A Dimer for Dinner: The Impact of GHS-R1a Heterodimerization on Feeding Circuits

Growth hormone-releasing hormone receptor 1a (GHS-R1a) is a key G protein-coupled receptor (GPCR) governing feeding and energy homeostasis. Accumulating evidence shows that GHS-R1a forms functional heterodimers with multiple metabolic-related GPCRs, including dopamine 2 receptor (D2R), melanocortin 3 receptor (MC3R), 5-hydroxytryptamine 2c receptor (5-HT2cR), orexin receptor 1 (OX1R) and cannabinoid receptor 1 (CB1R). These heterodimers undergo distinct signal transduction reprogramming, generating novel physiological effects that are not observed with individual receptors: for instance, GHS-R1a/D2R mediates an atypical calcium signaling pathway to regulate appetite, while GHS-R1a/5-HT2cR antagonizes ghrelin-induced orexigenic effects. Meanwhile, diverse detection techniques, including co-immunoprecipitation and fluorescence resonance energy transfer, have been developed to identify and validate GHS-R1a heterodimerization, laying a solid foundation for mechanistic research. This review systematically summarizes the molecular mechanisms of GHS-R1a heterodimer formation, the characteristic signal regulation patterns of different heterodimers, and their specific regulatory roles in feeding circuits. Furthermore, we discuss the existing research gaps in this field, such as the lack of in vivo detection methods for heterodimers and the unclear structural basis of dimerization. Finally, we highlight the potential of targeting specific GHS-R1a heterodimers as a novel therapeutic strategy for obesity and anorexia, providing new directions for future pharmaceutical development and clinical translation.