Amberg Gregory C, Rossow Charles F, Navedo Manuel F, Santana Luis F
Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195, USA.
J Biol Chem. 2004 Nov 5;279(45):47326-34. doi: 10.1074/jbc.M408789200. Epub 2004 Aug 22.
Voltage-gated K+ (Kv) channels control the excitability of arterial smooth muscle. However, the molecular mechanisms regulating Kv channel function in smooth muscle remain unclear. We examined the hypothesis that the vasoactive peptide angiotensin II (Ang II) regulates arterial smooth muscle Kv channel function via calcineurin-dependent activation of the transcription factor NFAT. We found that sustained administration of Ang II decreased Kv currents (IKv) by reducing the expression of Kv2.1 K+ channel subunits. This effect of Ang II was independent of pressure but required Ca2+ influx through L-type Ca2+ channels. Consistent with our hypothesis, we found that calcineurin and NFATc3 are obligatory components of the signaling cascade mediating reduced IKv by Ang II. We conclude that sustained Ang II exposure increases smooth muscle Ca2+, which leads to activation of calcineurin and NFATc3, culminating in decreased Kv2.1 expression and reduced IKv function. These results support the novel concept that NFATc3 controls the excitability of arterial smooth muscle by regulating Kv2.1 expression.
电压门控钾离子（Kv）通道控制着动脉平滑肌的兴奋性。然而，调节平滑肌中Kv通道功能的分子机制仍不清楚。我们检验了血管活性肽血管紧张素II（Ang II）通过钙调神经磷酸酶依赖性激活转录因子NFAT来调节动脉平滑肌Kv通道功能的假说。我们发现持续给予Ang II可通过降低Kv2.1钾通道亚基的表达来减少Kv电流（IKv）。Ang II的这种作用与压力无关，但需要通过L型钙通道的钙内流。与我们的假说一致，我们发现钙调神经磷酸酶和NFATc3是介导Ang II降低IKv的信号级联反应的必需成分。我们得出结论，持续暴露于Ang II会增加平滑肌中的钙离子，导致钙调神经磷酸酶和NFATc3激活，最终导致Kv2.1表达降低和IKv功能减弱。这些结果支持了NFATc3通过调节Kv2.1表达来控制动脉平滑肌兴奋性的新概念。
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