K(ATP) channel action in vascular tone regulation: from genetics to diseases.
K(ATP) channel action in vascular tone regulation: from genetics to diseases.
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发表时间：
2012-02
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通讯作者：
Weiwei Shi;Yang Yang-Yang;Yun Shi;Chun Jiang
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作者：
Weiwei Shi;Yang Yang-Yang;Yun Shi;Chun Jiang
ATP敏感性钾通道（K（ATP））广泛分布于血管系统，在血管张力调节中起重要作用。K（ATP）通道由4个成孔内向整流性K（+）通道（Kir）亚单位和4个调节性磺酰脲受体（SUR）组成。K（ATP）通道的主要血管同种型由Kir6.1/SUR 2B组成，尽管低水平的其他亚基也存在于血管床中。来自携带Kir6.1/SUR 2B通道突变的转基因小鼠和人类的观察结果强烈支持Kir6.1/SUR 2B通道的正常活性对心血管功能至关重要。Kir6.1/SUR 2B通道受细胞内ATP和ADP的调节。该通道是几种血管扩张剂和血管收缩剂的共同靶点。内源性血管加压药如精氨酸加压素和α-肾上腺素受体激动剂可刺激蛋白激酶C（PKC）并抑制K（ATP）通道，而血管舒张药如β-肾上腺素受体激动剂和血管活性肠肽可通过激活腺苷酸环化酶-cAMP-蛋白激酶A（PKA）途径增加K（ATP）通道活性。PKC磷酸化Kir6.1的C-末端的4个丝氨酸残基的簇，而PKA作用于SUR 2B的核苷酸结合结构域2中的Ser 1387。Kir6.1/SUR 2B通道也被氧化剂抑制，包括活性氧物质，允许在氧化应激中进行血管调节。这种通道抑制的分子基础可能是由Kir6.1中几个半胱氨酸残基，特别是Cys 176处的S-谷胱甘肽化介导的。此外，由于Kir6.1/SUR 2B表达的上调，通道活性在内毒素血症或脓毒性休克中增强。核因子-κB依赖性转录机制的激活有助于脂多糖和可能的其他toll样受体配体上调Kir6.1/SUR 2 B通道。本文综述了血管K（ATP）通道在生理和病理生理条件下的调节作用，并讨论了K（ATP）通道作为一个潜在的靶点在心血管疾病治疗和预防中的重要性。
ATP-sensitive potassium (K(ATP)) channels are widely distributed in vasculatures, and play an important role in the vascular tone regulation. The K(ATP) channels consist of 4 pore-forming inward rectifier K(+) channel (Kir) subunits and 4 regulatory sulfonylurea receptors (SUR). The major vascular isoform of K(ATP) 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 K(ATP) channels, while vasodilators such as β-adrenoceptor agonists and vasoactive intestinal polypeptide increase K(ATP) 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 K(ATP) channel regulation under physiological and pathophysiological conditions, and discuss the importance of K(ATP) channel as a potentially useful target in the treatment and prevention of cardiovascular diseases.