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.

 尊敬的编辑：

人 G 蛋白偶联受体 55 （GPR55） 是一种孤儿 GPCR，称为非典型大麻素受体 CB₃ ^R.1 研究表明，CB₁R 和 CB₂R 的内源性配体安非他命 （AEA） 和 2-花生四烯酰甘油 （2-AG） 及其合成激动剂CP55940可以激活 GPR55。² 有趣的是，据报道，CB₁R 拮抗剂（如利莫那班和 AM251）也对 GPR55 表现出活性，尽管关于利莫那班对 GPR55 影响的报告在不同实验室中不一致。^2,3 与主要与 G prtoein 偶联的 CB₁R 或 CB₂R 不同，⁴ GPR55 激活通过与 G_12/13 或 G_q 蛋白偶联来诱导不同的细胞反应。^2,3 然而，最近的研究表明，溶血磷脂酰肌醇 （LPI） 及其 2-花生四烯酰类似物，而不是内源性大麻素，可能是 GPR55 的内源性激动剂。^5,6 因此，GPR55 的去孤儿化仍然存在争议。GPR55 主要在脊髓和大直径背根神经节 （DRG） 中表达，据报道参与调节伤害感受器兴奋性和轴突生长。^5,6,7 此外，GPR55 还参与代谢疾病、癌症和动脉粥样硬化。这些生理和病理生理过程强调了 GPR55 的治疗潜力。值得注意的是，据报道，GPR55 在某些组织中与 CB₁R 或 CB₂R 形成异二聚体，增加了其药理学特征的复杂性。⁸ 然而，由于缺乏 GPR55 的三维 （3D） 结构，配体识别和信号转导的分子机制仍然令人费解。