Abstract
Cocaine causes cardiac arrhythmias, sudden death, and occasionally long QT syndrome in humans. We investigated the effect of cocaine on the human K+ channels HERG and KvLQT1+minK that encode native rapidly (IKr) and slowly (IKs) activating delayed rectifier K+ channels in the heart. HERG and KvLQT1+minK channels were heterologously expressed in human embryonic kidney 293 cells, and whole-cell currents were recorded. Cocaine had no effect on KvLQT1+minK current in concentrations up to 200 μM. In contrast, cocaine reversibly blocked HERG current with half-maximal block of peak tail current of 7.2 μM. By using a protocol to quickly activate HERG channels, we found that cocaine block developed rapidly after channel activation. At 0 mV, the time constants for the development of block were 38.2 ± 2.1, 15.2 ± 0.8, and 6.9 ± 1.1 ms in 10, 50 and 200 μM cocaine, respectively. Cocaine-blocked channels also recovered rapidly from block after repolarization. At −100 mV, recovery from block followed a biphasic time course with fast and slow time constants of 3.5 ± 0.7 and 100.3 ± 15.4 ms, respectively. UsingN-methyl-cocaine, a permanently charged, membrane-impermeable cocaine analog, block of HERG channels rapidly developed when the drug was applied intracellularly through the patch pipette, suggesting that the cocaine binding site on the HERG protein is located on a cytoplasmic accessible domain. These results indicate that cocaine suppresses HERG, but not KvLQT1+minK, channels by preferentially blocking activated channels, that it unblocks upon repolarization, and does so with unique ultrarapid kinetics. Because the cocaine concentration range we studied is achieved in humans, HERG block may provide an additional mechanism for cocaine-induced arrhythmias and sudden death.
Footnotes
- Received October 16, 2000.
- Accepted January 16, 2001.
-
Send reprint requests to: Craig T. January, M.D., Ph.D., Section of Cardiology, Room H6/354, University of Wisconsin Hospital, 600 Highland Ave., Madison, WI 53792. E-mail: ctj{at}medicine.wisc.edu
-
This work was supported, in part, by National Institutes of Health Grants HL60723 and GM33138. S.Z. and S.R. are supported by postdoctoral fellowship awards from the American Heart Association, Northland Affiliate. Z.Z. is the recipient of a Scientist Development Grant from the American Heart Association.
-
Part of this work has been reported in abstract form: Zhang S, Zhou Z, Chen Y, Gong Q, Ruoho AE, January CT. Cocaine blocks HERG potassium channels (Abstract). Circulation 100(Suppl):I-424, 1999 and Zhang S, Rajamani S, Robertson GA, January CT. Mechanism of cocaine block of HERG potassium channels (Abstract). Biophys J 78(Suppl):221A, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|