Structural insight into GPR55 ligand recognition and G-protein coupling
Ruixue Xia, Qingning Yuan, Na Wang, Li Hou, Junpei Abe, Jing Song, Yukishige Ito, H. Eric Xu, Yuanzheng He
Abstract
GPR55 was originally considered the third cannabinoid receptor (CB3) due to its high expression in the central nervous system and its association with endocannabinoids, such as N -arachidonoylethanolamine (AEA). 1 However, subsequent studies indicate that GPR55 lacks a traditional ‘cannabinoid-binding pocket’, 2 and the activation of GPR55 by endocannabinoids may be mediated by other receptors. In 2007, Oka et al. demonstrated that L -α- lysophosphatidylinositol (LPI) robustly activates GPR55 and that this effect is absent in GPR55 knockdown cells. 3 Following similar discoveries by other groups, LPI has gradually been accepted as the endogenous ligand of GPR55. In the meantime, synthetic CB1 antagonists, such as AM251 and SR141716A, have been shown to activate GPR55 in cell-based reporter assays. 4 Despite the lasting debate over whether GPR55 is a cannabinoid receptor, it is known to play crucial roles in the nervous and metabolic systems. In the nervous system, GPR55 is highly expressed in hippocampus, brain stem, cerebellum, frontal cortex, hypothalamus, and striatum. It is closely associated with sensation, cognition, and pain perception, making it a promising target for treating Parkinson’s disease. 5 Of note, GPR55 agonists, O-1602 and palmitoylethanolamide, have been used to relieve pain in animal models. In the metabolic system, GPR55 is abundantly expressed in adipocytes, pancreas islet, gastrointestinal tract and adrenals. Consistent with its expression pattern, GPR55 regulates insulin secretion, intestinal inflammatory factors, and plasma glucose levels, presenting a promising target for metabolic disorders, such as diabetes and nonalcoholic steatohepatitis. 6 Notably, GPR55 agonists AM251 and SR141716A have been demonstrated to reduce body weight by decreasing food intake in animal models. 1 Given the significance of GPR55 in both nervous and metabolic systems, we aimed to gain structural insight into GPR55 ligand recognition and G-protein coupling.