Mutant TRPV4-mediated Toxicity Is Linked to Increased Constitutive Function in Axonal Neuropathies
Mutant TRPV4-mediated Toxicity Is Linked to Increased Constitutive Function in Axonal Neuropathies
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DOI：
10.1074/jbc.m111.237685
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发表时间：
2011-05-13
影响因子：
4.8
通讯作者：
Deng, Han-Xiang
中科院分区：
文献类型：
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作者：
Fecto, Faisal;Shi, Yong;Deng, Han-Xiang
TRPV4的突变与三种不同的轴突神经病变有关。然而，这些疾病背后的致病机制仍不清楚。突变体TRPV4的钙通道活性既有增加也有丧失。在这里，我们证明了之前报道的三个TRPV4突变通道具有生理定位，并显示出增加的钙通道活性，导致在三种不同类型的细胞中增加细胞毒性。膜片钳实验表明，表达突变型TRPV4的细胞比表达野生型TRPV4通道的细胞具有更大的全细胞电流。单通道记录表明，由于门控的修改，突变通道具有更高的开放概率，而单通道电导没有变化。这些数据支持这一假说，即可能导致细胞内钙内流增加的“功能获得”机制是TRPV4相关轴突神经病发病机制的基础，并可能对设计合理的治疗方案具有直接意义。
Mutations in TRPV4 have been linked to three distinct axonal neuropathies. However, the pathogenic mechanism underlying these disorders remains unclear. Both gain and loss of calcium channel activity of the mutant TRPV4 have been suggested. Here, we show that the three previously reported TRPV4 mutant channels have a physiological localization and display an increased calcium channel activity, leading to increased cytotoxicity in three different cell types. Patch clamp experiments showed that cells expressing mutant TRPV4 have much larger whole-cell currents than those expressing the wild-type TRPV4 channel. Single channel recordings showed that the mutant channels have higher open probability, due to a modification of gating, and no change in single-channel conductance. These data support the hypothesis that a "gain of function" mechanism, possibly leading to increased intracellular calcium influx, underlies the pathogenesis of the TRPV4-linked axonal neuropathies, and may have immediate implications for designing rational therapies.