Effects of lithium on receptor-mediated activation of G proteins in rat brain cortical membranes.

The underlying molecular mechanism of action of lithium in the treatment of manic-depressive illness is not clear. The effect of chronic lithium on GTP-binding and toxin-mediated ADP-ribosylation of specific G proteins in brain cortical membranes was examined. Incubation of cortical membranes with 5-HT increased [35S]GTPgammaS binding to Galphas, Galphai, Galphao and Galphaq proteins. Six weeks but not 1 week of lithium treatment reduced the increases in [35S]GTPgammaS binding to Galphas, Galphai and Galphao which are produced by 5-HT by 75-85%, whereas 5-HT stimulated [35S]GTPgammaS binding to Galphaq was reduced by 38%. No changes in membrane levels of Galpha and Gbeta proteins were noted in lithium-treated rats. Pertussis toxin (PTX)-mediated ADP-ribosylation of Galphai/o was increased by 60% in cortical membranes of chronically treated rats. Lithium treatment did not affect cholera toxin-mediated ribosylation of Galphas. Increases in [35S]GTPgammaS binding to Galpha proteins evoked by 5-HT were also inhibited by 0.5-2.0 mM lithium chloride added in vitro to the assay mixture. Rubidium and cesium did not change 5-HT-stimulated G protein activation. ADP-ribosylation of Galphai/o catalyzed by PTX was not changed by in vitro LiCl. The inhibitions of 5-HT-stimulated increases in [35S]GTPgammaS-binding to Galphas and Galphaq were completely suppressed by 2.4 mM MgCl2 this concentration of MgCl2 inhibited the effect of lithium on Galphai and Galphao by 50%. Similar findings were also noted when [alpha-32P]GTP was used in the binding assay. The results suggest that lithium interferes with receptor-G protein coupling via a Mg2+-sensitive mechanism. This action of the drug is more effective for Gs, Gi and Go than for Gq and may result from its interference with the recycling of trimeric G proteins.