Effect of Li+ upon the Mg2+-Dependent Activation of Recombinant Giα1

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, rGiα1, and found that Li+ at therapeutic levels significantly inhibited the formation of the GDP.AlF−4.rGiα1 complex. Because our studies were conducted with a purified, metal-reconstitutedG-protein rather than with cell membrane suspensions, our Li+ inhibition results lend additional support to the G-protein hypothesis for Li+ action.