Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels
Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels
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DOI：
10.1073/pnas.192367299
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发表时间：
2002-09-17
影响因子：
11.1
通讯作者：
Sanguinetti, MC
中科院分区：
文献类型：
--
作者：
Chen, J;Seebohm, G;Sanguinetti, MC
HERG K+通道的非预期阻滞是许多常见药物的副作用，也是获得性长QT综合征的最常见原因，与危及生命的心律失常风险增加相关。通过结构多样的化合物的高亲和力HERG阻断的分子机制已归因于药物的π堆积和阳离子-π相互作用（例如，西沙必利），其在S6 α-螺旋结构域中具有特定的芳香族氨基酸残基（Tyr-652和Phe-656），所述结构域面向通道的中心腔。也有人提出HERG的强C型失活促进了高亲和性药物结合或者是高亲和性药物结合的主要决定因素。结构相关但非失活的eag通道对HERG阻断剂不敏感，除非失活由特定氨基酸突变诱导[Ficker，E.，Jarolimek，W. & Brown，A. M.（2001）Mol. Pharmacol. 60，1343-1348]。在这里，我们研究了S6芳香残基的失活与定位在确定HERG和eag通道对西沙必利阻断的敏感性方面的相对重要性。Tyr-652或Phe-656沿着HERG的S6 α-螺旋结构域的重新定位降低了通道对西沙必利阻断的敏感性。此外，独立的失活，在果蝇eag通道中的等同芳香残基的重新定位诱导西沙必利阻断的敏感性。这些发现表明，S6芳香族残基相对于通道中心腔的定位，而不是灭活本身决定了HERG或eag通道的药物阻断。
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.