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Am J Physiol Heart Circ Physiol 277: H1081-H1088, 1999;
0363-6135/99 $5.00
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Vol. 277, Issue 3, H1081-H1088, September 1999

Inactivation gating determines nicotine blockade of human HERG channels

Hui-Zhen Wang1, Hong Shi1, Shu-Jie Liao3, and Zhiguo Wang1,2

1 Research Center, Montreal Heart Institute, Montreal H1T 1C8; 2 Department of Medicine, University of Montreal, Montreal, Quebec, Canada H3C 3J7; and 3 Department of Pharmacology, Zhelimumeng Medical School, Tongliao, Inner Mongolia 028000, China

We have previously found that nicotine blocked multiple K+ currents, including the rapid component of delayed rectifier K+ currents (IKr), by interacting directly with the channels. To shed some light on the mechanisms of interaction between nicotine and channels, we performed detailed analysis on the human ether-à-go-go-related gene (HERG) channels, which are believed to be equivalent to the native IKr when expressed in Xenopus oocytes. Nicotine suppressed the HERG channels in a concentration-dependent manner with greater potency with voltage protocols, which favor channel inactivation. Nicotine caused dramatic shifts of the voltage-dependent inactivation curve to more negative potentials and accelerated the inactivation process. Conversely, maneuvers that weakened the channel inactivation gating considerably relieved the blockade. Elevating the extracellular K+ concentration from 5 to 20 mM increased the nicotine concentration (by ~100-fold) needed to achieve the same degree of inhibition. Moreover, nicotine lost its ability to block the HERG channels when a single mutation was introduced to a residue located after transmembrane domain 6 (S631A) to remove the rapid channel inactivation. Our data suggest that the inactivation gating determines nicotine blockade of the HERG channels.

Xenopus oocyte; voltage-clamp techniques


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