The Hv1 proton channel responds to mechanical stimuli.
The Hv1 proton channel responds to mechanical stimuli.
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DOI：
10.1085/jgp.201611672
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Tombola F
中科院分区：
文献类型：
--
作者：
Pathak MM;Tran T;Hong L;Joós B;Morris CE;Tombola F
Hv1是一种电压门控质子通道，由两个电压敏感域组成，每个电压敏感域对质子都是可渗透的。Pathak等人发现，这些电压敏感结构域是机械敏感的，并且膜拉伸导致Hv1激活的长期促进。电压门控质子通道Hv1在全身组织中表达，在pH稳态和NADPH氧化酶调节中起重要作用。Hv1在生理或病理条件下经历强机械力的膜隔室中工作。例如，在小胶质细胞中，Hv1活性因细胞肿胀而增强，并导致中风后脑损伤增加。通道复合物由两个质子可渗透的电压敏感结构域（VSD）连接的细胞质卷曲螺旋结构域。在这里，我们报告说，这些VSD直接响应机械刺激。我们发现，膜拉伸有利于Hv1通道开放，通过增加激活速率和移动的稳态激活曲线，以减少去极化电位。在跨膜pH梯度的存在下，膜拉伸单独打开通道而不需要强去极化。膜拉伸的效果持续几分钟后，机械刺激被关闭，这表明通道切换到一个“促进”模式，其中开放发生更容易，然后慢慢恢复到正常模式下观察到的膜拉伸的情况下。电导模拟与六状态模型概括的所有功能的通道的机械刺激的反应。因此，Hv1机械敏感性提供了小胶质细胞通道激活和中风后脑损伤之间的机械联系。
Hv1 is a voltage-gated proton channel that is composed of two voltage-sensing domains, each of which is permeable to protons. Pathak et al. find that these voltage-sensing domains are mechanosensitive and that membrane stretch results in a long-lived facilitation of Hv1 activation. The voltage-gated proton channel, Hv1, is expressed in tissues throughout the body and plays important roles in pH homeostasis and regulation of NADPH oxidase. Hv1 operates in membrane compartments that experience strong mechanical forces under physiological or pathological conditions. In microglia, for example, Hv1 activity is potentiated by cell swelling and causes an increase in brain damage after stroke. The channel complex consists of two proton-permeable voltage-sensing domains (VSDs) linked by a cytoplasmic coiled-coil domain. Here, we report that these VSDs directly respond to mechanical stimuli. We find that membrane stretch facilitates Hv1 channel opening by increasing the rate of activation and shifting the steady-state activation curve to less depolarized potentials. In the presence of a transmembrane pH gradient, membrane stretch alone opens the channel without the need for strong depolarizations. The effect of membrane stretch persists for several minutes after the mechanical stimulus is turned off, suggesting that the channel switches to a “facilitated” mode in which opening occurs more readily and then slowly reverts to the normal mode observed in the absence of membrane stretch. Conductance simulations with a six-state model recapitulate all the features of the channel’s response to mechanical stimulation. Hv1 mechanosensitivity thus provides a mechanistic link between channel activation in microglia and brain damage after stroke.
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