Structure basis of ligand recognition and activation of GPR55

Dear Editor,

Human G protein-coupled receptor 55 (GPR55) is an orphan GPCR, termed an atypical cannabinoid receptor, CB₃R.¹ This classification was further supported by studies demonstrating that the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG) of CB₁R and CB₂R, along with their synthetic agonist CP55940, could activate GPR55.² Interestingly, CB₁R antagonists such as rimonabant and AM251 were also reported to exhibit activity on GPR55, although reports on rimonabant’s effect on GPR55 are inconsistent across different laboratories.^2,3 Unlike CB₁R or CB₂R, which primarily couple with G_i prtoein,⁴ GPR55 activation induces diverse cellular responses by coupling with G_12/13 or G_q protein.^2,3 However, recent studies suggest that lysophosphatidylinositol (LPI) and its 2-arachidonyl analogs, rather than endocannabinoids, may serve as endogenous agonists of GPR55.^5,6 Therefore, the deorphanization of GPR55 still remains debatable. GPR55 is mainly expressed in the spinal cord and large-diameter dorsal root ganglia (DRG) and is reported to be involved in modulating nociceptor excitability and axon growth.^5,6,7 Additionally, GPR55 is also involved in metabolic diseases, cancer, and atherosclerosis. These physiological and pathophysiological processes underscore the therapeutic potential of GPR55. Notably, GPR55 was reported to form heterodimers with CB₁R or CB₂R in certain tissues, adding complexity to its pharmacological profile.⁸ However, the molecular mechanisms of ligand recognition and signaling remain puzzling due to the lack of a three-dimensional (3D) structure of GPR55.