Document Detail

Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways.
MedLine Citation:
PMID:  21321328     Owner:  NLM     Status:  MEDLINE    
Ion cotransporters, such as the Na(+)/Cl(-) cotransporter (NCC), control renal salt re-absorption and are regulated by the WNK-signalling pathway, which is over-stimulated in patients suffering from Gordon's hypertension syndrome. Here, we study the regulation of the NKCC2 (SLC12A1) ion cotransporter that contributes towards ~25% of renal salt re-absorption and is inhibited by loop-diuretic hypertensive drugs. We demonstrate that hypotonic low-chloride conditions that activate the WNK1-SPAK and OSR1 pathway promote phosphorylation of NKCC2 isoforms (A, B and F) at five residues (Ser91, Thr95, Thr100, Thr105 and Ser130). We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. In contrast with NCC, whose membrane translocation is triggered by SPAK-OSR1 phosphorylation, NKCC2 appears to be constitutively at the membrane. Our findings provide new insights into how NKCC2 is regulated and suggest that inhibitors of SPAK and/or OSR1 for the treatment of hypertension would be therapeutically distinct from thiazide or loop diuretics, as they would suppress the activity of both NCC and NKCC2.
Ciaran Richardson; Kei Sakamoto; Paola de los Heros; Maria Deak; David G Campbell; Alan R Prescott; Dario R Alessi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cell science     Volume:  124     ISSN:  1477-9137     ISO Abbreviation:  J. Cell. Sci.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-15     Completed Date:  2011-06-27     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0052457     Medline TA:  J Cell Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  789-800     Citation Subset:  IM    
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MeSH Terms
AMP-Activated Protein Kinases / metabolism
Amino Acid Sequence
Cell Membrane / metabolism
HEK293 Cells
Ions / metabolism
Mice, Inbred C57BL
Molecular Sequence Data
Protein Isoforms / genetics,  metabolism
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Sequence Alignment
Serine / metabolism
Signal Transduction / physiology
Sodium-Potassium-Chloride Symporters / genetics,  metabolism*
Solute Carrier Family 12, Member 1
Threonine / metabolism
Transcription Factors / genetics,  metabolism*
Grant Support
MC_U127070193//Medical Research Council; MC_U127088492//Medical Research Council; //Medical Research Council
Reg. No./Substance:
0/Ions; 0/OSR1 protein, human; 0/Protein Isoforms; 0/SLC12A1 protein, human; 0/Slc12a1 protein, mouse; 0/Sodium-Potassium-Chloride Symporters; 0/Solute Carrier Family 12, Member 1; 0/Transcription Factors; 2ZD004190S/Threonine; 452VLY9402/Serine; EC Protein Kinases; EC Kinases; EC protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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