Blockade of the human ether‐a‐go‐go‐related gene potassium channel by ketamine. (10th July 2013)

• Record Type: Journal Article
• Authors: Zhang, Peihua; Xing, Junlian; Luo, Antao; Feng, Juan; Liu, Zhipei; Gao, Chenghao; Ma, Jihua
• Is Part Of: Journal of pharmacy and pharmacology. Volume 65:Number 9(2013:Sep.)
• Page Start: 1321
• Page End: 1328
• Publication Date: 2013-07-10
• Subjects: Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/jphp.12095
• Languages: English
• ISSNs: 0022-3573

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jphp12095-sec-0001" sec-type="section"> <title>Objectives</title> <p>The inhibition of the cardiac rapid delayed rectifier potassium current (<italic>I<sub>Kr</sub></italic>) and its cloned equivalent human ether‐a‐go‐go‐related gene (hERG) channel illustrate QT interval prolonging effects of a wide range of clinically used drugs. In this study, the direct interaction of the intravenous anaesthetic ketamine with wild‐type (WT) and mutation hERG currents (<italic>I</italic><sub>hERG</sub>) was investigated.</p> </sec> <sec id="jphp12095-sec-0002" sec-type="section"> <title>Methods</title> <p>The hERG channel (WT, Y652A and F656A) was expressed in Xenopus oocytes and studied using standard two‐microelectrode voltage‐clamp techniques.</p> </sec> <sec id="jphp12095-sec-0003" sec-type="section"> <title>Key findings</title> <p>WT hERG is blocked in a concentration‐dependent manner with IC<sub>50</sub> = 12.05 ± 1.38 μ<sc>m</sc> by ketamine, and the steady‐state inactivation curves are shifted to more negative potentials (about −27 mV). The mutation to Ala of Y652 and F656 located on the S6 domain attenuate <italic>I</italic><sub>hERG</sub> blockade by ketamine, and produced approximately 9‐fold and 2.5‐fold increases in IC<sub>50</sub> compared with that of WT hERG channel, respectively.</p> </sec> <sec id="jphp12095-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Ketamine blocks WT <italic>I</italic><sub>hERG</sub> expressed in Xenopus oocytes in a concentration‐dependent manner and predominantly interacts with the open hERG channels. The interaction of ketamine with hERG channel may involve the aromatic residues Tyr652 and Phe656.</p> </sec> </abstract>