Dyachenko V, Rueckschloss U, Isenberg G
Department of Physiology, Martin-Luther-University, Halle, Germany.
Cell Calcium. 2009 Jan;45(1):55-64. doi: 10.1016/j.ceca.2008.06.002. Epub 2008 Jul 18.
In murine ventricular myocytes, activation of mechanosensitive ion channels (MSCs) includes activation of non-selective cation currents and deactivation of inwardly rectifying potassium currents. Using pharmacological inhibitors and knockout models, we analyzed signaling steps that are critical to transduce the mechanical signal (stretch) into electrophysiological events (MSC). We provide evidence for an activation of NAD(P)H oxidase and NOS3 in response to stretch putatively via the angiotensin II receptor type 1. The involvement of superoxide and nitric oxide was verified by the block of MSC using specific scavengers (tiron and PTIO, respectively). Superoxide and nitric oxide are known to combine very rapidly to form peroxynitrite. Accordingly, MSC were blocked by the peroxynitrite scavenger uric acid and could be mimicked by application of exogenous peroxynitrite. Peroxynitrite formation may activate phospholipases generating amphipaths that modulates channel function via changing the curvature of the surrounding lipid bilayer. This conclusion is supported by our findings that MSC were suppressed by inhibitors of phospholipases but could be mimicked by exogenous phospholipases or by amphipaths (oleic acid, Triton X-100).
在小鼠心室肌细胞中，机械敏感离子通道（MSC）的激活包括非选择性阳离子电流的激活和内向整流钾电流的失活。利用药理学抑制剂和基因敲除模型，我们分析了将机械信号（拉伸）转化为电生理事件（MSC）的关键信号步骤。我们提供证据表明，响应拉伸，NAD（P）H氧化酶和NOS3可能通过1型血管紧张素II受体被激活。通过分别使用特异性清除剂（钛铁试剂和PTIO）阻断MSC，证实了超氧化物和一氧化氮的参与。已知超氧化物和一氧化氮会非常迅速地结合形成过氧亚硝酸盐。因此，过氧亚硝酸盐清除剂尿酸可阻断MSC，并且外源性过氧亚硝酸盐的应用可模拟这种阻断作用。过氧亚硝酸盐的形成可能会激活磷脂酶，产生两亲分子，通过改变周围脂质双层的曲率来调节通道功能。我们的研究结果支持了这一结论，即MSC被磷脂酶抑制剂抑制，但外源性磷脂酶或两亲分子（油酸、 Triton X-100）可模拟这种抑制作用。
