Structure basis of ligand recognition and activation of GPR55

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemistry Biochemistry 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
Biochemistry Biochemistry
Biochemistry Biochemistry 生物-生化与分子生物学
CiteScore
5.50
自引率
3.40%
发文量
336
审稿时长
1-2 weeks
期刊介绍: Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.
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