Cocaine blocks HERG, but not KvLQT1+minK, potassium channels

Cocaine causes cardiac arrhythmias, sudden death, and occasionally long QT syndrome in humans. We investigated the effect of cocaine on the human K+ c hannels HERG and KvLQT1+minK that encode native rapidly (I-Kr) and slowly ( I-Ks) activating delayed rectifier K+ channels in the heart. HERG and KvLQT 1+minK channels were heterologously expressed in human embryonic kidney 293 cells, and whole-cell currents were recorded. Cocaine had no effect on KvL QT1+minK current in concentrations up to 200 muM. In contrast, cocaine reve rsibly blocked HERG current with half-maximal block of peak tail current of 7.2 muM. By using a protocol to quickly activate HERG channels, we found t hat 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 muM cocaine, respectively. Cocaine-b locked 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. Usi ng N-methyl-cocaine, a permanently charged, membrane-impermeable cocaine an alog, block of HERG channels rapidly developed when the drug was applied in tracellularly through the patch pipette, suggesting that the cocaine bindin g site on the HERG protein is located on a cytoplasmic accessible domain. T hese results indicate that cocaine suppresses HERG, but not KvLQT1+minK, ch annels by preferentially blocking activated channels, that it unblocks upon repolarization, and does so with unique ultrarapid kinetics. Because the c ocaine concentration range we studied is achieved in humans, HERG block may provide an additional mechanism for cocaine-induced arrhythmias and sudden death.