Selective potentiation of L-type calcium channel currents by cocaine in cardiac myocytes.
Cocaine use poses a major health problem not only because of the dependence it causes but also because of the generation of life-threatening cardiac arrhythmias following overdose. Elucidating the molecular mechanisms of action of cocaine, therefore, remains a critical step in developing treatment for cocaine addiction and preventing cardiac complications. Although the neurotransmitter transporters are suggested to be primary targets for cocaine, the continued drug-seeking behavior of transporter knock-out mice suggests the involvement of additional mechanisms. Several studies have shown that voltage-gated calcium channel blockers can prevent the behavioral and reinforcing effects of the drug and also cocaine-induced cardiac events, including lethal ventricular fibrillation. However, the role of voltage-gated calcium channels in cocaine-induced responses is not clear. Herein, I show that cocaine, in pharmacological doses, selectively and potently enhances L-type calcium channel currents in isolated rat ventricular myocytes. This potentiation by cocaine is due to an increase and decrease, respectively, in the calcium channel opening and closing rates, with no apparent effects on voltage-dependence or single-channel conductance. The effects of cocaine are rapidly reversible and unaffected by prior ATPgammaS-induced channel phosphorylation. These results suggest that cocaine directly binds and facilitates the opening of L-type calcium channels. Importantly, elevated intracellular calcium levels via this mechanism triggering second messenger pathways and gene activation may contribute to many of the cardiovascular and central nervous system effects of cocaine.
Premkumar
L S
LS
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA. lpremkumar@wpsmtp.siumed.edu
D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D004594:Electrophysiology; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D016276:Ventricular Function
D020746:Calcium Channels, L-Type; D014662:Vasoconstrictor Agents; D003042:Cocaine