RT Journal Article SR Electronic T1 Selective Potentiation of L-Type Calcium Channel Currents by Cocaine in Cardiac Myocytes JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1138 OP 1142 DO 10.1124/mol.56.6.1138 VO 56 IS 6 A1 Premkumar, Louis S. YR 1999 UL http://molpharm.aspetjournals.org/content/56/6/1138.abstract AB 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 ATPĪ³S-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.