Vasodilators mobilize SK3 channels in endothelial cells to produce arterial relaxation.
Vasodilators mobilize SK3 channels in endothelial cells to produce arterial relaxation.
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DOI：
10.1073/pnas.2303238120
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发表时间：
2023-08
影响因子：
11.1
通讯作者：
Jaggar, Jonathan H.
中科院分区：
文献类型：
--
作者：
Peixoto-Neves, Dieniffer;Yadav, Shambhu;MacKay, Charles E.;Mbiakop, Ulrich C.;Mata-Daboin, Alejandro;Leo, M. Dennis;Jaggar, Jonathan H.
SK通道在多种细胞类型中表达，包括内皮细胞。以往的研究表明，血管舒张剂刺激内皮细胞的SK电流，从而增强血管舒张。生理刺激调节内皮细胞中SK通道的表面丰度以引起血管舒张的概念尚未被探索。在这里，我们表明，ACh刺激TRPV4通道，导致Ca2+内流激活Rab11A迅速提供细胞内池的SK3通道的表面位置的TRPV4通道在内皮细胞。这种运输机制增加了表面SK3通道簇的大小，这放大了SK电流以产生血管舒张。内皮细胞（EC）排列在所有血管的管腔中并调节功能，包括收缩性。生理刺激，如乙酰胆碱（ACh）和血管内流量，激活瞬时受体电位香草酸4（TRPV 4）通道，刺激EC中的小（SK 3）和中（IK）电导Ca 2+激活的钾通道，产生血管舒张。生理性血管扩张剂是否也调节EC中这些离子通道的表面丰度以引起功能反应尚不清楚。在这里，我们表明，乙酰胆碱和血管内流刺激快速顺行贩运的细胞内池SK3通道的EC的阻力大小的动脉，增加表面SK3蛋白的两倍以上。相反，ACh和流量不改变IK或TRPV 4通道的表面丰度。ACh通过激活TRPV4介导的Ca2+内流触发SK3通道运输，这刺激Rab11A，一种与再循环内体相关的Rab GT3。超分辨率显微镜数据表明，SK3贩运专门增加的大小与TRPV4集群重叠的表面SK3集群。我们还表明，Rab11A依赖的SK3通道的运输是一个重要的贡献者血管扩张剂诱导的SK电流激活EC和血管舒张。总之，我们的数据表明，血管扩张剂激活Rab11A，它迅速提供了一个细胞内池的SK3通道附近的表面TRPV4通道的EC。这种运输机制增加了表面SK3簇的大小，提高了SK3电流密度，并产生血管舒张。这些数据还表明，SK3和IK通道的差异调节交通依赖性和非依赖性的信号转导机制在内皮细胞。
SK channels are expressed in a wide variety of cell types, including endothelial cells. Previous studies have demonstrated that vasodilators stimulate SK currents in endothelial cells, which elicits vasorelaxation. The concept that physiological stimuli modulate the surface abundance of SK channels in endothelial cells to elicit vasodilation has not been explored. Here, we show that ACh stimulates TRPV4 channels, leading to Ca2+ influx which activates Rab11A to rapidly deliver an intracellular pool of SK3 channels to the surface location of TRPV4 channels in endothelial cells. This trafficking mechanism increases the size of surface SK3 channel clusters, which amplifies SK currents to produce vasodilation. Endothelial cells (ECs) line the lumen of all blood vessels and regulate functions, including contractility. Physiological stimuli, such as acetylcholine (ACh) and intravascular flow, activate transient receptor potential vanilloid 4 (TRPV4) channels, which stimulate small (SK3)- and intermediate (IK)-conductance Ca2+-activated potassium channels in ECs to produce vasodilation. Whether physiological vasodilators also modulate the surface abundance of these ion channels in ECs to elicit functional responses is unclear. Here, we show that ACh and intravascular flow stimulate rapid anterograde trafficking of an intracellular pool of SK3 channels in ECs of resistance-size arteries, which increases surface SK3 protein more than two-fold. In contrast, ACh and flow do not alter the surface abundance of IK or TRPV4 channels. ACh triggers SK3 channel trafficking by activating TRPV4-mediated Ca2+ influx, which stimulates Rab11A, a Rab GTPase associated with recycling endosomes. Superresolution microscopy data demonstrate that SK3 trafficking specifically increases the size of surface SK3 clusters which overlap with TRPV4 clusters. We also show that Rab11A-dependent trafficking of SK3 channels is an essential contributor to vasodilator-induced SK current activation in ECs and vasorelaxation. In summary, our data demonstrate that vasodilators activate Rab11A, which rapidly delivers an intracellular pool of SK3 channels to the vicinity of surface TRPV4 channels in ECs. This trafficking mechanism increases surface SK3 cluster size, elevates SK3 current density, and produces vasodilation. These data also demonstrate that SK3 and IK channels are differentially regulated by trafficking-dependent and -independent signaling mechanisms in endothelial cells.
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影响因子：
7.3
作者：
Leo MD;Zhai X;Muralidharan P;Kuruvilla KP;Bulley S;Boop FA;Jaggar JH
通讯作者：
Jaggar JH
RAB GTPases在膜交通和细胞生理学中的作用。
影响因子：
33.6
作者：
Hutagalung AH;Novick PJ
通讯作者：
Novick PJ
影响因子：
5.5
作者：
Lin, Mike T.;Adelman, John P.;Maylie, James
通讯作者：
Maylie, James
DOI：
10.1073/pnas.1317527111
发表时间：
2014-02-11
影响因子：
11.1
作者：
Leo, M. Dennis;Bannister, John P.;Jaggar, Jonathan H.
通讯作者：
Jaggar, Jonathan H.
影响因子：
5.5
作者：
Bannister, John P.;Bulley, Simon;Jaggar, Jonathan H.
通讯作者：
Jaggar, Jonathan H.