Molecular physiology of the thiazide-sensitive sodium-chloride cotransporter.

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Ko B, Hoover RS

Molecular physiology of the thiazide-sensitive sodium-chloride cotransporter.

Curr Opin Nephrol Hypertens. 2009 Sep;18(5):421-7. doi: 10.1097/MNH.0b013e32832f2fcb.

PubMed ID

19636250 [ View in PubMed

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Abstract

PURPOSE OF REVIEW: This review summarizes recent advances in the understanding of the molecular physiology and regulation of the thiazide-sensitive sodium-chloride cotransporter (NCC). RECENT FINDINGS: Mutations of with-no-lysine (WNK) kinases 1 and 4 result in hyperactivity of NCC and familial hyperkalemic hypertension, a genetic syndrome of hypertension. Recent studies have shown that WNK1 and WNK4 activate the STE20 family protein kinases Ste20-related proline/alanine-rich kinase and odd-skipped-related 1, resulting in phosphorylation and activation of NCC. Additionally, a mouse knock-in model for a WNK4 familial hyperkalemic hypertension mutant demonstrated increased Ste20-related proline/alanine-rich kinase/odd-skipped-related 1 and NCC phosphorylation. It is unclear how these studies fit with the data indicating that WNK4 inhibits NCC, and the familial hyperkalemic hypertension mutations of WNK4 are loss-of-function mutations. Another WNK kinase, WNK3, also regulates NCC, activating NCC and antagonizing the effect of WNK4. Extracellular signal-related kinase 1/2 mitogen-activated protein kinase activation by Ras guanyl nucleotide-releasing protein 1 is another kinase pathway that appears to be a potent regulator of NCC. Other studies have described a role for angiotensin II in pressure natriuresis via actions on NCC. Recent studies examining the hormonal regulation of NCC have implicated angiotensin II and aldosterone in regulation of the WNK4-Ste20-related proline/alanine-rich kinase-NCC pathway. SUMMARY: NCC is subject to a complex regulatory network of kinases, which appear quite sensitive to alterations of the hormonal and physiologic milieu.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Quinethazone	Solute carrier family 12 member 1	Protein	Humans	Yes	Inhibitor	Details
Quinethazone	Solute carrier family 12 member 2	Protein	Humans	Yes	Inhibitor	Details
Quinethazone	Solute carrier family 12 member 3	Protein	Humans	Yes	Inhibitor	Details