SK3 channel trafficking in endothelial cells

内皮细胞中的 SK3 通道运输

基本信息

项目摘要

Project Summary Endothelial cells line the wall of all blood vessels and regulate a wide variety of functions, including contractility and systemic blood pressure. Endothelial cell dysfunction is a hallmark of several cardiovascular diseases, but pathological mechanisms involved are unclear. Endothelial cells express small-conductance calcium-activated potassium (SK3) channels, which regulate contractility. Currents (I) generated by SK3 channels in endothelial cells is the product of the number of channels (N), their open probability (PO) and amplitude (i), such that I=N.PO.i. Previous studies have focused on identifying mechanisms that regulate the activity of surface SK channels in endothelial cells. In contrast, mechanisms that control the number (N) of surface SK3 channels in endothelial cells are poorly understood. Importantly, it is unclear whether physiological stimuli regulate the abundance of surface SK3 channels to alter arterial contractility. Similarly uncertain is if pathological alterations in the control of surface SK3 channel abundance occurs during hypertension, leading to attenuated vasodilation. Using a wide variety of approaches, we provide evidence that vasodilator stimuli activate trafficking mechanisms that rapidly increase surface SK3 channel abundance in endothelial cells to induce vasodilation. Preliminary data also suggest that SK3 channel trafficking is dysfunctional during hypertension, which attenuates this vasodilatory signaling mechanism. In this proposal, we will investigate three specific aims. Aim 1 will investigate signaling mechanisms by which physiological stimuli alter the surface abundance of SK3 channels and examine their functional significance. Aim 2 will examine trafficking mechanisms that control surface SK3 channels in endothelial cells to modify arterial contractility. Aim 3 will study the hypothesis that hypertension is associated with pathological alterations in SK3 channel trafficking in endothelial cells that inhibit vasodilation by these proteins. Methods used will include biotinylation, Western blotting, FRET, RNAi, co-IP, immunofluorescence, super-resolution microscopy, patch-clamp electrophysiology, membrane potential recording, intracellular Ca2+ imaging, arterial myography, blood pressure telemetry and transgenic mice. This project will provide significant novel information concerning vasoregulation by SK3 channel trafficking in endothelial cells.
项目摘要 内皮细胞排列在所有血管的壁上,调节各种功能,包括收缩性 和全身血压。内皮细胞功能障碍是几种心血管疾病的标志,但 涉及的病理机制尚不清楚。内皮细胞表达小电导钙激活的 钾(SK 3)通道,其调节收缩性。内皮细胞中SK 3通道产生的电流(I) 单元是通道数(N)、它们的开放概率(PO)和幅度(i)的乘积,使得 I= N.P.i.以前的研究主要集中在确定调节表面SK活性的机制 内皮细胞中的通道。相比之下,控制细胞中表面SK 3通道的数量(N)的机制, 对内皮细胞了解甚少。重要的是,目前还不清楚生理刺激是否调节了 丰富的表面SK 3通道来改变动脉收缩性。同样不确定的是, 在控制表面SK 3通道丰度发生在高血压,导致衰减 血管舒张通过各种各样的方法,我们提供了血管扩张刺激激活 快速增加内皮细胞中表面SK 3通道丰度以诱导 血管舒张初步数据还表明,SK 3通道运输在高血压期间功能失调, 其减弱这种血管舒张信号机制。在这份报告中,我们将研究三个具体问题。 目标。目的1将调查信号机制,通过生理刺激改变表面丰度 的SK 3通道,并研究其功能意义。目标2将审查贩运机制, 控制内皮细胞中的表面SK 3通道以改变动脉收缩性。目标3将研究假设 高血压与内皮细胞中SK 3通道运输的病理改变有关, 通过这些蛋白质抑制血管舒张。使用的方法将包括生物素化、蛋白质印迹、FRET、RNAi, co-IP,免疫荧光,超分辨显微镜,膜片钳电生理,膜电位 记录,细胞内Ca 2+成像,动脉肌电图,血压遥测和转基因小鼠。这 该项目将提供关于SK 3通道运输的血管调节的重要新信息, 内皮细胞

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
STIMulating blood pressure.
  • DOI:
    10.7554/elife.77978
  • 发表时间:
    2022-03-24
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Garrud TAC;Jaggar JH
  • 通讯作者:
    Jaggar JH
A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation.
  • DOI:
    10.7554/elife.74765
  • 发表时间:
    2022-03-01
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    MacKay CE;Floen M;Leo MD;Hasan R;Garrud TAC;Fernández-Peña C;Singh P;Malik KU;Jaggar JH
  • 通讯作者:
    Jaggar JH
Vasodilators mobilize SK3 channels in endothelial cells to produce arterial relaxation.
Vascular polycystin proteins in health and disease.
健康和疾病中的血管多囊蛋白。
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Jonathan H Jaggar其他文献

Jonathan H Jaggar的其他文献

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{{ truncateString('Jonathan H Jaggar', 18)}}的其他基金

Chloride channels in endothelial cells
内皮细胞中的氯离子通道
  • 批准号:
    10564697
  • 财政年份:
    2023
  • 资助金额:
    $ 63.6万
  • 项目类别:
PKD proteins in endothelial cells
内皮细胞中的 PKD 蛋白
  • 批准号:
    10097912
  • 财政年份:
    2021
  • 资助金额:
    $ 63.6万
  • 项目类别:
PKD proteins in endothelial cells
内皮细胞中的 PKD 蛋白
  • 批准号:
    10560613
  • 财政年份:
    2021
  • 资助金额:
    $ 63.6万
  • 项目类别:
SK3 channel trafficking in endothelial cells
内皮细胞中的 SK3 通道运输
  • 批准号:
    10426319
  • 财政年份:
    2021
  • 资助金额:
    $ 63.6万
  • 项目类别:
SK3 channel trafficking in endothelial cells
内皮细胞中的 SK3 通道运输
  • 批准号:
    10275918
  • 财政年份:
    2021
  • 资助金额:
    $ 63.6万
  • 项目类别:
PKD proteins in endothelial cells
内皮细胞中的 PKD 蛋白
  • 批准号:
    10339327
  • 财政年份:
    2021
  • 资助金额:
    $ 63.6万
  • 项目类别:
Blood pressure regulation by smooth muscle cell ion channels
平滑肌细胞离子通道调节血压
  • 批准号:
    9912820
  • 财政年份:
    2017
  • 资助金额:
    $ 63.6万
  • 项目类别:
Blood pressure regulation by smooth muscle cell ion channels
平滑肌细胞离子通道调节血压
  • 批准号:
    9310737
  • 财政年份:
    2017
  • 资助金额:
    $ 63.6万
  • 项目类别:
Endothelial cell potassium channels
内皮细胞钾通道
  • 批准号:
    9363956
  • 财政年份:
    2017
  • 资助金额:
    $ 63.6万
  • 项目类别:
Arterial Smooth Muscle Chloride Channels
动脉平滑肌氯离子通道
  • 批准号:
    8195349
  • 财政年份:
    2011
  • 资助金额:
    $ 63.6万
  • 项目类别:

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