Magnesium reversal of lithium inhibition of beta-adrenergic and muscarinic receptor coupling to G proteins.
Recently, lithium was found to inhibit the coupling of both muscarinic cholinergic and beta-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.
Avissar
S
S
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892.
Murphy
D L
DL
Schreiber
G
G
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008094:Lithium / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*
D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D006160:Guanosine Triphosphate; D002217:Carbachol; D008094:Lithium; D019204:GTP-Binding Proteins; D008274:Magnesium; D007545:Isoproterenol