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.