Missing links: mechanisms of protean agonism

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). Although first proposed in the mid-1990s, the pharmacological and therapeutic importance of these concepts is now receiving wider support. Two articles in recent issues of Molecular Pharmacology, Lane et al. (p. 1349, current issue) and Galandrin and Bouvier (Mol Pharmacol 70:1575-1584, 2006), provide new mechanistic information on functionally selective ligands at the pharmacologically important D2 dopamine receptor and the beta(1) and beta(2) adrenergic receptors. Each article 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 D(2) dopamine receptor ligands. These range from equivalent responses for Galpha(o) and Galpha(i) activation by norapomorphine and 7-hydroxy-2-dipropylaminotetralin to S-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine, which is an agonist for Galpha(o) activation and an inverse agonist at Galpha(i1) and Galpha(i2). Likewise, Galandrin and Bouvier describe a two-dimensional Cartesian efficacy approach in which propranolol is an agonist for extracellular signal-regulated kinase activation, probably through beta-arrestin, while functioning as an inverse agonist for adenylyl cyclase activation. Thus, these two important articles further solidify the concepts of functional selectivity and protean agonism and begin to define the first postreceptor step in actions of protean agonist ligands.