Chen Jun, Seebohm Guiscard, Sanguinetti Michael C
Department of Internal Medicine, University of Utah, 15 North 2030 East, Room 4220, Salt Lake City, UT 84112, USA.
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12461-6. doi: 10.1073/pnas.192367299. Epub 2002 Sep 3.
Unintended block of HERG K+ channels is a side effect of many common medications and is the most common cause of acquired long QT syndrome associated with increased risk of life-threatening arrhythmias. The molecular mechanism of high-affinity HERG block by structurally diverse compounds has been attributed to pi-stacking and cation-pi interactions of a drug (e.g., cisapride) with specific aromatic amino acid residues (Tyr-652 and Phe-656) in the S6 alpha-helical domain that face the central cavity of the channel. It also has been proposed that strong C-type inactivation of HERG facilitates or is the primary determinant of high-affinity drug binding. The structurally related, but noninactivating eag channel is insensitive to HERG blockers unless inactivation is induced by specific amino acid mutations [Ficker, E., Jarolimek, W. & Brown, A. M. (2001) Mol. Pharmacol. 60, 1343-1348]. Here we examine the relative importance of inactivation vs. positioning of S6 aromatic residues in determining sensitivity of HERG and eag channels to block by cisapride. The repositioning of Tyr-652 or Phe-656 along the S6 alpha-helical domain of HERG reduced sensitivity of channels to block by cisapride. Moreover, independent of inactivation, repositioning of the equivalent aromatic residues in Drosophila eag channels induced sensitivity to block by cisapride. These findings suggest that positioning of S6 aromatic residues relative to the central cavity of the channel, not inactivation per se determines drug block of HERG or eag channels.
许多常用药物的副作用是意外阻断HERG钾通道，这也是获得性长QT综合征最常见的病因，会增加危及生命的心律失常风险。结构多样的化合物对HERG的高亲和力阻断的分子机制，被认为是药物（如西沙必利）与S6α-螺旋结构域中面对通道中心腔的特定芳香族氨基酸残基（Tyr-652和Phe-656）之间的π-堆积和阳离子-π相互作用。也有人提出，HERG强烈的C型失活促进或决定了高亲和力药物结合。结构相关但不发生失活的eag通道对HERG阻断剂不敏感，除非通过特定氨基酸突变诱导失活[Ficker, E., Jarolimek, W. & Brown, A. M. (2001) Mol. Pharmacol. 60, 1343 - 1348]。在这里，我们研究了失活与S6芳香族残基定位在决定HERG和eag通道对西沙必利阻断敏感性方面的相对重要性。HERG的S6α-螺旋结构域中Tyr-652或Phe-656的重新定位降低了通道对西沙必利阻断的敏感性。此外，独立于失活情况，果蝇eag通道中等效芳香族残基的重新定位诱导了对西沙必利阻断的敏感性。这些发现表明，相对于通道中心腔的S6芳香族残基的定位，而非失活本身决定了HERG或eag通道的药物阻断。
