Membrane signalling complexes: implications for development of functionally selective ligands modulating heptahelical receptor signalling.
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".
Piñeyro
Graciela
G
Centre de Recherche Fernand Seguin, Hôpital L.H. Lafontaine, Université de Montréal, Canada. graciela.pineyro.filpo@umontreal.ca
D000262:Adenylyl Cyclases / Q000378:metabolism; D000494:Allosteric Regulation; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D031541:Fluorescence Resonance Energy Transfer; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D008024:Ligands; D008163:Luminescent Measurements; D011487:Protein Conformation; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D015220:Calcium Channels; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases