Constitutive Activity of Brain Serotonin Receptors: Inverse Agonist Activity of Antipsychotic Drugs

Several lines of evidence indicate that G-protein coupled receptors (GPCR) may exist in a state that allows a tonic level of stimulation in vivo (constitutive activity). Several native forms of GPCR, when expressed in recombinant cell lines, display significant signal transduction stimulation in the absence of activating ligand. Many GPCR, including four serotonin receptors, display robust constitutive activation upon the mutation of a single amino acid, indicating mutations producing inappropriate constitutive activation may be etiological factors in diseases. If constitutive activity of GPCR is as common a phenomenon as some researchers suspect, this would suggest significant alterations in the classical model of ligand-receptor interactions. One of the most significant implications of constitutive activity for pharmacologists and medicinal chemists, is the possibility of developing drugs that lower the level of constitutive activity. Such compounds have been termed “inverse agonists”. These drugs, in theory, would have different physiological effects, and therefore possibly different therapeutic potential, than classical competitive receptor antagonists (“neutral antagonists”). In this review, theoretical issues concerning constitutive activity in the GPCR family and evidence supporting the existence of constitutively active GPCR are discussed. Data demonstrating the activation of human 5-HT 2A, 5-HT2C, 5-HT6, and 5-HT7 receptors by single amino acid substitutions are presented. These studies demonstrate the procedures for producing and characterizing constitutively active forms of serotonin receptors, including the demonstration of inverse agonist activity of drugs on these receptors.