Molecular physiology of the thiazide-sensitive sodium-chloride cotransporter.
Article Details
- CitationCopy to clipboard
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]
- 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 YesInhibitorDetails Quinethazone Solute carrier family 12 member 2 Protein Humans YesInhibitorDetails Quinethazone Solute carrier family 12 member 3 Protein Humans YesInhibitorDetails