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Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1
Lipid regulation of ion channels is largely explored using in silico modeling with minimal experimentation in intact tissue; thus, the functional consequences of these predicted lipid-channel interactions within native cellular environments remain elusive. The goal of this study is to investigate ho...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10243826/ https://www.ncbi.nlm.nih.gov/pubmed/37014698 http://dx.doi.org/10.1172/jci.insight.165715 |
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author | Ruddiman, Claire A. Peckham, Richard Luse, Melissa A. Chen, Yen-Lin Kuppusamy, Maniselvan Corliss, Bruce A. Hall, P. Jordan Lin, Chien-Jung Peirce, Shayn M. Sonkusare, Swapnil K. Mecham, Robert P. Wagenseil, Jessica E. Isakson, Brant E. |
author_facet | Ruddiman, Claire A. Peckham, Richard Luse, Melissa A. Chen, Yen-Lin Kuppusamy, Maniselvan Corliss, Bruce A. Hall, P. Jordan Lin, Chien-Jung Peirce, Shayn M. Sonkusare, Swapnil K. Mecham, Robert P. Wagenseil, Jessica E. Isakson, Brant E. |
author_sort | Ruddiman, Claire A. |
collection | PubMed |
description | Lipid regulation of ion channels is largely explored using in silico modeling with minimal experimentation in intact tissue; thus, the functional consequences of these predicted lipid-channel interactions within native cellular environments remain elusive. The goal of this study is to investigate how lipid regulation of endothelial Kir2.1 — an inwardly rectifying potassium channel that regulates membrane hyperpolarization — contributes to vasodilation in resistance arteries. First, we show that phosphatidylserine (PS) localizes to a specific subpopulation of myoendothelial junctions (MEJs), crucial signaling microdomains that regulate vasodilation in resistance arteries, and in silico data have implied that PS may compete with phosphatidylinositol 4,5-bisphosphate (PIP(2)) binding on Kir2.1. We found that Kir2.1-MEJs also contained PS, possibly indicating an interaction where PS regulates Kir2.1. Electrophysiology experiments on HEK cells demonstrate that PS blocks PIP(2) activation of Kir2.1 and that addition of exogenous PS blocks PIP(2)-mediated Kir2.1 vasodilation in resistance arteries. Using a mouse model lacking canonical MEJs in resistance arteries (Eln(fl/fl)/Cdh5-Cre), PS localization in endothelium was disrupted and PIP(2) activation of Kir2.1 was significantly increased. Taken together, our data suggest that PS enrichment to MEJs inhibits PIP(2)-mediated activation of Kir2.1 to tightly regulate changes in arterial diameter, and they demonstrate that the intracellular lipid localization within the endothelium is an important determinant of vascular function. |
format | Online Article Text |
id | pubmed-10243826 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-102438262023-06-07 Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1 Ruddiman, Claire A. Peckham, Richard Luse, Melissa A. Chen, Yen-Lin Kuppusamy, Maniselvan Corliss, Bruce A. Hall, P. Jordan Lin, Chien-Jung Peirce, Shayn M. Sonkusare, Swapnil K. Mecham, Robert P. Wagenseil, Jessica E. Isakson, Brant E. JCI Insight Research Article Lipid regulation of ion channels is largely explored using in silico modeling with minimal experimentation in intact tissue; thus, the functional consequences of these predicted lipid-channel interactions within native cellular environments remain elusive. The goal of this study is to investigate how lipid regulation of endothelial Kir2.1 — an inwardly rectifying potassium channel that regulates membrane hyperpolarization — contributes to vasodilation in resistance arteries. First, we show that phosphatidylserine (PS) localizes to a specific subpopulation of myoendothelial junctions (MEJs), crucial signaling microdomains that regulate vasodilation in resistance arteries, and in silico data have implied that PS may compete with phosphatidylinositol 4,5-bisphosphate (PIP(2)) binding on Kir2.1. We found that Kir2.1-MEJs also contained PS, possibly indicating an interaction where PS regulates Kir2.1. Electrophysiology experiments on HEK cells demonstrate that PS blocks PIP(2) activation of Kir2.1 and that addition of exogenous PS blocks PIP(2)-mediated Kir2.1 vasodilation in resistance arteries. Using a mouse model lacking canonical MEJs in resistance arteries (Eln(fl/fl)/Cdh5-Cre), PS localization in endothelium was disrupted and PIP(2) activation of Kir2.1 was significantly increased. Taken together, our data suggest that PS enrichment to MEJs inhibits PIP(2)-mediated activation of Kir2.1 to tightly regulate changes in arterial diameter, and they demonstrate that the intracellular lipid localization within the endothelium is an important determinant of vascular function. American Society for Clinical Investigation 2023-05-08 /pmc/articles/PMC10243826/ /pubmed/37014698 http://dx.doi.org/10.1172/jci.insight.165715 Text en © 2023 Ruddiman et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Ruddiman, Claire A. Peckham, Richard Luse, Melissa A. Chen, Yen-Lin Kuppusamy, Maniselvan Corliss, Bruce A. Hall, P. Jordan Lin, Chien-Jung Peirce, Shayn M. Sonkusare, Swapnil K. Mecham, Robert P. Wagenseil, Jessica E. Isakson, Brant E. Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1 |
title | Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1 |
title_full | Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1 |
title_fullStr | Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1 |
title_full_unstemmed | Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1 |
title_short | Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1 |
title_sort | polarized localization of phosphatidylserine in the endothelium regulates kir2.1 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10243826/ https://www.ncbi.nlm.nih.gov/pubmed/37014698 http://dx.doi.org/10.1172/jci.insight.165715 |
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