K(ATP) channel action in vascular tone regulation: from genetics to diseases.
- Author:
Wei-Wei SHI
1
;
Yang YANG
;
Yun SHI
;
Chun JIANG
Author Information
1. Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Emory University, Atlanta, GA 30308, USA. wshi6@emory.edu
- Publication Type:Journal Article
- MeSH:
ATP-Binding Cassette Transporters;
genetics;
physiology;
Animals;
Endotoxemia;
metabolism;
physiopathology;
Humans;
KATP Channels;
genetics;
physiology;
Mice;
Mice, Transgenic;
Muscle, Smooth, Vascular;
metabolism;
physiology;
Potassium Channels, Inwardly Rectifying;
genetics;
physiology;
Receptors, Drug;
genetics;
physiology;
Shock, Septic;
metabolism;
physiopathology;
Sulfonylurea Receptors;
Vasoconstriction;
physiology;
Vasodilation;
physiology;
Vasomotor System;
physiology
- From:
Acta Physiologica Sinica
2012;64(1):1-13
- CountryChina
- Language:English
-
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.
