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.
Wang
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Department of Pharmacology, MCP-Hahnemann School of Medicine, Philadelphia, PA 19129, USA.
Friedman
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D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D004334:Drug Administration Schedule; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D007700:Kinetics; D018021:Lithium Chloride / Q000494:pharmacology*; D015636:Magnesium Chloride / Q000494:pharmacology; D008297:Male; D009243:NAD / Q000378:metabolism; D037342:Pertussis Toxin; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D013997:Time Factors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D011985:Receptors, Serotonin; D010566:Virulence Factors, Bordetella; D015636:Magnesium Chloride; D009243:NAD; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D018021:Lithium Chloride