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Distinct signaling profiles of beta1 and beta2 adrenergic receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase reveals the pluridimensionality of efficacy.

Galandrin S, Bouvier M

Department of Biochemistry, Groupe de Recherche Universitaire sur le Médicament and Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal, QC, Canada, H3C 3J7.

Drug efficacy is typically considered an intrinsic property of a ligand/receptor couple. However, recent observations suggest that efficacy may also be influenced by the signaling effectors engaged by a unique receptor. To directly and systematically test this possibility, we assessed the ability of a panel of beta-adrenergic ligands to modulate the activity of two effector systems, the adenylyl cyclase (AC) and the mitogen-activated protein kinase (MAPK), via beta(1) and beta(2) adrenergic receptors. Although some compounds displayed similar efficacies toward the two pathways, others showed complex efficacy profiles. For example, compounds that are inverse agonists for the AC activity were found to be either agonists, neutral antagonists, or inverse agonists for the MAPK pathway. Likewise, agonists for the AC were either agonists or neutral antagonists for MAPK. Given this complexity, we propose a Cartesian representation of the efficacies that takes into account the activities of the different effectors that can be engaged by a given receptor. In addition, compounds considered as nonselective for beta(1) and beta(2) adrenergic receptors, based on their binding affinities, showed distinct relative efficacy profiles toward AC and MAPK, adding a new dimension to the concept of ligand selectivity. Taken together, the results suggest that binding of different ligands promote distinct conformational changes leading to specific signaling outcomes. Our data therefore clearly illustrate that efficacy is a pluridimensional parameter that is not an intrinsic characteristic of a ligand/receptor couple. This should have important implications for the future design of screening assays used in drug discovery campaigns.

Mol. Pharmacol. 2006;70(5):1575-84.

Pubmed ID: 16901982

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