Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1.
Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1.
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DOI：
10.1172/jci.insight.165715
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发表时间：
2023-05-08
期刊：
影响因子：
8
通讯作者：
Isakson, Brant E.
中科院分区：
文献类型：
--
作者：
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.
离子通道的脂质调节主要是使用在完整组织中进行最少实验的计算机模拟模型进行探索;因此，这些预测的天然细胞环境中的脂质通道相互作用的功能后果仍然难以捉摸。本研究的目的是探讨如何脂质调节内皮Kir2.1 -内向整流钾通道，调节膜超极化-有助于阻力动脉血管舒张。首先，我们发现磷脂酰丝氨酸（PS）定位于肌内皮连接（MEJs）的特定亚群，这是调节阻力动脉血管舒张的关键信号微结构域，并且计算机数据表明PS可能与磷脂酰肌醇4，5-二磷酸（PIP 2）竞争Kir2.1结合。我们发现Kir2.1-MEJs也含有PS，可能表明PS调节Kir2.1的相互作用。对HEK细胞的电生理学实验表明，PS阻断了PIP 2对Kir2.1的激活，并且外源性PS的加入阻断了PIP 2介导的阻力动脉中Kir2.1血管舒张。使用在阻力动脉中缺乏典型MEJ的小鼠模型（Elnfl/fl/Cdh 5-Cre），内皮中的PS定位被破坏，并且Kir2.1的PIP 2活化显著增加。综上所述，我们的数据表明，PS富集MEJ抑制PIP 2介导的Kir2.1激活，以严格调节动脉直径的变化，并且他们证明内皮内的细胞内脂质定位是血管功能的重要决定因素。
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.
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影响因子：
64.8
作者：
Hansen, Scott B.;Tao, Xiao;MacKinnon, Roderick
通讯作者：
MacKinnon, Roderick
DOI：
10.3390/antiox10030428
发表时间：
2021-03-11
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Jander K;Greulich J;Gonnissen S;Ale-Agha N;Goy C;Jakobs P;Farrokh S;Marziano C;Sonkusare SK;Haendeler J;Altschmied J
通讯作者：
Altschmied J
影响因子：
5.5
作者：
Hager NA;McAtee CK;Lesko MA;O'Donnell AF
通讯作者：
O'Donnell AF
DOI：
10.1126/science.aab1370
发表时间：
2015-07-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung J;Torta F;Masai K;Lucast L;Czapla H;Tanner LB;Narayanaswamy P;Wenk MR;Nakatsu F;De Camilli P
通讯作者：
De Camilli P
影响因子：
7.8
作者：
Dasgupta, Swapan K.;Guchhait, Prasenjit;Thiagarajan, Perlimal
通讯作者：
Thiagarajan, Perlimal