title: Integrating the GPCR transactivation-dependent and biased signalling paradigms in the context of PAR1 signalling.
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.
authors.affiliation: School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia. p.little@uq.edu.au.|School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia. p.little@uq.edu.au.|Xinhua College of Sun Yat-sen University, Guangzhou, China. p.little@uq.edu.au.
authors.forename: P J
authors.initials: PJ
authors.lastname: Little
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.|Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Hollenberg
authors.affiliation: School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Kamato
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, Australia.
authors.forename: W
authors.initials: W
authors.lastname: Thomas
authors.affiliation: Xinhua College of Sun Yat-sen University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Xinhua College of Sun Yat-sen University, Guangzhou, China.|Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China.|Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-sen University, Guangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Zheng
authors.affiliation: School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.|Department of Immunology, Monash University, Melbourne, VIC, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Osman
mesh_terms: D000818:Animals; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D043562:Receptors, G-Protein-Coupled