Magnesium reversal of lithium inhibition of β-adrenergic and muscarinic receptor coupling to G proteins

Recently, lithium was found to inhibit the coupling of both muscarinic cholinergic and β-adrenergic receptors to pertussis toxin-sensitive and cholera toxin-sensitive G proteins respectively. These findings suggest that G proteins are the common site for both the antimanic and antidepressant therapeutic effects of lithium. Magnesium ions are crucial to the function of G proteins and interact with them at multiple sites. In the present study using rat cerebral cortex, we determined that magnesium can reverse the ability of lithium to inhibit isoprenaline- and carbamylcholine-induced increases in guanosine triphosphate (GTP) binding to G proteins. Lithium concentrations effective in attenuating G protein function were found to be hyperbolically dependent on free Mg²⁺ concentrations, suggesting multiple sites of competition between lithium and magnesium on G proteins. Free intracellular Mg²⁺ concentrations in rat cerebral cortex in vivo are known to be less than 1 mM. At such Mg²⁺ concentrations, therapeutically efficacious lithium concentrations (1 to 1.5 mM) were still able to alter G protein function, which supports the physiological and clinical relevance of lithium action on G proteins.