Dissection of the components for PIP2 activation and thermosensation in TRP channels
Dissection of the components for PIP2 activation and thermosensation in TRP channels
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DOI：
10.1073/pnas.0703420104
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发表时间：
2007-06-12
影响因子：
11.1
通讯作者：
Latorre, Ramon
中科院分区：
文献类型：
--
作者：
Brauchi, Sebastian;Orta, Gerardo;Latorre, Ramon
磷脂酰肌醇4,5-二磷酸（PIPA）在几种瞬时受体电位（TRIP）通道的激活中起核心作用。PIP2在热TRP通道温度门控中的作用尚未被详细探讨，温度激活的过程在很大程度上无法解释。在这项工作中，我们在冷敏（TRPM8）和热敏（TRPV1）通道之间交换了c端区域的不同片段，试图了解该片段在PIP2和温度激活中的作用。TRPV1的c端近端部分取代TRPM8 c端等效部分的嵌合体被PIP2激活并赋予热激活表型。当交换区所含的正电荷残基被中和时，PIP2消失，但不具有温度敏感性。将交换段缩短到11aa的长度会产生电压依赖和温度不敏感的通道。我们的发现表明温度、PIP2和电压存在不同的激活域。我们使用TRPV1和PIP2对接分析的全原子分子模型来解释通道-PIP2相互作用。
Phosphatidylinositol 4,5-bisphosphate (PIPA plays a central role in the activation of several transient receptor potential (TRIP) channels. The role of PIP2 on temperature gating of thermo TRP channels has not been explored in detail, and the process of temperature activation is largely unexplained. In this work, we have exchanged different segments of the C-terminal region between cold-sensitive (TRPM8) and heat-sensitive (TRPV1) channels, trying to understand the role of the segment in PIP2 and temperature activation. A chimera in which the proximal part of the C-terminal of TRPV1 replaces an equivalent section of TRPM8 C-terminal is activated by PIP2 and confers the phenotype of heat activation. PIP2, but not temperature sensitivity, disappears when positively charged residues contained in the exchanged region are neutralized. Shortening the exchanged segment to a length of 11 aa produces voltage-dependent and temperature-insensitive channels. Our findings suggest the existence of different activation domains for temperature, PIP2, and voltage. We provide an interpretation for channel-PIP2 interaction using a full-atom molecular model of TRPV1 and PIP2 docking analysis.