Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion
Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion
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DOI：
10.1073/pnas.1800201115
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发表时间：
2018-04-10
影响因子：
11.1
通讯作者：
Nelson, Mark T.
中科院分区：
文献类型：
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作者：
Harraz, Osama F.;Longden, Thomas A.;Nelson, Mark T.
脑毛细血管在感知神经活动并将其转化为脑血流的动态变化以满足大脑的代谢需求方面起着关键作用。该机制的分子基石是毛细血管内皮细胞内向整流钾离子（Kir2.1）通道，其通过神经元活性依赖性的外部钾离子浓度增加而激活，产生扩张上游小动脉的传播超极化电信号。在这里，我们确定了这一过程的关键调节，证明磷脂酰肌醇4，5-二磷酸（PIP 2）是一个内在的调制器毛细血管Kir2.1介导的信号。我们进一步表明，通过G（q）蛋白偶联受体（G（q）PCR）的激活，PIP 2消耗削弱毛细血管到小动脉的信号转导在体外和体内，突出G（q）PCR依赖性和电神经血管耦合机制之间的潜在调节联系。这些结果共同表明，PIP 2通过调节Kir2.1通道设置毛细血管启动的电信号的增益。因此，内皮细胞PIP 2水平将影响逆行信号传导的程度并调节脑血流。
Brain capillaries play a critical role in sensing neural activity and translating it into dynamic changes in cerebral blood flow to serve the metabolic needs of the brain. The molecular cornerstone of this mechanism is the capillary endothelial cell inward rectifier K+ (Kir2.1) channel, which is activated by neuronal activity-dependent increases in external K+ concentration, producing a propagating hyperpolarizing electrical signal that dilates upstream arterioles. Here, we identify a key regulator of this process, demonstrating that phosphatidylinositol 4,5-bisphosphate (PIP2) is an intrinsic modulator of capillary Kir2.1-mediated signaling. We further show that PIP2 depletion through activation of G(q) protein-coupled receptors (G(q)PCRs) cripples capillary-to-arteriole signal transduction in vitro and in vivo, highlighting the potential regulatory linkage between G(q)PCR-dependent and electrical neurovascular-coupling mechanisms. These results collectively show that PIP2 sets the gain of capillary-initiated electrical signaling by modulating Kir2.1 channels. Endothelial PIP2 levels would therefore shape the extent of retrograde signaling and modulate cerebral blood flow.