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Effects of lithium on receptor-mediated activation of G proteins in rat brain cortical membranes
Journal article   Peer reviewed

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

Hoau-Yan Wang and Eitan Friedman
Neuropharmacology, v 38(3), pp 403-414
1999
DOI: https://doi.org/10.1016/S0028-3908(98)00197-X
PMID: 10219978
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

G proteins GTP-binding Serotonin receptors
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]GTP γS binding to G αs, G αi, G αo and G αq proteins. Six weeks but not 1 week of lithium treatment reduced the increases in [ 35S]GTP γS binding to G αs, G αi and G αo which are produced by 5-HT by 75–85%, whereas 5-HT stimulated [ 35S]GTP γS binding to G αq was reduced by 38%. No changes in membrane levels of G α and G β proteins were noted in lithium-treated rats. Pertussis toxin (PTX)-mediated ADP-ribosylation of G αi/o was increased by 60% in cortical membranes of chronically treated rats. Lithium treatment did not affect cholera toxin-mediated ribosylation of G αs. Increases in [ 35S]GTPγS binding to G α 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 G αi/o catalyzed by PTX was not changed by in vitro LiCl. The inhibitions of 5-HT-stimulated increases in [ 35S]GTPγS-binding to G αs and G αq were completely suppressed by 2.4 mM MgCl 2; this concentration of MgCl 2 inhibited the effect of lithium on G αi and G αo by 50%. Similar findings were also noted when [ α- 32P]GTP was used in the binding assay. The results suggest that lithium interferes with receptor-G protein coupling via a Mg 2+-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.

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Web of Science research areas
Neurosciences
Pharmacology & Pharmacy
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