Bennett award paper| Volume 32, ISSUE 7, P549-579, October 01, 1992

Signal-transducing G proteins and antidepressant Drugs: Evidence for modulation of α subunit gene expression in rat brain

  • Klaus-Peter Lesch
    Address reprint request to K.P. Lesch, M.D., Department of Psychiatry, Fuechsleinstr. 15, 8700 Wuerzburg, Germany.
    From the Section of Neuropharmacology, Laboratory of Clinical Science and Section on Clinical Pharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, Maryland, USA
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  • Husseini K. Manji
    From the Section of Neuropharmacology, Laboratory of Clinical Science and Section on Clinical Pharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, Maryland, USA
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      Signal-transducing G proteins, heterotrimers formed of α, β, and γ 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 α subunits, which confer receptor and effector specificity on the heterotrimer, have defined four major classes, Gs, Gi, Gq, and G12, with at least 16 isotopes. 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 s, i1, i2, o, q, and 12 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 o and rat Gα12, illustrate the regional distribution of Gα mRNA and protein in rat brain, and provide evidence that different classes of antidepressants alter expression and/or stability of the recently identified 12 mRNA. We conclude that long-term treatment with antidepressant drugs exerts differential effects on Gα 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.
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