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Cocaine blocks HERG, but not KvLQT1+minK, potassium channels.
Mol Pharmacol. 2001 May; 59(5):1069-76.MP

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 (I(Kr)) and slowly (I(Ks)) 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 microM. In contrast, cocaine reversibly blocked HERG current with half-maximal block of peak tail current of 7.2 microM. 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 microM 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.

Authors+Show Affiliations

Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11306689

Citation

Zhang, S, et al. "Cocaine Blocks HERG, but Not KvLQT1+minK, Potassium Channels." Molecular Pharmacology, vol. 59, no. 5, 2001, pp. 1069-76.
Zhang S, Rajamani S, Chen Y, et al. Cocaine blocks HERG, but not KvLQT1+minK, potassium channels. Mol Pharmacol. 2001;59(5):1069-76.
Zhang, S., Rajamani, S., Chen, Y., Gong, Q., Rong, Y., Zhou, Z., Ruoho, A., & January, C. T. (2001). Cocaine blocks HERG, but not KvLQT1+minK, potassium channels. Molecular Pharmacology, 59(5), 1069-76.
Zhang S, et al. Cocaine Blocks HERG, but Not KvLQT1+minK, Potassium Channels. Mol Pharmacol. 2001;59(5):1069-76. PubMed PMID: 11306689.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cocaine blocks HERG, but not KvLQT1+minK, potassium channels. AU - Zhang,S, AU - Rajamani,S, AU - Chen,Y, AU - Gong,Q, AU - Rong,Y, AU - Zhou,Z, AU - Ruoho,A, AU - January,C T, PY - 2001/4/18/pubmed PY - 2001/5/18/medline PY - 2001/4/18/entrez SP - 1069 EP - 76 JF - Molecular pharmacology JO - Mol Pharmacol VL - 59 IS - 5 N2 - 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 (I(Kr)) and slowly (I(Ks)) 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 microM. In contrast, cocaine reversibly blocked HERG current with half-maximal block of peak tail current of 7.2 microM. 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 microM 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/11306689/Cocaine_blocks_HERG_but_not_KvLQT1+minK_potassium_channels_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11306689 DB - PRIME DP - Unbound Medicine ER -