Structure basis of ligand recognition and activation of GPR55

IF 28.1 1区 生物学 Q1 CELL BIOLOGY Cell Research Pub Date : 2024-10-31 DOI:10.1038/s41422-024-01046-8
Hao Chang, Xiaoting Li, Ling Shen, Xuanrui Ge, Shuming Hao, Lijie Wu, Shenhui Liu, Junlin Liu, Vadim Cherezov, Tian Hua
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Abstract

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 Gi prtoein,4 GPR55 activation induces diverse cellular responses by coupling with G12/13 or Gq 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.

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配体识别和激活 GPR55 的结构基础
亲爱的编辑,人类 G 蛋白偶联受体 55(GPR55)是一种孤儿 GPCR,被称为非典型大麻素受体,即 CB3R。2 有趣的是,据报道利莫那班和 AM251 等 CB1R 拮抗剂也对 GPR55 具有活性,但不同实验室关于利莫那班对 GPR55 的作用的报道并不一致。与主要与 Gi 蛋白偶联的 CB1R 或 CB2R 不同,4 GPR55 激活后可通过与 G12/13 或 Gq 蛋白偶联诱导多种细胞反应。2,3 然而,最近的研究表明,溶血磷脂酰肌醇(LPI)及其 2-arachidonyl 类似物而非内源性大麻素可能是 GPR55 的内源性激动剂。GPR55 主要在脊髓和大直径背根神经节(DRG)中表达,据报道参与调节痛觉感受器的兴奋性和轴突生长。这些生理和病理生理过程凸显了 GPR55 的治疗潜力。值得注意的是,有报道称 GPR55 在某些组织中与 CB1R 或 CB2R 形成异二聚体,这增加了其药理特征的复杂性。
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来源期刊
Cell Research
Cell Research 生物-细胞生物学
CiteScore
53.90
自引率
0.70%
发文量
2420
审稿时长
2.3 months
期刊介绍: Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.
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