Cardiac K channels in health and disease

Kane, Garvan C.; Liu, Xiao Ke; Yamada, Satsuki; Olson, Timothy M.; Terzic, André

doi:10.1016/j.yjmcc.2005.02.026

Cited by 183 publications

(217 citation statements)

References 74 publications

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“…Sarcolemmal ATP-sensitive K + (K ATP ) channels, ion channels that couple metabolic status of the cell with membrane excitability (3), have been implicated in cardioprotective signaling (4,5). These channels are selectively permeable to K + ions and are closed by high intracellular ATP levels (3).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of SUR2A generates a cardiac phenotype resistant to ischemia

et al. 2006

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ATP-sensitive K + (K ATP ) channels are present in the sarcolemma of cardiac myocytes where they link membrane excitability with the cellular bioenergetic state. These channels are in vivo composed of Kir6.2, a pore-forming subunit, SUR2A, a regulatory subunit, and at least four accessory proteins. In the present study, real-time RT-PCR has demonstrated that of all six sarcolemmal K ATP channelforming proteins, SUR2A was probably the least expressed protein. We have generated mice where the SUR2A was under the control of a cytomegalovirus promoter, a promoter that is more efficient than the native promoter. These mice had an increase in SUR2A mRNA/protein levels in the heart whereas levels of mRNAs of other channel-forming proteins were not affected at all. Imunoprecipitation/Western blot and patch clamp electrophysiology has shown an increase in K ATP channel numbers in the sarcolemma of transgenic mice. Cardiomyocytes from transgenic mice responded to hypoxia with shortening of action membrane potential and were significantly more resistant to this insult than cardiomyocytes from the wild-type. The size of myocardial infarction in response to ischemia-reperfusion was much smaller in hearts from transgenic mice compared to those in wild-type. We conclude that overexpression of SUR2A generates cardiac phenotype resistant to hypoxia/ischemia/reperfusion injury due at least in part to increase in levels of sarcolemmal K ATP channels. KeywordsSUR2A; K ATP channel; cardioprotection; hypoxia; heart Throughout a lifetime, the heart is subjected to a variety of metabolic stresses, including ischemia/hypoxia. Work carried out over the last 15 years has demonstrated that powerful cardioprotective signaling pathways exist in cardiomyocytes that, when activated, enable cardiac cells to function under adverse conditions (1,2).Sarcolemmal ATP-sensitive K + (K ATP ) channels, ion channels that couple metabolic status of the cell with membrane excitability (3), have been implicated in cardioprotective signaling (4,5). These channels are selectively permeable to K + ions and are closed by high intracellular ATP levels (3). It has been suggested that the opening of K ATP channels protects against myocardial infarction, mediates ischemic preconditioning (a phenomenon when brief periods of ischemia/reperfusion protect the heart against sustained ischemia, 2), and promotes survival of cardiomyocytes exposed to different kinds of metabolic stresses (4,5). Conditions associated 1Correspondence: Maternal and Child Health Sciences, Ninewells Hospital & Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK. E-mail: a.jovanović@dundee.ac.uk. UKPMC Funders GroupAuthor Manuscript UKPMC Funders Group Author Manuscript UKPMC Funders Group Author Manuscriptwith an increase in expression of sarcolemmal K ATP channels, such as estrogen treatment and chronic hypoxia, are associated with increased cardiac resistance to stress (6-8). Also, ischemic preconditioning seems to be mediated by recruitment and an increase in number ...

