Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors

Min, Chengchun; Zhang, Xiaohan; Zheng, Mei; Sun, Ningning; Acharya, Srijan; Zhang, Xiaowei; Kim, Kyeong Man

Abstract

Desensitization and acute tolerance are terms used to describe the attenuation of receptor responsiveness by prolonged or intermittent exposure to an agonist. Unlike desensitization of G protein-coupled receptors (GPCRs), which is commonly explained by steric hindrance caused by the Î²-arrestins that are translocated to the activated receptors, molecular mechanisms involved in the acute tolerance of GPCRs remain unclear. Our studies with several GPCRs and related mutants showed that the acute tolerance of GPCRs could occur independently of agonist-induced Î²-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, Î²-arrestin2, and GÎ²Î³. GÎ²Î³ displayed a stable interaction with receptors and Î²-arrestin2 in cells expressing GPCRs that were prone to undergo tolerance compared to the GPCRs that were resistant to acute tolerance. Strengthening the interaction between GÎ²Î³ and Î²-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and GÎ²Î³ complex is required for the formation of a complex with Î²-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, Î²-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and GÎ²Î³.