Journal article
OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant
Proceedings of the National Academy of Sciences - PNAS, Vol.115(15), pp.3840-3845
03/26/2018
DOI: 10.1073/pnas.1802339115
PMCID: PMC5899495
PMID: 29581290
Abstract
With-no-lysine (K) (WNK) protein kinases regulate ion transport. Mutations in WNKs 1 and 4 can cause a monogenic hypertension, pseudohypoaldosteronism type II (PHA2). The WNK-regulated protein kinases STE20/SPS1-related proline- and alanine-rich kinase (SPAK) and oxidative stress-responsive 1 (OSR1) mediate actions of WNKs on cation chloride cotransporters. The conserved C-terminal domains (CCTs) of OSR1/SPAK recognize linear R-F-x-V/I motifs in transporters and other protein targets. We discovered that OSR1/SPAK CCTs also recognize a motif variant, R-x-F-x-V/I, found in 8 of 16 inward rectifier K
+
(IRK) channels. We show that WNK and OSR1 regulate IRK channels, dependent on the presence of the variant motif. WNK kinase activity-dependent regulation of ion channels reveals a previously unknown mechanism and expands knowledge of potential WNK-OSR1/SPAK actions in cardiac and renal physiology.
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.
Details
- Title: Subtitle
- OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant
- Creators
- Clinton A. Taylor - The University of Texas Southwestern Medical CenterSung-Wan An - The University of Texas Southwestern Medical CenterSachith Gallolu Kankanamalage - The University of Texas Southwestern Medical CenterSteve Stippec - The University of Texas Southwestern Medical CenterSvetlana Earnest - The University of Texas Southwestern Medical CenterAshesh T. Trivedi - The University of Texas Southwestern Medical CenterJonathan Zijiang Yang - The University of Texas Southwestern Medical CenterHamid Mirzaei - The University of Texas Southwestern Medical CenterChou-Long Huang - The University of Texas Southwestern Medical CenterMelanie H. Cobb - The University of Texas Southwestern Medical Center
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.115(15), pp.3840-3845
- Publisher
- National Academy of Sciences
- DOI
- 10.1073/pnas.1802339115
- PMID
- 29581290
- PMCID
- PMC5899495
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- p30CA142543 / HHS | NIH | National Cancer Institute (NCI) I1243 / Welch Foundation R01 DK111542 / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R37 DK34128 / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Language
- English
- Date published
- 03/26/2018
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984359768402771
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