Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6
Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6
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DOI：
10.1016/j.molcel.2007.01.021
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发表时间：
2007-02-23
期刊：
影响因子：
16
通讯作者：
Montell, Craig
中科院分区：
文献类型：
--
作者：
Kwon, Young;Hofmann, Thomas;Montell, Craig
多个TRIP通道由磷酸肌醇（PI）调节。然而，目前还不知道PI是否直接与TRP通道结合。此外，PI调节TRP通道的机制还不清楚。为了分析PI/TRP相互作用的作用，我们使用了生物化学方法，重点是TRPC 6。TRPC 6直接与PI结合，并且以最高效力与磷脂酰肌醇3，4，5-三磷酸（PIP 3）结合。我们发现PIP 3结合破坏了钙调素（CaM）与TRPC 6的结合。我们鉴定了PIP 3结合位点，发现增加或降低PIP 3/TRPC 6相互作用亲和力的突变分别增强或降低TRPC 6依赖性电流。Pi介导的CaM结合的破坏似乎是适用于其他TRP通道（如TRPV 1）以及电压门控通道KCNQ 1和Ca（v）1.2的主题。我们建议，由Pis的钙调素结合的调节提供了一种模式，整合通道调节的Ca 2+和Pis。
Multiple TRIP channels are regulated by phosphoinositides (Pis). However, it is not known whether Pis bind directly to TRP channels. Furthermore, the mechanisms through which Pis regulate TRP channels are obscure. To analyze the role of Pl/TRP interactions, we used a biochemical approach, focusing on TRPC6. TRPC6 bound directly to Pis, and with highest potency to phosphatidylinositol 3,4,5-trisphosphate (PIP3). We found that PIP3 binding disrupted the association of calmodulin (CaM) with TRPC6. We identified the PIP3-binding site and found that mutations that increased or decreased the affinity of the PIP3/TRPC6 interaction enhanced or reduced the TRPC6-dependent current, respectively. Pi-mediated disruption of CaM binding appears to be a theme that applies to other TRP channels, such as TRPV1, as well as to the voltage-gated channels KCNQ1 and Ca(v)1.2. We propose that regulation of CaM binding by Pis provides a mode for integration of channel regulation by Ca2+ and Pis.