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首页> 外文期刊>American Journal of Physiology >Enhancement of closed-state inactivation in long QT syndrome sodium channel mutation DeltaKPQ.
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Enhancement of closed-state inactivation in long QT syndrome sodium channel mutation DeltaKPQ.

机译：长QT综合征钠通道突变DeltaKPQ的闭环失活的增强。

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摘要

DeltaKPQ, a three amino acid [lysine (K), proline (P), glutamine (Q)] deletion mutation of the human cardiac Na channel (hH1), which is one cause of long QT syndrome (LQT3), has impaired inactivation resulting in a late sodium current. To better understand inactivation in DeltaKPQ, we applied a site-3 toxin anthopleurin A, which has been shown to inhibit inactivation from the open state with little or no effect on inactivation from the closed state(s) in wild-type hH1. In contrast to the effect of site-3 toxins on wild-type hH1, inactivation from closed state(s) in toxin-modified DeltaKPQ demonstrated a large negative shift in the Na channel availability curve of nearly -14 mV. Recovery from inactivation showed that toxin-modified DeltaKPQ channels recovered slightly faster than those in control, whereas development of inactivation at potentials negative to -80 mV showed that inactivation developed much more rapidly in toxin-modified DeltaKPQ channels compared with control. An explanation for our results is that closed-state inactivation in toxin-modified DeltaKPQ is enhanced by the mutated inactivation lid being positioned "closer" to its receptor resulting in an increased rate of association between the inactivation lid and its receptor.
机译：DeltaKPQ是人心脏Na通道（hH1）的三个氨基酸[赖氨酸（K），脯氨酸（P），谷氨酰胺（Q）]缺失突变，是长期QT综合征（LQT3）的原因之一，导致失活受损在后期钠电流中。为了更好地了解DeltaKPQ中的失活，我们应用了Site-3毒素花青素A，已证明它可以抑制开放状态的失活，而对野生型hH1中封闭状态的失活几乎没有影响。与位点3毒素对野生型hH1的影响相反，毒素修饰的DeltaKPQ中封闭状态的失活表明Na通道可利用性曲线中出现了很大的负移，接近-14 mV。从灭活中恢复表明，毒素修饰的DeltaKPQ通道比对照中恢复的速度稍快，而在-80 mV负电势下灭活的发展表明，与对照相比，毒素修饰的DeltaKPQ通道中灭活的发展要快得多。我们的结果的解释是，毒素修饰的DeltaKPQ的闭环失活通过突变的失活盖位于受体附近而增强，导致失活盖与其受体之间的缔合速率增加。

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