PIP(2) depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells.
PIP(2) depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells.
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DOI：
10.7554/elife.38689
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发表时间：
2018-08-07
期刊：
影响因子：
7.7
通讯作者：
Nelson MT
中科院分区：
文献类型：
--
作者：
Harraz OF;Longden TA;Hill-Eubanks D;Nelson MT
我们最近报道，脑毛细血管内皮细胞（cECs）的内向整流Kir2.1通道通过介导神经元活动依赖性的传播血管舒张（超极化）信号在神经血管耦联（NVC）中起着重要作用。我们进一步证明，Kir2.1活性受到质膜磷脂酰肌醇4，5-二磷酸（PIP2）耗竭的抑制。cEC是否表达与Kir2.1介导的信号传导交叉的去极化通道仍然未知。在这里，我们报告说，Ca2 +/Na+渗透TRPV4（瞬时受体电位香草酸4）通道在CEC中表达，并受到PIP2的张力抑制。我们进一步证明，PIP2的激动剂，包括推定的NVC介质，通过Gq蛋白偶联受体（GqPCR）的信号传导促进PIP2水解的消耗引起TRPV4通道的同时解除抑制和Kir2.1通道的抑制。这些发现共同支持了GqPCR激活作为分子开关的概念，以有利于毛细血管TRPV4活性超过Kir2.1信号传导，这一观察结果对脑血流控制具有潜在的深远意义。荚膜形成分支网络，包围身体的所有细胞。它们允许血液和组织之间的氧气和营养交换，但这不是它们唯一的作用。大脑中的captured形成了一个紧密的屏障，防止血液中携带的成分轻易到达脑室。它们还检测神经元的活动，并按需触发大脑活动区域的血流量增加。这一作用最近才被揭示出来，它依赖于毛细血管细胞表面的离子通道。活跃的神经元释放钾离子，钾离子打开一种称为Kir2.1的离子通道，允许细胞内的钾流出。这个过程在相邻的毛细血管细胞中重复，直到它到达上游血管，在那里它导致血管松弛并增加血流。Kir2.1通道横跨毛细血管细胞的膜，在那里它们可以与其他膜分子相互作用。其中一种称为PIP2的分子在将信号从细胞外传递到细胞内方面起着几种作用。它还与膜中的通道（包括Kir2.1通道）发生物理相互作用。如果PIP2水平低，Kir2.1通道活性降低。在这里，Harraz等人发现毛细血管细胞含有另一种类型的离子通道，称为TRPV 4，它也受PIP2调节。但与Kir2.1不同的是，当PIP2水平下降时，它的活性会增加。此外，TRPV4通道允许钠离子和钙离子流入细胞，这与钾离子流出细胞的效果相反。毛细血管细胞也有称为GqPCR的受体蛋白，它被大脑中活跃的神经元释放的化学信号激活。GqPCR会分解PIP2，因此它们的活动会关闭Kir2.1通道，开启TRPV4通道，从而重置系统，使其准备好对来自活跃神经元的新信号做出反应。GqPCR作为分子开关控制Kir2.1和TRPV 4通道之间的平衡，并使脑血流上下波动。依赖于PIP2的GqPCR和离子通道也可以在其他类型的细胞中找到。这些发现可以揭示信号如何在不同细胞中打开和关闭的线索。了解PIP2在信号传导中的作用也可以揭示信号传导出错时会发生什么。
We recently reported that the inward-rectifier Kir2.1 channel in brain capillary endothelial cells (cECs) plays a major role in neurovascular coupling (NVC) by mediating a neuronal activity-dependent, propagating vasodilatory (hyperpolarizing) signal. We further demonstrated that Kir2.1 activity is suppressed by depletion of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2). Whether cECs express depolarizing channels that intersect with Kir2.1-mediated signaling remains unknown. Here, we report that Ca2+/Na+-permeable TRPV4 (transient receptor potential vanilloid 4) channels are expressed in cECs and are tonically inhibited by PIP2. We further demonstrate that depletion of PIP2 by agonists, including putative NVC mediators, that promote PIP2 hydrolysis by signaling through Gq-protein-coupled receptors (GqPCRs) caused simultaneous disinhibition of TRPV4 channels and suppression of Kir2.1 channels. These findings collectively support the concept that GqPCR activation functions as a molecular switch to favor capillary TRPV4 activity over Kir2.1 signaling, an observation with potentially profound significance for the control of cerebral blood flow. Capillaries form branching networks that surround all cells of the body. They allow oxygen and nutrient exchange between blood and tissue, but this is not their only role. Capillaries in the brain form a tight barrier that prevents components carried in the blood from easily reaching the brain compartment. They also detect the activity of neurons and trigger on-demand increases in blood flow to active regions of the brain. This role, revealed only recently, depends upon ion channels on the surface of the capillary cells. Active neurons release potassium ions, which open a type of ion channel called Kir2.1 that allows potassium inside the cell to flow out. This process is repeated in neighboring capillary cells until it reaches an upstream vessel, where it causes the vessel to relax and increase the blood flow. Kir2.1 channels sit astride the membranes of capillary cells, where they can interact with other membrane molecules. One such molecule, called PIP2, plays several roles in relaying signals from the outside to the inside of cells. It also physically interacts with channels in the membrane, including Kir2.1 channels. If PIP2 levels are low, Kir2.1 channel activity decreases. Here, Harraz et al. discovered that capillary cells contain another type of ion channel, called TRPV4, which is also regulated by PIP2. But unlike Kir2.1, its activity increases when PIP2 levels drop. Moreover, TRPV4 channels allow sodium and calcium ions to flow into the cell, which has an effect opposite to that of potassium flowing out of the cell. Capillary cells also have receptor proteins called GqPCRs that are activated by chemical signals released by active neurons in the brain. GqPCRs break down PIP2, so their activity turns Kir2.1 channels off and TRPV4 channels on. This resets the system so that it is ready to respond to new signals from active neurons. GqPCRs work as molecular switches to control the balance between Kir2.1 and TRPV4 channels and turn brain blood flow up and down. GqPCRs and ion channels that depend on PIP2 can also be found in other types of cells. These findings could reveal clues about how signals are switched on and off in different cells. Understanding the role of PIP2 in signaling could also unveil what happens when signaling go wrong.
核苷酸和decavanate对脑毛细血管中天然Ca2+ - 和ATP敏感阳离子通道的拮抗调节。
影响因子：
3.8
作者：
Csanady, Laszlo;Adam-Vizi, Vera
通讯作者：
Adam-Vizi, Vera