Received for publication February 7, 2007.
Revised February 9, 2007.
Accepted for publication February 9, 2007.

Missing links: Mechanisms of Protean Agonism (Relates to article by Lane, et al., Fast Forward 7 February 2007)

Abstract

The concept of pharmacological efficacy has been much discussed recently with significant interest both in inverse agonists and in protean agonists (i.e. compounds with functional selectivity for different effector responses). While first proposed in the mid-90's the pharmacological and therapeutic importance of these concepts is now receiving wider support. Two papers in recent issues of Molecular Pharmacology, Lane et al in the current issue and Galandrin and Bouvier in the November, 2006 issue, provide new mechanistic information on functionally selective ligands at the pharmacologically important D2 dopamine receptor and the ₁ and ₂ adrenergic receptors. Each paper bridges a gap between recent biophysical studies showing distinct receptor conformations produced by different ligands and the increasing number of reports of discordant outputs by a single ligand to two effector readouts. The Lane et al study clearly demonstrates G protein-specific actions of D2 dopamine receptor ligands. These range from equivalent responses for G_o and G_i activation by NPA and 7-OH-DPAT to S-(-)-3-PPP which is an agonist for Gao activation and an inverse agonist at G_i1 and G_i2. Similarly, Galandrin and Bouvier describe a 2-dimensional Cartesian efficacy approach where propranolol is an agonist for ERK activation, probably through beta arrestin, while functioning as an inverse agonist for adenylyl cyclase activation. Thus, these two important papers further solidify the concepts of functional selectivity and protean agonism and begin to define the first post-receptor step in actions of protean agonist ligands.

Key words: Adrenergic, Dopamine, Gi family, Gs family, Adenylyl cyclases, GRKs, barrestins, MAP Kinase

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