Molecular physiology of the thiazide-sensitive sodium-chloride cotransporter.
Molecular physiology of the thiazide-sensitive sodium-chloride cotransporter.
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DOI：
10.1097/mnh.0b013e32832f2fcb
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发表时间：
2009-09
影响因子：
3.2
通讯作者：
Hoover RS
中科院分区：
文献类型：
--
作者：
Ko B;Hoover RS
本文综述了近年来对噻嗪敏感协同转运蛋白（NCC）的分子生理学及其调控的研究进展。无赖氨酸（WNK）激酶1和4的突变导致NCC和FHHt（家族性高钾血症高血压）的过度活跃，这是一种遗传性高血压综合征。最近的研究表明，WNK 1和WNK 4激活STE20家族蛋白激酶SPAK和OSR 1，导致NCC的磷酸化和激活。此外，WNK 4 FHHt突变体的小鼠敲入模型显示SPAK/OSR 1和NCC磷酸化增加。目前尚不清楚这些研究如何与表明WNK 4抑制NCC和WNK 4的FHHt突变是功能丧失突变的数据相吻合。另一种WNK激酶WNK 3调节NCC，激活NCC并拮抗WNK 4的作用。最近研究NCC的激素调节涉及血管紧张素II和醛固酮调节WNK 4-SPAK-NCC途径。血管紧张素II也可能通过对NCC的作用在压力性尿钠排泄中发挥作用。NCC受到一个复杂的激酶调节网络的影响，这些激酶对激素和生理环境的改变很敏感。
This review summarizes recent advances in the understanding of the molecular physiology and regulation of the thiazide-sensitive cotransporter (NCC). Mutations of With-No-Lysine (WNK) Kinases 1 and 4 result in hyperactivity of NCC and FHHt (Familial Hyperkalemic Hypertension), a genetic syndrome of hypertension. Recent studies have shown that WNK1 and WNK4 activate the STE20 family protein kinases SPAK and OSR1, resulting in phosphorylation and activation of NCC. Additionally, a mouse knock-in model for a WNK4 FHHt mutant demonstrated increased SPAK/OSR1 and NCC phosphorylation. It is unclear how these studies fit with the data indicating that WNK4 inhibits NCC and the FHHt mutations of WNK4 are loss-of-function mutations. Another WNK kinase, WNK3, regulates NCC, activating NCC and antagonizing WNK4's effect. Recent studies examining the hormonal regulation of NCC have implicated angiotensin II and aldosterone in regulation of the WNK4-SPAK-NCC pathway. Angiotensin II may also play a role in pressure natriuresis via actions on NCC. NCC is subject to a complex regulatory network of kinases which appear sensitive to alterations of the hormonal and physiologic milieu.