Received for publication December 7, 2007.
Revised March 27, 2008.
Accepted for publication April 2, 2008.

Conformational Rearrangements and Signaling Cascades Involved in Ligand-Biased MAPK Signaling through the 1-Adrenergic Receptor

Abstract

In recent years, several studies have demonstrated that different ligands can have distinct efficacy profiles towards various signaling pathways through a unique receptor. For instance, 1-adrenergic compounds that are inverse agonists toward the adenylyl cyclase (AC) can display agonist activity for the mitogenic-activated protein kinase (MAPK) pathway. Such phenomenon, often termed functional selectivity, has now been clearly established for many G protein-coupled receptors when considering distinct signaling output. However, the possibility that ligands could selectively engage distinct effectors to activate a single signaling output by promoting specific receptor conformations has not been extensively examined. Here, we took advantage of the fact that isoproterenol, bucindolol and propranolol (full, partial and inverse agonists for the AC pathway, respectively) all activate MAPK through the 1-adrenergic receptor (1AR) to probe such conformational-biased signaling. Although the three compounds stimulated MAPK in a src-dependent manner, isoproterenol acted through both Gi and G-protein independent pathways whereas bucindolol and propranolol promoted MAPK activation through the G protein-independent pathway only. The existence of such distinct signaling cascades linking 1AR to MAPK activation was correlated with ligand-specific conformational rearrangements of receptor/G protein complexes measured by Bioluminescence Resonance Energy Transfer. Taken together, our data indicate that discrete local conformational changes can selectively promote the recruitment of distinct proximal signaling partners that can engage distinct signaling output and/or converge on the same one.

Key words: Adrenergic, Gi family, Gs family, Adenylyl cyclases, cAMP, Src and other nonreceptor tyrosine kinases, MAP Kinase, Fluorescence techniques, Structure/function/mechanism

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