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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-05-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.165715 |
| _version_ | 1827767958397517824 |
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| author | Claire A. Ruddiman Richard Peckham Melissa A. Luse Yen-Lin Chen Maniselvan Kuppusamy Bruce A. Corliss P. Jordan Hall Chien-Jung Lin Shayn M. Peirce Swapnil K. Sonkusare Robert P. Mecham Jessica E. Wagenseil Brant E. Isakson |
| author_facet | Claire A. Ruddiman Richard Peckham Melissa A. Luse Yen-Lin Chen Maniselvan Kuppusamy Bruce A. Corliss P. Jordan Hall Chien-Jung Lin Shayn M. Peirce Swapnil K. Sonkusare Robert P. Mecham Jessica E. Wagenseil Brant E. Isakson |
| author_sort | Claire A. Ruddiman |
| collection | DOAJ |
| 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 (PIP2) 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 PIP2 activation of Kir2.1 and that addition of exogenous PS blocks PIP2-mediated Kir2.1 vasodilation in resistance arteries. Using a mouse model lacking canonical MEJs in resistance arteries (Elnfl/fl/Cdh5-Cre), PS localization in endothelium was disrupted and PIP2 activation of Kir2.1 was significantly increased. Taken together, our data suggest that PS enrichment to MEJs inhibits PIP2-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. |
| first_indexed | 2024-03-11T12:05:43Z |
| format | Article |
| id | doaj.art-7e3053ea3fba4f4ebcd0e85d89274a84 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:43Z |
| publishDate | 2023-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-7e3053ea3fba4f4ebcd0e85d89274a842023-11-07T16:25:35ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-05-0189Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1Claire A. RuddimanRichard PeckhamMelissa A. LuseYen-Lin ChenManiselvan KuppusamyBruce A. CorlissP. Jordan HallChien-Jung LinShayn M. PeirceSwapnil K. SonkusareRobert P. MechamJessica E. WagenseilBrant E. IsaksonLipid 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 (PIP2) 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 PIP2 activation of Kir2.1 and that addition of exogenous PS blocks PIP2-mediated Kir2.1 vasodilation in resistance arteries. Using a mouse model lacking canonical MEJs in resistance arteries (Elnfl/fl/Cdh5-Cre), PS localization in endothelium was disrupted and PIP2 activation of Kir2.1 was significantly increased. Taken together, our data suggest that PS enrichment to MEJs inhibits PIP2-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.https://doi.org/10.1172/jci.insight.165715Vascular biology |
| spellingShingle | Claire A. Ruddiman Richard Peckham Melissa A. Luse Yen-Lin Chen Maniselvan Kuppusamy Bruce A. Corliss P. Jordan Hall Chien-Jung Lin Shayn M. Peirce Swapnil K. Sonkusare Robert P. Mecham Jessica E. Wagenseil Brant E. Isakson Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1 JCI Insight Vascular biology |
| 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 | Vascular biology |
| url | https://doi.org/10.1172/jci.insight.165715 |
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