ATP-sensitive K+ channel in the mitochondrial inner membrane

Inoue, Ituro; Nagase, Hideki; Kishi, Kuki; Higuti, Tomihiko

doi:10.1038/352244a0

Cited by 697 publications

(450 citation statements)

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“…Cardiac adenosine triphosphate-sensitive K + (K ATP ) channels, first identified in the sarcolemma (Noma, 1983), and more recently in the mitochondria (Inoue et al, 1991) are thought to remain closed under physiological conditions. It is well recognised that under certain pathological conditions, such as myocardial ischaemia, however, opening of sarcolemmal K ATP channels may contribute to the shortening of action potential duration (Wilde and Janse, 1994; Wilde, 1997).…”

Section: : Introductionmentioning

confidence: 99%

A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

Workman

Mackenzie

Northover

2001

European Journal of Pharmacology

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Low concentrations of certain K ATP openers have been reported to exert a moderate inhibitory effect on arrhythmias during post-ischaemic early myocardial reperfusion, but the accompanying effects on the time course of changes in action potentials in intact hearts have not yet been studied.We report that, in rat isolated hearts reperfusion following 10 min of regional no-flow ischaemia was associated with both an acute, marked, but transient, shortening of ventricular repolarisation (by 63%) during reperfusion, and a high incidence (90%) of ventricular tachyarrhythmias. The K ATP opener Ro 31-6930 [2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine 1-oxide] delivered prior to ischaemia at a relatively low concentration (0.5 µM), significantly reduced the incidence and duration of reperfusion arrhythmias, and prevented the associated acute action potential shortening during reperfusion, each in a glibenclamide (1 µM)-sensitive manner (P<0.05, n=10-15 hearts). This was associated with a moderate, and non-arrhythmogenic, action potential shortening during ischaemia (a potentially "cardioprotective" effect). However, these data highlight the potential harm these drugs may cause, since a higher concentration of Ro 31-6930 caused marked shortening of action potentials and significant pro-arrhythmia during ischaemia. KeywordsATP-sensitive potassium channel; Reperfusion; Isolated heart; Action potential; Ventricular arrhythmias. 1: IntroductionCardiac adenosine triphosphate-sensitive K + (K ATP ) channels, first identified in the sarcolemma (Noma, 1983), and more recently in the mitochondria (Inoue et al., 1991) are thought to remain closed under physiological conditions. It is well recognised that under certain pathological conditions, such as myocardial ischaemia, however, opening of sarcolemmal K ATP channels may contribute to the shortening of action potential duration (Wilde and Janse, 1994; Wilde, 1997). We recently reported (Workman et al., 2000) that in the rat isolated heart, ischaemia in the presence (but not the absence) of pharmacological K ATP activation, caused action potential shortening of a sufficient degree to cause ventricular tachyarrhythmias.It is also recognised that K ATP activation-induced action potential shortening, under certain conditions may help to protect the myocardium from the injury caused by excessive Ca 2+ influx and ATP consumption [see (Grover and Garlid, 2000) for recent review]. Several studies have highlighted the protective effects on the myocardium of pharmacological K ATP activation. In many cases such protection was demonstrated during post-ischaemic reperfusion. For example, K ATP openers have been shown, during reperfusion, to improve recovery of contractile function (Docherty et al., 1997), to restrain the rise in the intracellular Ca 2+ concentration, [Ca 2+ ] i (Behling and Malone, 1995), to enhance the restoration of high energy phosphates (Tanonaka et al., 1999), as well as limiting the extent of myocardial infarction after reperfusion (Grover et al., 1...

