磷酸肌醇和钙调蛋白介导的TRPC6调节的整合
Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6.
作者信息
Kwon Young, Hofmann Thomas, Montell Craig
机构信息
Department of Biological Chemistry, Center for Sensory Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Mol Cell. 2007 Feb 23;25(4):491-503. doi: 10.1016/j.molcel.2007.01.021.
Multiple TRP 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 PI/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 (PIP(3)). We found that PIP(3) binding disrupted the association of calmodulin (CaM) with TRPC6. We identified the PIP(3)-binding site and found that mutations that increased or decreased the affinity of the PIP(3)/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 Ca(2+) and PIs.
多种瞬时受体电位（TRP）通道受磷酸肌醇（PIs）调控。然而，PIs是否直接与TRP通道结合尚不清楚。此外，PIs调控TRP通道的机制也不明确。为了分析PI/TRP相互作用的作用，我们采用了一种生化方法，重点研究TRPC6。TRPC6直接与PIs结合，对磷脂酰肌醇3,4,5-三磷酸（PIP(3)）的亲和力最高。我们发现PIP(3)结合破坏了钙调蛋白（CaM）与TRPC6的结合。我们确定了PIP(3)结合位点，并发现增加或降低PIP(3)/TRPC6相互作用亲和力的突变分别增强或降低了TRPC6依赖性电流。PI介导的CaM结合破坏似乎是一个适用于其他TRP通道（如TRPV1）以及电压门控通道KCNQ1和Ca(v)1.2的主题。我们提出，PIs对CaM结合的调控为Ca(2+)和PIs对通道的综合调控提供了一种模式。
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