Targeting mitochondrial ATP-sensitive potassium channels—a novel approach to neuroprotection

Busija, David W.; Lacza, Zsombor; Rajapakse, Nishadi; Shimizu, Katsuyoshi; Kis, Béla; Bari, Ferenc; Domoki, Ferenc; Horiguchi, Takashi

doi:10.1016/j.brainresrev.2004.06.011

Cited by 123 publications

(108 citation statements)

References 79 publications

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“…Acta Pharmacologica Sinica npg K ATP channels in dorsal root ganglia (DRG) neurons may involve nociception and neuropathic pain K ATP channels are also expressed in DRG neurons [104,105] . The subunits Kir6.2, SUR1 and SUR2, but not Kir6.1, are identified in the DRG neurons using immunohistochemistry and electrophysiology [104,105] .…”

Section: Wwwchinapharcom Sun Hs Et Almentioning

confidence: 99%

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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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Section: Wwwchinapharcom Sun Hs Et Almentioning

confidence: 99%

“…The subunits Kir6.2, SUR1 and SUR2, but not Kir6.1, are identified in the DRG neurons using immunohistochemistry and electrophysiology [104,105] . The neuronal injury in axotomy decreases the K ATP channel current in the primary afferent neurons in the DRG, which is mediated by CaMKII [106] .…”

Section: Wwwchinapharcom Sun Hs Et Almentioning

confidence: 99%

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Sun

Feng

2012

Acta Pharmacol Sin

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“…In the present study, we used the inhibitor apocynin, which has been demonstrated to prevent traslocation of p47 and p67 subunits from the cytoplasm to membrane, and to prevent the assembly of NADPH oxidase (Stolk et al, 1994). KATP channels occur in various parts of cells, including the surface of the plasmalemmal membrane (pKATP) and the inner mitochondrial membrane (mitoKATP) channels (Busija et al, 2004). MitoKATP channels open up in response to partial complex I inhibition and in response to increased OS/ROS (Liss et al, 1999;Avshalumov et al, 2005), and mito-KATP opening increases generation of ROS by mitochondria (Obata and Yamanaka, 2000;Costa and Garlid, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…MitoKATP channels open up in response to partial complex I inhibition and in response to increased OS/ROS (Liss et al, 1999;Avshalumov et al, 2005), and mito-KATP opening increases generation of ROS by mitochondria (Obata and Yamanaka, 2000;Costa and Garlid, 2008). KATP channels were originally discovered in the heart, although they are particularly abundant in the CNS, and occur at highest levels in the substantia nigra and striatum (Zini et al, 1993;Busija et al, 2004). The structure of the pKATP channels has been studied extensively, and consists of multimeric proteins composed of inwardly rectifying-poreforming Kir6.x (Kir6.1/Kir6.2) and regulatorysulfonylurea receptor subunits (SUR1/ SUR/2).…”

Section: Discussionmentioning

confidence: 99%

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Effect of inhibitors of NADPH oxidase complex and mitochondrial ATP‐sensitive potassium channels on generation of dopaminergic neurons from neurospheres of mesencephalic precursors

Rodríguez‐Pallares

Joglar

Díaz-Ruiz

et al. 2010

Developmental Dynamics

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Reactive oxygen species signaling has been suggested to regulate stem cell development. In the present study, we treated neurospheres of rat mesencephalic precursors with inhibitors of the NADPH oxidase complex and mitochondrial ATP-sensitive potassium (mitoKATP) channel blockers during the proliferation and/or the differentiation periods to study the effects on generation of dopaminergic neurons. Treatment with low doses (100 or 250 mM) of the NADPH inhibitor apocynin during the proliferation period increased the generation of dopaminergic neurons. However, higher doses (1 mM) were necessary during the differentiation period to induce the same effect. Treatment with general (glibenclamide) or mitochondrial (5-hydroxydecanoate) KATP channel blockers during the proliferation and differentiation periods increased the number of dopaminergic neurons. Furthermore, neither increased proliferation rate nor apoptosis had a major role in the observed increase in generation of dopaminergic neurons, which suggests that the redox state is able to regulate differentiation of precursors into dopaminergic neurons. Developmental Dynamics 239:3247-3259,

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Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

Busija

Rutkai

Dutta

et al. 2016

Comprehensive Physiology

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Mitochondria not only produce energy in the form of ATP to support the activities of cells comprising the neurovascular unit, but mitochondrial events, such as depolarization and/or ROS release, also initiate signaling events which protect the endothelium and neurons against lethal stresses via pre-/postconditioning as well as promote changes in cerebral vascular tone. Mitochondrial depolarization in vascular smooth muscle (VSM), via pharmacological activation of the ATP-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels), leads to vasorelaxation through generation of calcium sparks by the sarcoplasmic reticulum and subsequent downstream signaling mechanisms. Increased release of ROS by mitochondria has similar effects. Relaxation of VSM can also be indirectly achieved via actions of nitric oxide (NO) and other vasoactive agents produced by endothelium, perivascular and parenchymal nerves, and astroglia following mitochondrial activation. Additionally, NO production following mitochondrial activation is involved in neuronal preconditioning. Cerebral arteries from female rats have greater mitochondrial mass and respiration and enhanced cerebral arterial dilation to mitochondrial activators. Preexisting chronic conditions such as insulin resistance and/or diabetes impair mitoKATP channel relaxation of cerebral arteries and preconditioning. Surprisingly, mitoKATP channel function after transient ischemia appears to be retained in the endothelium of large cerebral arteries despite generalized cerebral vascular dysfunction. Thus, mitochondrial mechanisms may represent the elusive signaling link between metabolic rate and blood flow as well as mediators of vascular change according to physiological status. Mitochondrial mechanisms are an important, but underutilized target for improving vascular function and decreasing brain injury in stroke patients. © 2016 American Physiological Society. Compr Physiol 6:1529-1548, 2016.

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Targeting mitochondrial ATP-sensitive potassium channels—a novel approach to neuroprotection

Cited by 123 publications

References 79 publications

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Effect of inhibitors of NADPH oxidase complex and mitochondrial ATP‐sensitive potassium channels on generation of dopaminergic neurons from neurospheres of mesencephalic precursors

Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

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