SIGNAL-TRANSDUCING G-PROTEINS AND ANTIDEPRESSANT DRUGS - EVIDENCE FOR MODULATION OF ALPHA-SUBUNIT GENE-EXPRESSION IN RAT-BRAIN

Signal-transducing G proteins, heterotrimers formed of alpha, beta, and gamma subunits, are central to the coordination of receptor-effector communication. They are derived from a large gene family, and recent cloning and sequencing of cDNAs encoding the a subunits, which confer receptor and effector specificity on the heterotrimer, have defined four major classes, G(s), G(i), G(q), and G12, with at least 16 isotypes. The G proteins that coordinate receptor-effector activity are especially important in the central nervous system (CNS), where they serve widespread, critical roles in the regulation of neuronal function, maintain the functional balance between neurotransmitter systems, and, as such, represent attractive potential targets for antidepressant drugs. We describe an integrated series of animal and cell culture studies aimed at testing the hypothesis that alterations in G protein function may contribute the complex neuroadaptive mechanisms involved in the clinical actions of antidepressants, and demonstrate that long-term administration of a wide spectrum of antidepressant drugs regulate Galpha(s), Galpha(i1), Galpha(i2), Galpha(o), Galpha(q), and Galpha12 mRNA and protein expression in various areas of the rat brain. Additionally, we present the polymerase chain reaction-(PCR) mediated cross-species partial cDNA cloning and sequencing of rat and human Galpha(o) and rat Galpha12, illustrate the regional distribution of Galpha mRNA and protein in rat brain, and provide evidence that different classes of antidepressants alter expression and/or stability of the recently identified Galpha12 mRNA. We conclude that long-term treatment with antidepressant drugs exerts differential effects on Galpha mRNA and protein expression in rat brain, thus modifying signal transduction as an integral part of complex neuroadaptive mechanisms that may underlie their therapeutic efficacy. The development of novel drugs with G proteins as primary targets remains an attractive prospect for the future.