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Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways

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Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. / Richardson, Ciaran; Sakamoto, Kei; de los Heros, Paola; Deak, Maria; Campbell, David G.; Prescott, Alan R.; Alessi, Dario R.

In: Journal of Cell Science, Vol. 124, No. 5, 01.03.2011, p. 789-800.

Research output: Contribution to journalArticle

Harvard

Richardson, C, Sakamoto, K, de los Heros, P, Deak, M, Campbell, DG, Prescott, AR & Alessi, DR 2011, 'Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways' Journal of Cell Science, vol 124, no. 5, pp. 789-800.

APA

Richardson, C., Sakamoto, K., de los Heros, P., Deak, M., Campbell, D. G., Prescott, A. R., & Alessi, D. R. (2011). Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. Journal of Cell Science, 124(5), 789-800doi: 10.1242/jcs.077230

Vancouver

Richardson C, Sakamoto K, de los Heros P, Deak M, Campbell DG, Prescott AR et al. Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. Journal of Cell Science. 2011 Mar 1;124(5):789-800.

Author

Richardson, Ciaran; Sakamoto, Kei; de los Heros, Paola; Deak, Maria; Campbell, David G.; Prescott, Alan R.; Alessi, Dario R. / Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways.

In: Journal of Cell Science, Vol. 124, No. 5, 01.03.2011, p. 789-800.

Research output: Contribution to journalArticle

Bibtex - Download

@article{acff91cfbdc841d6845dd24e48600cde,
title = "Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways",
author = "Ciaran Richardson and Kei Sakamoto and {de los Heros}, Paola and Maria Deak and Campbell, {David G.} and Prescott, {Alan R.} and Alessi, {Dario R.}",
year = "2011",
volume = "124",
number = "5",
pages = "789--800",
journal = "Journal of Cell Science",
issn = "0021-9533",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways

A1 - Richardson,Ciaran

A1 - Sakamoto,Kei

A1 - de los Heros,Paola

A1 - Deak,Maria

A1 - Campbell,David G.

A1 - Prescott,Alan R.

A1 - Alessi,Dario R.

AU - Richardson,Ciaran

AU - Sakamoto,Kei

AU - de los Heros,Paola

AU - Deak,Maria

AU - Campbell,David G.

AU - Prescott,Alan R.

AU - Alessi,Dario R.

PY - 2011/3/1

Y1 - 2011/3/1

N2 - <p>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 similar to 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.</p>

AB - <p>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 similar to 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.</p>

KW - AMPK

KW - Blood pressure

KW - NCC

KW - NKCC2

KW - SPAK-OSR1

KW - WNK

KW - K-CL COTRANSPORTER

KW - ACTIVATED PROTEIN-KINASE

KW - PSEUDOHYPOALDOSTERONISM TYPE-II

KW - CATION-CHLORIDE COTRANSPORTERS

KW - NA+-K+-2CL(-) COTRANSPORTER

KW - NA-K-2CL COTRANSPORTER

KW - GITELMANS-SYNDROME

KW - MOLECULAR PATHOGENESIS

KW - HYPOKALEMIC ALKALOSIS

KW - BARTTERS-SYNDROME

U2 - 10.1242/jcs.077230

DO - 10.1242/jcs.077230

M1 - Article

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 5

VL - 124

SP - 789

EP - 800

ER -

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