Heptahelical receptors communicate extracellular information to the cytosolic compartment by binding an extensive variety of ligands. They do so through conformational changes that propagate to intracellular signaling partners as the receptor switches from a resting to an active conformation. This active state has been classically considered unique and responsible for regulation of all signaling pathways controlled by a receptor. However, recent functional studies have challenged this notion and called for a paradigm where receptors would exist in more than one signaling conformation. This study used bioluminescence resonance energy transfer assays in combination with ligands of different functional profiles to provide in vivo physical evidence of conformational diversity of ␦-opioid receptors (DORs). DORs and ␣ i1  1 ␥ 2 G protein subunits were tagged with Luc or green fluorescent protein to produce bioluminescence resonance energy transfer pairs that allowed monitoring DOR-G protein interactions from different vantage points. Results showed that DORs and heterotrimeric G proteins formed a constitutive complex that underwent structural reorganization upon ligand binding. Conformational rearrangements could not be explained by a two-state model, supporting the idea that DORs adopt ligand-specific conformations. In addition, conformational diversity encoded by the receptor was conveyed to the interaction among heterotrimeric subunits. The existence of multiple active receptor states has implications for the way we conceive specificity of signal transduction.Heptahelical receptors are versatile membrane proteins that play an important role in cellular communication. They do so by recognizing a large variety of extracellular ligands that convey information to the intracellular compartment by modifying receptor conformation upon binding. These structural modifications then trigger an array of biochemical changes that ultimately control vital processes within the cell. Traditionally, conformational changes induced by ligand binding have been thought to shift equilibrium between an active and an inactive conformation of the receptor. According to this classical view, all agonists would stabilize a single active state that equally effectively stimulates all signaling pathways controlled by the receptor (1). In consequence, ligand ability to stabilize this unique active state would be the only determinant of ligand efficacy at all functional readouts. Furthermore, this model predicts that ligand rank order of efficacy across different readouts should be maintained, representing a progressive accumulation (or decrease) of the single active state of the receptor (2).However, recent data have challenged this view, suggesting that the complexity of heptahelical receptor signaling cannot be based on the accumulation of a single active receptor conformation, and efficacy cannot be restricted to only a quantitative dimension (3, 4). Evidence supporting this assertion has been largely based on functional studies whose results ...
Résumé
Le port de Québec a joué un rôle majeur dans l’important commerce colonial transatlantique avec les métropoles française et britannique. L’historiographie canadienne a depuis longtemps mis l’accent sur le volet exportation des ressources naturelles de ces échanges, tant les fourrures que les produits du bois, mais a rencontré des obstacles à cerner la place des importations des produits autres que les alcools et certaines denrées taxées. Se fondant sur un dépouillement et une analyse statistique critique des importants registres de la douane britanniques (Archives nationales du Royaume-Uni, séries CUST), cet article fait ressortir la prédominance des produits industriels britanniques, essentiellement les textiles, ainsi que d’une multitude de produits métallurgiques, alimentaires et autres reflétant tout l’éventail des milliers de produits arrivés sur le marché de consommation canadien de 1760 jusqu’à 1850. Il amorce dans deux cas (textiles et métallurgie) une étude plus approfondie de la composition de ces importations et de leurs retombées sur la production locale, tant artisanale qu’industrielle. Globalement, il en ressort aussi que la valeur des importations surpasse nettement celle des exportations pour cette période, une conclusion surprenante et controversée.
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