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Vol. 59, Issue 5, 1069-1076, May 2001
Departments of Medicine (S.Z., S.R., Q.G., Z.Z., C.T.J.),
Pharmacology (Y.C., Y.R., A.R.), and Physiology (C.T.J.),
University of Wisconsin Medical School, Madison, Wisconsin
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. 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.
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