OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant

Clinton A. Taylor, Sung Wan An, Sachith Gallolu Kankanamalage, Steve Stippec, Svetlana Earnest, Ashesh T. Trivedi, Jonathan Zijiang Yang, Hamid Mirzaei, Chou Long Huang, Melanie H. Cobb

Research output: Contribution to journalArticle

Abstract

The with-no-lysine (K) (WNK) signaling pathway to STE20/SPS1-related proline- and alanine-rich kinase (SPAK) and oxidative stress-responsive 1 (OSR1) kinase is an important mediator of cell volume and ion transport. SPAK and OSR1 associate with upstream kinases WNK 1-4, substrates, and other proteins through their C-terminal domains which interact with linear R-F-x-V/I sequence motifs. In this study we find that SPAK and OSR1 also interact with similar affinity with a motif variant, R-x-F-x-V/I. Eight of 16 human inward rectifier K+ channels have an R-x-F-x-V motif. We demonstrate that two of these channels, Kir2.1 and Kir2.3, are activated by OSR1, while Kir4.1, which does not contain the motif, is not sensitive to changes in OSR1 or WNK activity. Mutation of the motif prevents activation of Kir2.3 by OSR1. Both siRNA knockdown of OSR1 and chemical inhibition of WNK activity disrupt NaCl-induced plasma membrane localization of Kir2.3. Our results suggest a mechanism by which WNK-OSR1 enhance Kir2.1 and Kir2.3 channel activity by increasing their plasma membrane localization. Regulation of members of the inward rectifier K+ channel family adds functional and mechanistic insight into the physiological impact of the WNK pathway.

Original languageEnglish (US)
Pages (from-to)3840-3845
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number15
DOIs
StatePublished - Jan 1 2018

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Inwardly Rectifying Potassium Channel
Oxidative Stress
Phosphotransferases
Proline
Alanine
Cell Membrane
Ion Transport
Cell Size
Small Interfering RNA
Lysine
Mutation

Keywords

  • Hypertension
  • Kinase cascade
  • SPAK
  • WNK1

ASJC Scopus subject areas

  • General

Cite this

OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant. / Taylor, Clinton A.; An, Sung Wan; Kankanamalage, Sachith Gallolu; Stippec, Steve; Earnest, Svetlana; Trivedi, Ashesh T.; Yang, Jonathan Zijiang; Mirzaei, Hamid; Huang, Chou Long; Cobb, Melanie H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 15, 01.01.2018, p. 3840-3845.

Research output: Contribution to journalArticle

Taylor, Clinton A. ; An, Sung Wan ; Kankanamalage, Sachith Gallolu ; Stippec, Steve ; Earnest, Svetlana ; Trivedi, Ashesh T. ; Yang, Jonathan Zijiang ; Mirzaei, Hamid ; Huang, Chou Long ; Cobb, Melanie H. / OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 15. pp. 3840-3845.
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AU - An, Sung Wan

AU - Kankanamalage, Sachith Gallolu

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AU - Earnest, Svetlana

AU - Trivedi, Ashesh T.

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