‐INI, but not the edited 5‐HT2C‐VSV isoform, was shown to attenuate GHS‐R1a‐mediated signalling. Similarly, D1‐ induced cAMP signalling was reduced in cells co‐expressing both isoforms of the 5‐HT2C receptor. The 5‐HT2C‐mediated attenuation of both GHS‐R1a and D1 signalling was fully restored following pharmacological blockade of the 5‐HT2C receptor. These findings may uncover novel mechanisms important for the future pharmacological targeting of the GPCRs in the homeostatic regulation of body weight as well as hedonic appetite signalling, which both play a significant role in the development of obesity. The work was supported by Enterprise Ireland under Grant Number CC20080001.