ATP敏感钾通道调节血管张力的分子机制(英文)

K_(ATP) channel action in vascular tone regulation: from genetics to diseases

ATP敏感钾通道(ATP-sensitive potassium channel, KATP通道)广泛分布在血管系统,并在血管张力调节中发挥重要作用。 KATP通道由4个孔道形成的内向整流钾离子通道(inward rectifier K+ channels, Kir)亚基和4个磺脲受体调节亚基(sulfonylu-rea receptor, SUR)组成。尽管其它一些亚基在血管中也存在,Kir6.1/SUR2B是主要的血管亚型KATP通道。KATP通道转基因小鼠的研究以及人群中KATP通道基因突变的发现,都强烈支持KATP通道对于心血管系统的动态平衡调控是不可缺少的。大量的血管活性物质通过调节KATP通道活性来改变血管平滑肌细胞的膜电位,从而调节血管张力。多数内源性血管收缩物质,例如血管加压素,激活蛋白激酶C (protein kinase C, PKC),磷酸化KATP通道并抑制其活性;而血管扩张物质,如血管活性肠肽,通过增加cAMP的形成和提高蛋白激酶A (protein kinase A, PKA)的活性来增加KATP通道的活性。PKC作用于Kir6.1亚基C-末端,磷酸化4个保守的丝氨酸,而PKA磷酸化SUR2B亚基第2核苷酸结合域的Ser1387位点。血管KATP通道也受活性氧的调节,其中Kir6.1的Cys176是一个重要的过氧化物调节位点。此外,KATP通道功能可被一些慢性的病理生理条件上调,如感染性休克。核因子-κB依赖的基因转录是脂多糖诱导的血管KATP通道激活的一个机制。本综述将概括性描述血管KATP通道在生理和病理情况下受到的调节,以期阐明血管KATP通道在治疗和预防心血管疾病方面可能是一个有用的靶点。

ATP-sensitive potassium （KATP） channels are widely distributed in vasculatures, and play an important role in the vascular tone regulation. The KATP channels consist of 4 pore-forming inward rectifier K＋ channel （Kir） subunits and 4 regulatory sulfonylurea receptors （SUR）. The major vascular isoform of KATP channels is composed of Kir6.1/SUR2B, although low levels of other subunits are also present in vascular beds. The observation from transgenic mice and humans carrying Kir6.1/SUR2B channel mutations strongly supports that normal activity of the Kir6.1/SUR2B channel is critical for cardiovascular function. The Kir6.1/SUR2B channel is regulated by intracellular ATP and ADP. The channel is a common target of several vasodilators and vasoconstrictors. Endogenous vasopressors such as arginine vasopressin and α-adrenoceptor agonists stimulate protein kinase C （PKC） and inhibit the KATP channels, while vasodilators such as β-adrenoceptor agonists and vasoactive intestinal polypeptide increase KATP channel activity by activating the adenylate cyclase-cAMP-protein kinase A （PKA） pathway. PKC phosphorylates a cluster of 4 serine residues at C-terminus of Kir6.1, whereas PKA acts on Ser1387 in the nucleotide binding domain 2 of SUR2B. The Kir6.1/SUR2B channel is also inhibited by oxidants including reactive oxygen species allowing vascular regulation in oxidative stress. The molecular basis underlying such a channel inhibition is likely to be mediated by S-glutathionylation at a few cysteine residues, especially Cys176, in Kir6.1. Furthermore, the channel activity is augmented in endotoxemia or septic shock, as a result of the upregulation of Kir6.1/SUR2B expression. Activation of the nuclear factor-κB dependent transcriptional mechanism contributes to the Kir6.1/SUR2B channel upregulation by lipopolysaccharides and perhaps other toll-like receptor ligands as well. In this review, we summarize the vascular KATP channel regulation under physiological and pathophysiological conditions, and discuss the importance of KATP channel as a potentially useful target in the treatment and prevention of cardiovascular diseases.