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 (lKs) 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. Using N-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.
ASJC Scopus subject areas
- Molecular Medicine