Physiologic regulation of the epithelial sodium channel by phosphatidylinositides.
Physiologic regulation of the epithelial sodium channel by phosphatidylinositides.
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DOI：
10.1097/mnh.0b013e328308fff3
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发表时间：
2008-09
影响因子：
3.2
通讯作者：
Stockand JD
中科院分区：
文献类型：
--
作者：
Pochynyuk O;Bugaj V;Stockand JD
上皮Na+通道(ENaC)的活性限制了远端肾单位对Na+的重吸收。人类通过控制ENaC微调Na+平衡来调节血压。ENAC功能障碍是一些高血压和肾性盐耗疾病的原因。因此，了解控制ENaC活性的细胞机制是至关重要的。ENAC对磷脂酶C(PLC)介导的代谢靶标磷脂酰肌醇4，5-二磷酸(PIP2)和磷脂酰肌醇3-羟基激酶(PI3-K)产物磷脂酰肌醇3，4，5-三磷酸(PIP3)敏感。PIP2允许ENaC选通，可能与通道直接交互。远端肾单位P2Y受体的激活通过促进PIP2代谢来抑制ENaC的活性。这一点很重要，因为P2Y2受体的基因缺失会导致高血压与ENaC过度活跃相关。醛固酮是负反馈级联反应中的最后一种激素，由血压下降激活，增加ENaC的活性。PIP3位于醛固酮信号级联的关键分叉点，增加了ENaC开放的概率和数量。PIP3效应器通过抑制通道重现来调节ENaC数量的增加。PIP3在一个与PIP2调控不同的位置与ENaC结合，直接调节开放概率。肌醇磷脂在ENaC的生理调控中起关键作用，可能在与肾脏Na+处理异常相关的疾病中发挥作用。
Epithelial Na+ channel (ENaC) activity is limiting for Na+ reabsorption in the distal nephron. Humans regulate blood pressure by fine-tuning Na+ balance through control of ENaC. ENaC dysfunction is causative for some hypertensive and renal salt wasting diseases. Thus, it is critical to understand the cellular mechanisms controlling ENaC activity. ENaC is sensitive to phosphatidylinositol 4,5-bisphosphate (PIP2), the target of phospholipase C (PLC)-mediated metabolism, and phosphatidylinositiol 3,4,5-trisphosphate (PIP3,), the product of phosphatidylinositide 3-OH kinase (PI3-K). PIP2 is permissive for ENaC gating possibly interacting directly with the channel. Activation of distal nephron P2Y receptors tempers ENaC activity by promoting PIP2 metabolism. This is important because gene deletion of P2Y2 receptors causes hypertension associated with hyperactive ENaC. Aldosterone, the final hormone in a negative-feedback cascade activated by decreases in blood pressure, increases ENaC activity. PIP3 sits at a critical bifurcation in the aldosterone-signaling cascade, increasing ENaC open probability and number. PIP3-effectors mediate increases in ENaC number by suppressing channel retrieval. PIP3 binds ENaC, at a site distinct form that important to PIP2 regulation, to modulate directly open probability. Phosphoinositides play key roles in physiologic control of ENaC and perhaps dysregulation plays a role in disease associated with abnormal renal Na+ handling.