Extracellular Potassium Inhibits Kv7.1 Potassium Channels by Stabilizing an Inactivated State
Extracellular Potassium Inhibits Kv7.1 Potassium Channels by Stabilizing an Inactivated State
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DOI：
10.1016/j.bpj.2011.06.034
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发表时间：
2011-08-17
影响因子：
3.4
通讯作者：
Olesen, Soren-Peter
中科院分区：
文献类型：
--
作者：
Larsen, Anders Peter;Steffensen, Annette Buur;Olesen, Soren-Peter
Kv7.1 （KCNQ1）通道是多种生理过程的调节因子，包括血管舒张、心肌细胞复极化和分泌过程的控制。许多Kv7.1孔突变体对细胞外钾敏感。我们假设细胞外钾也调节野生型Kv7.1通道。在不同浓度的细胞外钾（1 ~ 50 mM）下，测定了非洲爪蟾卵母细胞的Kv7.1电流。随着细胞外钾的升高，Kv7.1电流的降低明显大于基于goldmanhodgkin - katz通量方程的理论计算的预期。钾抑制稳态电流的IC50值为6.0 +/- 0.2 mM。尾电流分析表明，钾增加了失活状态通道的比例。同样，钾减缓了失活后的恢复，这表明细胞外钾稳定了Kv7.1通道的失活状态。细胞外钾在Kv7.1/KCNE1和Kv7.1/KCNE3通道非失活中不存在作用，进一步支持稳定失活状态是其潜在机制。有趣的是，Kv7.1与KCNE2的共表达并未减弱钾的抑制作用。在许多其他Kv通道中，包括Kv1.5、Kv4.3和Kv7.2-5通道，正如预期的那样，细胞外钾离子的增加只会最小限度地降低电流。这些结果表明，细胞外钾可以调节Kv7.1通道，钾浓度的生理变化可能直接控制Kv7.1通道的功能。这可能代表了表达Kv7.1通道的组织中兴奋性和钾转运的一种新的调节机制。
Kv7.1 (KCNQ1) channels are regulators of several physiological processes including vasodilatation, repolarization of cardiomyocytes, and control of secretory processes. A number of Kv7.1 pore mutants are sensitive to extracellular potassium. We hypothesized that extracellular potassium also modulates wild-type Kv7.1 channels. The Kv7.1 currents were measured in Xenopus laevis oocytes at different concentrations of extracellular potassium (1-50 mM). As extracellular potassium was elevated, Kv7.1 currents were reduced significantly more than expected from theoretical calculations based on the Goldman-Hodgkin-Katz flux equation. Potassium inhibited the steady-state current with an IC50 of 6.0 +/- 0.2 mM. Analysis of tail-currents showed that potassium increased the fraction of channels in the inactivated state. Similarly, the recovery from inactivation was slowed by potassium, suggesting that extracellular potassium stabilizes an inactivated state in Kv7.1 channels. The effect of extracellular potassium was absent in noninactivating Kv7.1/KCNE1 and Kv7.1/KCNE3 channels, further supporting a stabilized inactivated state as the underlying mechanism. Interestingly, coexpression of Kv7.1 with KCNE2 did not attenuate the inhibition by potassium. In a number of other Kv channels, including Kv1.5, Kv4.3, and Kv7.2-5 channels, currents were only minimally reduced by an increase in extracellular potassium as expected. These results show that extracellular potassium modulates Kv7.1 channels and suggests that physiological changes in potassium concentrations may directly control the function of Kv7.1 channels. This may represent a novel regulatory mechanism of excitability and of potassium transport in tissues expressing Kv7.1 channels.