Integrating the GPCR transactivation-dependent and biased signalling paradigms in the context of PAR1 signalling

Little, P. J., Hollenberg, M. D, Kamato, D., Thomas, W., Chen, J., Wang, T., Zheng, W. and Osman, N. (2016) Integrating the GPCR transactivation-dependent and biased signalling paradigms in the context of PAR1 signalling. British Journal of Pharmacology, 173 20: 2992-3000. doi:10.1111/bph.13398


Author Little, P. J.
Hollenberg, M. D
Kamato, D.
Thomas, W.
Chen, J.
Wang, T.
Zheng, W.
Osman, N.
Title Integrating the GPCR transactivation-dependent and biased signalling paradigms in the context of PAR1 signalling
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 1476-5381
Publication date 2016-02-16
Year available 2016
Sub-type Article (original research)
DOI 10.1111/bph.13398
Open Access Status Not Open Access
Volume 173
Issue 20
Start page 2992
End page 3000
Total pages 9
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Subject 3004 Pharmacology
Abstract Classically, receptor-mediated signalling was conceived as a linear process involving one agonist, a variety of potential targets within a receptor family (e.g. α- and β-adrenoceptors) and a second messenger (e.g. cAMP)-triggered response. If distinct responses were stimulated by the same receptor in different tissues (e.g. lipolysis in adipocytes vs. increased beating rate in the heart caused by adrenaline), the differences were attributed to different second messenger targets in the different tissues. It is now realized that an individual receptor can couple to multiple effectors (different G proteins and different β-arrestins), even in the same cell, to drive very distinct responses. Furthermore, tailored agonists can mould the receptor conformation to activate one signal pathway versus another by a process termed 'biased signalling'. Complicating issues further, we now know that activating one receptor can rapidly trigger the local release of agonists for a second receptor via a process termed 'transactivation'. Thus, the end response can represent a cooperative signalling process involving two or more receptors linked by transactivation. This overview, with a focus on the GPCR, protease-activated receptor-1, integrates both of these processes to predict the complex array of responses that can arise when biased receptor signalling also involves the receptor transactivation process. The therapeutic implications of this signalling matrix are also briefly discussed. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc.
Formatted abstract
Classically, receptor-mediated signalling was conceived as a linear process involving one agonist, a variety of potential targets within a receptor family (e.g. α- and β-adrenoceptors) and a second messenger (e.g. cAMP)-triggered response. If distinct responses were stimulated by the same receptor in different tissues (e.g. lipolysis in adipocytes vs. increased beating rate in the heart caused by adrenaline), the differences were attributed to different second messenger targets in the different tissues. It is now realized that an individual receptor can couple to multiple effectors (different G proteins and different β-arrestins), even in the same cell, to drive very distinct responses. Furthermore, tailored agonists can mould the receptor conformation to activate one signal pathway versus another by a process termed ‘biased signalling’. Complicating issues further, we now know that activating one receptor can rapidly trigger the local release of agonists for a second receptor via a process termed ‘transactivation’. Thus, the end response can represent a cooperative signalling process involving two or more receptors linked by transactivation. This overview, with a focus on the GPCR, protease-activated receptor-1, integrates both of these processes to predict the complex array of responses that can arise when biased receptor signalling also involves the receptor transactivation process. The therapeutic implications of this signalling matrix are also briefly discussed.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Biomedical Sciences Publications
School of Pharmacy Publications
 
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