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

SHI Wei-Wei, YANG Yang, SHI Yun, JIANG Chun

Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Emory University, Atlanta, GA 30308, USA； Department of Neurology, Center for Neuroscience &； Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA； Neuroscience and Regeneration Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA

Abstract

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.

Key words: ATP-sensitive potassium channel; Kir6.1; SUR2B; protein phosphorylation; S-glutathionylation; nuclear factor-κB; sepsis; sudden infant death syndrome

Received: 2011-10-03　　Accepted: 2011-11-16

Corresponding author: 施巍巍　　E-mail: wshi6@emory.edu

Citing This Article：

SHI Wei-Wei, YANG Yang, SHI Yun, JIANG Chun. K(ATP) channel action in vascular tone regulation: from genetics to diseases.. Acta Physiol Sin 2012; 64 (1): 1-13 (in Chinese with English abstract).