{"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":28,"journal":{"name":"Biochemistry Biochemistry","volume":"6 1","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemistry Biochemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41422-024-01046-8","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR 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:
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