Activation of TRPP2 through mDia1-dependent voltage gating
Activation of TRPP2 through mDia1-dependent voltage gating
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DOI：
10.1038/emboj.2008.70
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发表时间：
2008-05-07
期刊：
影响因子：
11.4
通讯作者：
Tsiokas, Leonidas
中科院分区：
文献类型：
--
作者：
Bai, Chang-Xi;Kim, Sehyun;Tsiokas, Leonidas
TRPP2阳离子通道直接导致约15%的常染色体显性多囊肾病病例。然而，TRPP2调控的基本特性（如通道门控和激活）的机制尚不清楚。我们已经证明，TRPP2被EGF激活，并与RhoA的下游效应物哺乳动物蝶状体相关双胍1 （mDia1）发生物理相互作用。现在，我们发现mDia1通过特异性阻断TRPP2在负电位而非正电位的活性来调节TRPP2。通过rhoa诱导的mDia1从负电位的自抑制状态到正电位的激活状态的分子转换，介导了mDia1在正电位下对TRPP2的电压依赖性解除阻断。在生理静息电位下，EGF通过激活RhoA释放mdia1依赖性阻滞来激活TRPP2。我们的数据揭示了mDia1在离子通道调控中的新作用，并提出了TRP通道电压依赖性门控的分子基础。
The TRPP2 cation channel is directly responsible for similar to 15% of all cases of autosomal dominant polycystic kidney disease. However, the mechanisms underlying fundamental properties of TRPP2 regulation, such as channel gating and activation, are unknown. We have shown that TRPP2 was activated by EGF and physically interacted with the mammalian diaphanous-related formin 1 (mDia1), a downstream effector of RhoA. Now, we show that mDia1 regulates TRPP2 by specifically blocking its activity at negative but not positive potentials. The voltage-dependent unblock of TRPP2 by mDia1 at positive potentials is mediated through RhoA-induced molecular switching of mDia1 from its autoinhibited state at negative potentials to its activated state at positive potentials. Under physiological resting potentials, EGF activates TRPP2 by releasing the mDia1-dependent block through the activation of RhoA. Our data reveal a new role of mDia1 in the regulation of ion channels and suggest a molecular basis for the voltage-dependent gating of TRP channels.