Structure basis of ligand recognition and activation of GPR55  

作　　者：Hao Chang Xiaoting Li Ling Shen Xuanrui Ge Shuming Hao Lijie Wu Shenhui Liu Junlin Liu Vadim Cherezov Tian Hua 

机构地区：[1]iHuman Institute,ShanghaiTech University,Shanghai,China [2]School of Life Science and Technology,ShanghaiTech University,Shanghai,China [3]Bridge Institute,University of Southern California,Los Angeles,CA,USA [4]Viterbi School of Engineering,University of Southern California,Los Angeles,CA,USA [5]Department of Chemistry,University of Southern California,Los Angeles,CA,USA

出　　处：《Cell Research》2025年第1期80-83,共4页细胞研究(英文版)

基　　金：supported by the National Key R&D Program of China(2022YFA1302902,2023YFC2509100 to T.H.),the National Natural Science Foundation of China(32271262 to T.H.),Shanghai Sailing Program(23YF1427800 to X.L.).Shanghai Science and Technology Plan(21DZ2260400 to T.H.).We thank Dr.Zhi-Jie Liu from ShanghaiTech University for insightful discussions and valuable suggestions on the manuscript.We thank ONO PHARMA for providing ONO-9710531 and Dr.Fei Zhao from the iHuman Institute for synthesizing Cpd26.

摘　　要：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.

关 键 词：ENDOGENOUS ACTIVATION GPR 

分 类 号：R97[医药卫生—药品]