title: K(ATP) channel action in vascular tone regulation: from genetics to diseases.
abstract: 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.
authors.affiliation: Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Emory University, Atlanta, GA 30308, USA. wshi6@emory.edu
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Shi
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000818:Animals; D019446:Endotoxemia / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D054086:KATP Channels / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000502:physiology; D011955:Receptors, Drug / Q000235:genetics / Q000502:physiology; D012772:Shock, Septic / Q000378:metabolism / Q000503:physiopathology; D064233:Sulfonylurea Receptors; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology; D014666:Vasomotor System / Q000502:physiology*
chemical_list: D018528:ATP-Binding Cassette Transporters; C577511:Abcc9 protein, mouse; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C092520:uK-ATP-1 potassium channel