Effect of Li⁺ upon the Mg²⁺-dependent activation of recombinant G_iα1

Although lithium salts have been used in the treatment and prophylaxis of manic-depressive or bipolar patients for 50 years, the mechanism of the pharmacologic action of Li⁺ is unknown. Based on activity studies of inhibitory and stimulatory guanine-binding (G) proteins in rat cortical membranes, it was proposed that Li⁺ inhibition of G-proteins may account for its pharmacologic action. We used the purified α subunit of the recombinant inhibitory G-protein, rG_iα1, and found that Li⁺ at therapeutic levels significantly inhibited the formation of the GDP.AlF₄⁻.rG_iα1 complex. Because our studies were conducted with a purified, metal-reconstituted G-protein rather than with cell membrane suspensions, our Li⁺ inhibition results lend additional support to the G-protein hypothesis for Li⁺ action.