@article{39d07708d3824c85911134605beb530b,
title = "OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant",
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.",
keywords = "Hypertension, Kinase cascade, SPAK, WNK1",
author = "Taylor, {Clinton A.} and An, {Sung Wan} and Kankanamalage, {Sachith Gallolu} and Steve Stippec and Svetlana Earnest and Trivedi, {Ashesh T.} and Yang, {Jonathan Zijiang} and Hamid Mirzaei and Huang, {Chou Long} and Cobb, {Melanie H.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank members of the M.H.C. laboratory and Kate Luby-Phelps [Department of Cell Biology and Live Cell Imaging Facility, University of Texas Southwestern (UT Southwestern)] for their suggestions about this project and Dionne Ware for administrative support. The work was supported by Welch Foundation Grant I1243 (to M.H.C.), National Institutes of Health Grants R37DK34128 (to M.H.C.) and R01DK111542 (to C.-L.H.), and National Cancer Institute Grant P30CA142543 to the Harold C. Simmons Comprehensive Cancer Center for partial support of the Live Cell Imaging Facility. A.T.T. was supported by the Summer Undergraduate Research Fellowship Program, and J.Z.Y. was supported by the STARS Student Summer Research Program, both at UT Southwestern. Funding Information: We thank members of the M.H.C. laboratory and Kate Luby-Phelps [Department of Cell Biology and Live Cell Imaging Facility, University of Texas Southwestern (UT Southwestern)] for their suggestions about this project and Dionne Ware for administrative support. The work was supported by Welch Foundation Grant I1243 (to M.H.C.), National Institutes of Health Grants R37DK34128 (to M.H.C.) and R01DK111542 (to C.-L.H.), and National Cancer Institute Grant P30CA142543 to the Harold C. Simmons Comprehensive Cancer Center for partial support of the Live Cell Imaging Facility. A.T.T. was supported by the Summer Undergraduate Research Fellowship Program, and J.Z.Y. was supported by the STARS Student Summer Research Program, both at UT Southwestern. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",
year = "2018",
doi = "10.1073/pnas.1802339115",
language = "English (US)",
volume = "115",
pages = "3840--3845",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "15",
}