Membrane signalling complexes: implications for development of functionally selective ligands modulating heptahelical receptor signalling |
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| Authors: | Piñeyro Graciela |
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| Affiliation: | 1. 1nstitute of Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland;2. Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland;3. Surface Measurement Systems Ltd., Alperton, London;4. Tillotts Pharma AG, Rheinfelden, Switzerland;1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK;2. Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20852, USA;3. Protein Production Facility of the New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York 10027, NY, USA;1. Key Laboratory of Low-grade Energy Utilization Technologies and Systems of Ministry of Education, College of Power Engineering, Chongqing University, Chongqing 400044, China;2. Combustion and CCS Centre, Cranfield University, Cranfield, Bedfordshire MK43 0AL, United Kingdom;3. School of Mechanical and Mining Engineering, The University of Queensland, St Lucia, Queensland 4072, Australia |
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| Abstract: | Technological development has considerably changed the way in which we evaluate drug efficacy and has led to a conceptual revolution in pharmacological theory. In particular, molecular resolution assays have revealed that heptahelical receptors may adopt multiple active conformations with unique signalling properties. It is therefore becoming widely accepted that ligand ability to stabilize receptor conformations with distinct signalling profiles may allow to direct the stimulus generated by an activated receptor towards a specific signalling pathway. This capacity to induce only a subset of the ensemble of responses regulated by a given receptor has been termed "functional selectivity" (or "stimulus trafficking"), and provides the bases for a highly specific regulation of receptor signalling. Concomitant with these observations, heptahelical receptors have been shown to associate with G proteins and effectors to form multimeric arrays. These complexes are constitutively formed during protein synthesis and are targeted to the cell surface as integral signalling units. Herein we summarize evidence supporting the existence of such constitutive signalling arrays and analyze the possibility that they may constitute viable targets for developing ligands with "functional selectivity". |
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