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Section: : Introductionmentioning

confidence: 99%

A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

Workman

Mackenzie

Northover

2001

European Journal of Pharmacology

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“…1 Although these channels would normally be closed in cardiac myocytes, during myocardial ischemia, where the cellular ATP:ADP ratio falls substantially, activation of K ATP channels could contribute to cardioprotective mechanisms. 2,3 Functional K ATP channel currents have been demonstrated in both cardiac sarcolemmal 4 (sarcK ATP ) and mitochondrial (mitoK ATP ) membranes 5 . The mitoK ATP channel is much more sensitive to the potassium channel opener, diazoxide, and the K ATP channel antagonist, 5-hydroxydecanoate (5-HD) compared to the sarcK ATP channel, which is more sensitive to the blocker HMR1098.…”

Section: Introductionmentioning

confidence: 99%

Distribution of Kir6.0 and SUR2 ATP-sensitive potassium channel subunits in isolated ventricular myocytes

Singh¹

2003

Journal of Molecular and Cellular Cardiology

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The subcellular distribution of K ATP channel subunits in rat isolated ventricular myocytes was investigated using a panel of subunit specific antisera. Kir6.1 subunits were associated predominantly with myofibril structures and were co-localized with the mitochondrial marker MitoTracker red (correlation coefficient (cc) = 0.63 ± 0.05 ).Anti-Kir6.1 antibodies specifically recognized a polypeptide of 48 kDa in mitochondrial membrane fractions consistent with the presence of Kir6.1 subunits in this organelle.Both Kir6.2 and SUR2A subunits were distributed universally over the sarcolemma.Lower intensity antibody associated immunofluorescence was detected intracellularly, which was correlated with the distribution of MitoTracker red in both cases (cc, Kir6.2, 0.56 ± 0.05; SUR2A, 0.61 ± 0.06). A polypeptide of 40 kDa was recognized by antiKir6.2 subunit antibodies in Western blots of both microsomal and mitochondrial membrane fractions consistent with the presence of this subunit in the sarcolemma and mitochondria. Similarly, SUR2A and SUR2B subunits were detected in Western blots of microsomal membrane proteins consistent with a sarcolemmal localization for these polypeptides. SUR2B subunits were shown in confocal microscopy to co-localize strongly with t-tubules (cc, 0.81 ± 0.05). Together the results indicate that Kir6.2 and SUR2A subunits predominate in the sarcolemma of ventricular myocytes consistent with a Kir6.2/SUR2A subunit combination in the sarcolemmal K ATP (sarcK ATP ) channel.Kir6.1, Kir6.2 and SUR2A subunits were demonstrated in mitochondria. Combinations of these subunits would not explain the reported pharmacology of the mitochondrial K ATP (mitoK ATP ) channel (Lui et al. 2001. Mol. Pharmacol. 59:225-230) suggesting the possibility of further unidentified components of this channel.3

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“…Kir6.2 was cloned from a human genomic library and shares 96% amino acid identity with mouse and rat Kir6.2 [30] . Kir6.1 genes (KCNJ8) are mainly expressed in the mito chondria [12,31,32] . Two SUR subunits, SUR1 and SUR2, have been identified as the regulatory subunits of K ATP channels [33] .…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Sun

Feng

2012

Acta Pharmacol Sin

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ATP-sensitive potassium (K ATP ) channels are weak, inward rectifiers that couple metabolic status to cell membrane electrical activity, thus modulating many cellular functions. An increase in the ADP/ATP ratio opens K ATP channels, leading to membrane hyperpolarization. K ATP channels are ubiquitously expressed in neurons located in different regions of the brain, including the hippocampus and cortex. Brief hypoxia triggers membrane hyperpolarization in these central neurons. In vivo animal studies confirmed that knocking out the Kir6.2 subunit of the K ATP channels increases ischemic infarction, and overexpression of the Kir6.2 subunit reduces neuronal injury from ischemic insults. These findings provide the basis for a practical strategy whereby activation of endogenous K ATP channels reduces cellular damage resulting from cerebral ischemic stroke. K ATP channel modulators may prove to be clinically useful as part of a combination therapy for stroke management in the future.

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ATP-sensitive K+ channel in the mitochondrial inner membrane

Cited by 697 publications

References 20 publications

A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

Distribution of Kir6.0 and SUR2 ATP-sensitive potassium channel subunits in isolated ventricular myocytes

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

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