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Section: Introductionmentioning

confidence: 99%

Overexpression of SUR2A generates a cardiac phenotype resistant to ischemia

et al. 2006

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“…These results are in agreement with the widely accepted "dormant" nature of the sarcK ATP channel under conditions of metabolic abundance. Indeed, various studies using Kir6.2 knockout mice found that the phenotypic differences between the knockout and wild-type mice become apparent only when the mice are exposed to a certain type of stress (exercise, hypertension, ischemia-reperfusion) (25).…”

Section: Discussionmentioning

confidence: 99%

Role of sarcolemmal ATP-sensitive potassium channel in oxidative stress-induced apoptosis: mitochondrial connection

Marinović

Ljubković²,

Stadnicka³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Marinovic J, Ljubkovic M, Stadnicka A, Bosnjak ZJ, Bienengraeber M. Role of sarcolemmal ATP-sensitive potassium channel in oxidative stress-induced apoptosis: mitochondrial connection. Am J Physiol Heart Circ Physiol 294: H1317-H1325, 2008. First published January 11, 2008 doi:10.1152/ajpheart.00840.2007.-From time of their discovery, sarcolemmal ATP-sensitive K ϩ (sarcKATP) channels were thought to have an important protective role in the heart during stress whereby channel opening protects the heart from stress-induced Ca 2ϩ overload and resulting damage. In contrast, some recent studies indicate that sarcKATP channel closing can lead to cardiac protection. Also, the role of the sarcKATP channel in apoptotic cell death is unclear. In the present study, the effects of channel inhibition on apoptosis and the specific interaction between the sarcKATP channel and mitochondria were investigated. Apoptotic cell death of cultured HL-1 and neonatal cardiomyocytes following exposure to oxidative stress was significantly increased in the presence of sarcKATP channel inhibitor HMR-1098 as evidenced by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and caspase-3,7 assays. This was paralleled by an increased release of cytochrome c from mitochondria to cytosol, suggesting activation of the mitochondrial death pathway. sarcKATP channel inhibition during stress had no effect on Bcl-2, Bad, and phospho-Bad, indicating that the increase in apoptosis cannot be attributed to these modulators of the apoptotic pathway. However, monitoring of mitochondrial Ca 2ϩ with rhod-2 fluorescent indicator revealed that mitochondrial Ca 2ϩ accumulation during stress is potentiated in the presence of HMR-1098. In conclusion, this study provides novel evidence that opening of sarcKATP channels, through a specific Ca 2ϩ -related interaction with mitochondria, plays an important role in preventing cardiomyocyte apoptosis and mitochondrial damage during stress. cardioprotection; mitochondrial calcium; cardiomyocytes THE ATP-SENSITIVE K ϩ (K ATP ) channels, first discovered in the heart more than 20 years ago, represent a unique group of channels that are regulated predominantly by the cellular metabolic state (32). The function of the cardiac sarcolemmal K ATP channel (sarcK ATP ) from early on was associated with cardiac response to stress (32), which was later confirmed by a number of studies. Opening of sarcK ATP channels during metabolic stress affects excitability and other membrane potential-related functions such as Ca 2ϩ loading, thus helping to maintain cellular homeostasis during cardiac challenge (13, 32).The physiological importance of the cardiac sarcK ATP channel became more apparent after generation of an animal model that lacks the sarcK ATP channel, the Kir6.2 knockout mouse (39). The sarcK ATP channel-deficient mice were found to be less tolerant to different types of stress, with resulting abnormal cytosolic Ca 2ϩ handling, susceptibility to developing acute cardiac failure, and sudden cardiac death (24,42...

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“…Our intention here is to comment on recent studies with an emphasis on ABCC8 and not reiterate material covered in recent extensive reviews on the muscle-type K ATP channels [74,92,99,101,134,144].…”

Section: Introductionmentioning

confidence: 99%

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

Bryan

Muñoz

Zhang

et al. 2006

Pflugers Arch - Eur J Physiol

145

113

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The sulfonylurea receptors (SURs) ABCC8/ SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K + selective pores, either K IR 6.1/KCNJ8 or K IR 6.2/ KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K + channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K + (K ATP ) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotidebinding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic β cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K ATP channel activity by a K IR 6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K ATP channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.

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Cardiac K channels in health and disease

Cited by 183 publications

References 74 publications

Overexpression of SUR2A generates a cardiac phenotype resistant to ischemia

Overexpression of SUR2A generates a cardiac phenotype resistant to ischemia

Role of sarcolemmal ATP-sensitive potassium channel in oxidative stress-induced apoptosis: mitochondrial connection

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

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