Pivotal Role of Actin Depolymerization in the Regulation of Cochlear Outer Hair Cell Motility
Pivotal Role of Actin Depolymerization in the Regulation of Cochlear Outer Hair Cell Motility
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DOI：
10.1016/j.bpj.2010.08.015
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发表时间：
2010-10-06
影响因子：
3.4
通讯作者：
Kalinec, Federico
中科院分区：
文献类型：
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作者：
Matsumoto, Nozomu;Kitani, Rei;Kalinec, Federico
当外界刺激时，耳蜗外毛细胞会发生可逆的形状变化。这种被称为OHC运动的反应是耳蜗放大器的中心组件，耳蜗放大器是哺乳动物听力高度敏感的机制。我们报道，肌动蛋白解聚受LIMK/cofilin介导的通路的激活/抑制调节，在OHC的运动中起着关键作用。LIMK介导的Cofilin磷酸化抑制了该蛋白的肌动蛋白解聚活性，增加了豚鼠内毛细胞的电动幅度和全长。相反，COFILIN磷酸化的减少降低了OHC的电动幅度和OHC的长度。乙酰胆碱和溶血磷脂酸的实验表明，这些药物对OHC运动的影响与通过不同的信号级联调节Cofilin磷酸化有关。另一方面，非线性电容测量证实，所有观察到的OHC运动反应的变化都与运动蛋白预蛋白的性能无关。综上所述，这些结果有力地支持了细胞骨架在OHC运动调节中起主要作用的假设，并确认肌动蛋白解聚是调节耳蜗放大的关键过程。
Cochlear outer hair cells undergo reversible changes in shape when externally stimulated. This response, known as OHC motility, is a central component of the cochlear amplifier, the mechanism responsible for the high sensitivity of mammalian hearing. We report that actin depolymerization, as regulated by activation/inhibition of LIMK/cofilin-mediated pathways, has a pivotal role in OHC motility. LIMK-mediated cofilin phosphorylation, which inhibits the actin depolymerizing activity of this protein, increases both electromotile amplitude and total length of guinea pig OHCs. In contrast, a decrease in cofilin phosphorylation reduces both OHC electromotile amplitude and OHC length. Experiments with acetylcholine and lysophosphatidic acid indicate that the effects of these agents on OHC motility are associated with regulation of cofilin phosphorylation via different signaling cascades. On the other hand, nonlinear capacitance measurements confirmed that all observed changes in OHC motile response were independent of the performance of the motor protein prestin. Altogether, these results strongly support the hypothesis that the cytoskeleton has a major role in the regulation of OHC motility, and identify actin depolymerization as a key process for modulating cochlear amplification.