5-HT_2C constitutive receptor activity: Effector pathway dependence

Recent evidence suggests that receptors may exist in an “inactive” conformation (designated R) in equilibrium with one or more so-called “active” conformations (R*, R**, R***, etc.) that have the ability to activate cellular effector mechanisms in the absence of an agonist (constitutive activity). In addition, many current models of receptor function suggest that different active conformations may differentially interact (qualitatively and/or quantitatively) with cellular effector mechanisms. One of the predictions stemming from these models is that constitutive receptor activity should be effector pathway dependent. We demonstrate that inverse agonism at the serotonin_2C (5-HT_2C) receptor is effector pathway dependent and that the experimental observations can be described by a three-state model of receptor function. Further, we provide evidence for protean ligand activity of SB 242084. The results emphasize the importance of associating the pharmacological properties of ligands with the experimental conditions and responses measured.