Biomol Ther (Seoul)  
Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors
Chengchun Min, Xiaohan Zhang, Mei Zheng, Ningning Sun, Srijan Acharya, Xiaowei Zhang and Kyeong-Man Kim*
Pharmacology Laboratory, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
Tel: +82-62-530-2936, Fax: +82-62-530-2949
Received: September 1, 2016; Revised: October 8, 2016; Accepted: November 15, 2016; Published online: December 16, 2016.
© The Korean Society of Applied Pharmacology. All rights reserved.

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 β-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 β-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, β-arrestin2, and Gβγ. Gβγ displayed a stable interaction with receptors and β-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 Gβγ and β-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and Gβγ complex is required for the formation of a complex with β-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, β-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and Gβγ.
Keywords: GPCR, Acute tolerance, Desensitization, Gβγ, β-Arrestin, Dopamine D3 receptor

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