PT - JOURNAL ARTICLE AU - Jun Guo AU - Hongying Gang AU - Shetuan Zhang TI - Molecular Determinants of Cocaine Block of Human <em>Ether-á-go-go</em>-Related Gene Potassium Channels AID - 10.1124/jpet.105.098103 DP - 2006 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 865--874 VI - 317 IP - 2 4099 - http://jpet.aspetjournals.org/content/317/2/865.short 4100 - http://jpet.aspetjournals.org/content/317/2/865.full SO - J Pharmacol Exp Ther2006 May 01; 317 AB - The use of cocaine causes cardiac arrhythmias and sudden death. Blockade of the cardiac potassium channel human ether-á-go-go-related gene (hERG) has been implicated as a mechanism for the proarrhythmic action of cocaine. hERG encodes the pore-forming subunits of the rapidly activating delayed rectifier K+ channel (IKr), which is important for cardiac repolarization. Blockade of IKr/hERG represents a common mechanism for drug-induced long QT syndrome. The mechanisms for many common drugs to block the hERG channel are not well understood. We investigated the molecular determinants of hERG channels in cocaine-hERG interactions using site-targeted mutations and patch-clamp method. Wild-type and mutant hERG channels were heterologously expressed in human embryonic kidney 293 cells. We found that there was no correlation between inactivation gating and cocaine block of hERG channels. We also found that consistent with Thr-623, Tyr-652, and Phe-656 being critical for drug binding to hERG channels, mutations in these residues significantly reduced cocaine-induced block, and the hydrophobicity of the residues at position 656 dictated the cocaine sensitivity of the channel. Although the S620T mutation, which removed hERG inactivation, reduced cocaine block by 21-fold, the S620C mutation, which also completely removed hERG inactivation, did not affect the blocking potency of cocaine. Thus, Ser-620 is another pore helix residue whose mutation can interfere with cocaine binding independently of its effect on inactivation. The American Society for Pharmacology and Experimental Therapeutics