Muscle KATP Channels: Recent Insights to Energy Sensing and Myoprotection

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Physiological Reviews (Impact Factor: 27.32). 07/2010; 90(3):799-829. DOI: 10.1152/physrev.00027.2009
Source: PubMed


ATP-sensitive potassium (K(ATP)) channels are present in the surface and internal membranes of cardiac, skeletal, and smooth muscle cells and provide a unique feedback between muscle cell metabolism and electrical activity. In so doing, they can play an important role in the control of contractility, particularly when cellular energetics are compromised, protecting the tissue against calcium overload and fiber damage, but the cost of this protection may be enhanced arrhythmic activity. Generated as complexes of Kir6.1 or Kir6.2 pore-forming subunits with regulatory sulfonylurea receptor subunits, SUR1 or SUR2, the differential assembly of K(ATP) channels in different tissues gives rise to tissue-specific physiological and pharmacological regulation, and hence to the tissue-specific pharmacological control of contractility. The last 10 years have provided insights into the regulation and role of muscle K(ATP) channels, in large part driven by studies of mice in which the protein determinants of channel activity have been deleted or modified. As yet, few human diseases have been correlated with altered muscle K(ATP) activity, but genetically modified animals give important insights to likely pathological roles of aberrant channel activity in different muscle types.

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Available from: Thomas P Flagg, Aug 13, 2014
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    • "We have found out that H9c2 cells expressing Kir6.2AFA cannot be preconditioned by phenylephrine, which strongly supports the notion that the observed cardioprotection is mediated by increase in K ATP channels. SUR2B is a subunit found primarily in smooth muscle cells, although their presence was reported in other cell types as well (Nichols, 2006; Flagg et al., 2010; Du et al., 2010b ). In cardiomyocytes , their presence was detected, but functional role was not understood. "
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    ABSTRACT: ATP-sensitive K(+) (KATP) channels were originally described in cardiomyocytes, where physiological levels of intracellular ATP keep them in a closed state. Structurally, these channels are composed of pore-forming inward rectifier, Kir6.1 or Kir6.2, and a regulatory, ATP-binding subunit, SUR1, SUR2A or SUR2B. SUR1 and Kir6.2 form pancreatic type of KATP channels, SUR2A and Kir6.2 form cardiac type of KATP channels, SUR2B and Kir6.1 form vascular smooth muscle type of KATP channels. The presence of SUR2B has been described in cardiomyocytes, but its functional significance and role has remained unknown. Pretreatment with phenylephrine (100 nM) for 24h increased mRNA levels of SUR2B and Kir6.2, without affecting those levels of SUR1, SUR2A and Kir6.1 in embryonic heart H9c2 cells. Such increase was associated with increased K(+) current through KATP channels and Kir6.2SUR2B protein complexes as revealed by whole cell patch clamp electrophysiology and immunoprecipitation/Western blotting respectively. Pretreatment with phenylephrine (100 nM) generated a cellular phenotype that acquired resistance to chemical hypoxia induced by 2,4-dinitrophenol (DNP; 10mM), which was accompanied by increased in K(+) current in response to DNP (10mM). Cytoprotection afforded by phenylephrine (100 nM) was abolished by infection of H9c2 cells with adenovirus containing Kir6.2AFA, a mutant form of Kir6.2 with largely reduced K(+) conductance. Taking all together, the present findings demonstrate that the activation of α1-adrenoceptors up-regulates SUR2B/Kir6.2 to confer cardioprotection. This is the first account of possible physiological role of SUR2B in cardiomyocytes.
    Full-text · Article · Nov 2015 · The international journal of biochemistry & cell biology
    • "(8) The net effect of K ATP channel closing is to increase intracellular Ca ++ , contract smooth muscle in the tunica media of arterioles, and decrease local blood flow. This figure incorporates information from recent reviews (Flagg et al., 2010; Ko et al., 2008). Here we show cartoon depiction of the K ATP channel in smooth muscle cells but it should be kept in mind that K ATP channels have also been shown to affect endothelial cells, pericytes, and possibly perivascular astrocytes. "
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    ABSTRACT: The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium ("KATP") channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a "druggable target", relevant perhaps to both HS-Aging and Alzheimer's disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Ageing research reviews
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    • "The results underscore the key role of K ATP channels in coupling cell membrane potential with diverse tissue functions. Our results are consistent with the finding that vascular smooth muscle contractility is markedly decreased in the presence of K ATP channel openers [Flagg et al., 2010] and in transgenic mice expressing mutant Kir6.1 subunits with reduced sensitivity to inhibitory ATP [Li et al., 2013], potentially explaining some of the key findings in CS, including patent ductus arteriosus, as was present in the patient reported here. A novel finding is the puzzling combination of biochemical signs of absolute GH deficiency, yet postnatal growth with height within the normal range. "
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    ABSTRACT: ATP-sensitive potassium (KATP ) channels, composed of inward-rectifying potassium channel subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and regulatory sulfonylurea receptor (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively), couple metabolism to excitability in multiple tissues. Mutations in ABCC9 cause Cantú syndrome, a distinct multi-organ disease, potentially via enhanced KATP channel activity. We screened KCNJ8 in an ABCC9 mutation-negative patient who also exhibited clinical hallmarks of Cantú syndrome (hypertrichosis, macrosomia, macrocephaly, coarse facial appearance, cardiomegaly, and skeletal abnormalities). We identified a de novo missense mutation encoding Kir6.1[p.Cys176Ser] in the patient. Kir6.1[p.Cys176Ser] channels exhibited markedly higher activity than wild-type channels, as a result of reduced ATP sensitivity, whether co-expressed with SUR1 or SUR2A subunits. Our results identify a novel causal gene in Cantú syndrome, but also demonstrate that the cardinal features of the disease result from gain of KATP channel function, not from Kir6-independent SUR2 function. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2014 · Human Mutation
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