Arginine vasopressin inhibits Kir6.1/SUR2B channel and constricts the mesenteric artery via V1a receptor and protein kinase C
Arginine vasopressin inhibits Kir6.1/SUR2B channel and constricts the mesenteric artery via V1a receptor and protein kinase C
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DOI：
10.1152/ajpregu.00047.2007
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发表时间：
2007-07-01
影响因子：
2.8
通讯作者：
Jiang, Chun
中科院分区：
文献类型：
--
作者：
Shi, Weiwei;Cui, Ningren;Jiang, Chun
Kir6./ SUR 2B通道是血管平滑肌K-ATP通道的主要亚型。任何一个亚基的遗传破坏都会导致血管张力和局部血流的失调。为了验证Kir6.1/SUR 213通道是精氨酸加压素（AVP）靶分子的假设，我们对克隆的Kir6.1/SUR 2B通道和细胞内源性K-ATP通道进行了研究。Kir6.1/SUR 213通道在HEK-293细胞系中与V1 a受体一起表达。K-ATP通道开放剂吡那地尔可激活转染HEK细胞的全细胞电流，而K-ATP通道抑制剂格列本脲可抑制转染HEK细胞的全细胞电流。AVP对吡那地尔激活电流产生浓度依赖性抑制，IC 50为2.0 nM。电流抑制介导的抑制的开放状态的概率，而不影响单通道电导。暴露于100 nM PMA（一种强效PKC激活剂）可抑制吡那地尔激活的电流，并消除AVP对通道的抑制。无活性的佛波醇酯没有观察到这种效果。用选择性PKC阻断剂预处理细胞可明显减弱AVP的抑制作用。在急性分离的血管平滑肌细胞中，AVP强烈抑制细胞内源性K-ATP通道。在离体肠系膜动脉环中，AVP产生浓度依赖性血管收缩，EC 50为6.5 nM。在最大效应下，吡那地尔完全放松了持续暴露于AVP的血管收缩。calphostin-C显著降低AVP诱导的血管收缩幅度。这些结果表明Kir6.1/SUR 2B通道是AVP的靶分子，并且通道抑制涉及G（q）偶联的V1 a受体和PKC。
Kir6./SUR2B channel is the major isoform of K-ATP channels in the vascular smooth muscle. Genetic disruption of either subunit leads to dysregulation of vascular tone and regional blood flows. To test the hypothesis that the Kir6.1/ SUR213 channel is a target molecule of arginine vasopressin (AVP), we performed studies on the cloned Kir6.1/SUR2B channel and cell-endogenous K-ATP channel in rat mesenteric arteries. The Kir6.1/ SUR213 channel was expressed together with V1a receptor in the HEK-293 cell line. Whole cell currents of the transfected HEK cells were activated by K-ATP channel opener pinacidil and inhibited by K-ATP channel inhibitor glibenclamide. AVP produced a concentration-dependent inhibition of the pinacidil-activated currents with IC50 2.0 nM. The current inhibition was mediated by a suppression of the open-state probability without effect on single-channel conductance. An exposure to 100 nM PMA, a potent PKC activator, inhibited the pinacidil-activated currents, and abolished the channel inhibition by AVP. Such an effect was not seen with inactive phorbol ester. A pretreatment of the cells with selective PKC blocker significantly diminished the inhibitory effect of AVP. In acutely dissociated vascular smooth myocytes, AVP strongly inhibited the cell-endogenous K-ATP channel. In isolated mesenteric artery rings, AVP produced concentration-dependent vasoconstrictions with EC50 6.5 nM. At the maximum effect, pinacidil completely relaxed vasoconstriction in the continuing exposure to AVP. The magnitude of the AVP-induced vasoconstriction was significantly reduced by calphostin-C. These results therefore indicate that the Kir6.1/SUR2B channel is a target molecule of AVP, and the channel inhibition involves G(q)-coupled V1 a receptor and PKC.