{"title":"Structure basis of ligand recognition and activation of GPR55","authors":"Hao Chang, Xiaoting Li, Ling Shen, Xuanrui Ge, Shuming Hao, Lijie Wu, Shenhui Liu, Junlin Liu, Vadim Cherezov, Tian Hua","doi":"10.1038/s41422-024-01046-8","DOIUrl":null,"url":null,"abstract":"<p>Dear Editor,</p><p>Human G protein-coupled receptor 55 (GPR55) is an orphan GPCR, termed an atypical cannabinoid receptor, CB<sub>3</sub>R.<sup>1</sup> This classification was further supported by studies demonstrating that the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG) of CB<sub>1</sub>R and CB<sub>2</sub>R, along with their synthetic agonist CP55940, could activate GPR55.<sup>2</sup> Interestingly, CB<sub>1</sub>R 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.<sup>2,3</sup> Unlike CB<sub>1</sub>R or CB<sub>2</sub>R, which primarily couple with G<sub>i</sub> prtoein,<sup>4</sup> GPR55 activation induces diverse cellular responses by coupling with G<sub>12/13</sub> or G<sub>q</sub> protein.<sup>2,3</sup> However, recent studies suggest that lysophosphatidylinositol (LPI) and its 2-arachidonyl analogs, rather than endocannabinoids, may serve as endogenous agonists of GPR55.<sup>5,6</sup> 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.<sup>5,6,7</sup> 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 CB<sub>1</sub>R or CB<sub>2</sub>R in certain tissues, adding complexity to its pharmacological profile.<sup>8</sup> However, the molecular mechanisms of ligand recognition and signaling remain puzzling due to the lack of a three-dimensional (3D) structure of GPR55.</p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1000,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41422-024-01046-8","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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.