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

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...

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Autores principales: Min, Chengchun, Zhang, Xiaohan, Zheng, Mei, Sun, Ningning, Acharya, Srijan, Zhang, Xiaowei, Kim, Kyeong-Man
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Korean Society of Applied Pharmacology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424633/
https://www.ncbi.nlm.nih.gov/pubmed/27956717
http://dx.doi.org/10.4062/biomolther.2016.193
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author Min, Chengchun
Zhang, Xiaohan
Zheng, Mei
Sun, Ningning
Acharya, Srijan
Zhang, Xiaowei
Kim, Kyeong-Man
author_facet Min, Chengchun
Zhang, Xiaohan
Zheng, Mei
Sun, Ningning
Acharya, Srijan
Zhang, Xiaowei
Kim, Kyeong-Man
author_sort Min, Chengchun
collection PubMed
description 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.
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spelling pubmed-54246332017-05-10 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 Biomol Ther (Seoul) Original Article 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. The Korean Society of Applied Pharmacology 2017-05 2016-12-16 /pmc/articles/PMC5424633/ /pubmed/27956717 http://dx.doi.org/10.4062/biomolther.2016.193 Text en Copyright ©2017, The Korean Society of Applied Pharmacology http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Min, Chengchun
Zhang, Xiaohan
Zheng, Mei
Sun, Ningning
Acharya, Srijan
Zhang, Xiaowei
Kim, Kyeong-Man
Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors
title Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors
title_full Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors
title_fullStr Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors
title_full_unstemmed Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors
title_short Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors
title_sort molecular signature that determines the acute tolerance of g protein-coupled receptors
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424633/
https://www.ncbi.nlm.nih.gov/pubmed/27956717
http://dx.doi.org/10.4062/biomolther.2016.193
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