Influence of ATP-dependent K+-channel opener on K+-cycle and oxygen consumption in rat liver mitochondria

Акопова, О. В.; Nosar, V. I.; Bouryi, V. A.; Mankovskaya, I. N.; Сагач, В. Ф.

doi:10.1134/s0006297910090075

Cited by 18 publications

(24 citation statements)

References 17 publications

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“…With liver mitochondria, we not only have shown the activation of mK ATP channel by DZ in the absence of Mg·ATP, but observed high sensitivity of the channel to this opener within nanomolar concentration range. Using indirect methods (polarography and light absorbance to monitor the oxygen consumption and mitochondrial volume changes), we have shown full activation of native liver mK ATP channel elicited by ≤500 nM of DZ [55]. Likewise, with the same methods we observed that channel blockage by glibenclamide and 5-HD did not require the presence of Mg·ATP in isolated liver and brain mitochondria [55,56].…”

Section: Mkatp Channels As the Target Of Diazoxidementioning

confidence: 58%

“…Because mitochondrial membrane potential and the uncoupling of the respiratory chain (assessed as RCR ratio) were both dependent on the state 4 oxygen consumption, this allowed us to estimate the share of mK ATP channel in bioenergetic effects of DZ and total potassium transport regardless of the presence of ATP-insensitive component [55,56]. Thus we obtained a reliable appraisal of the share of mK ATP channel in potassium transport and mitochondrial uncoupling by DZ in liver mitochondria [55].…”

Section: Appraisal Of Functional Consequences Of K Atp Channels Openimentioning

confidence: 83%

“…But although in liver mitochondria we obtained a reliable evidence on full mK ATP channel and K+-cycle activation by DZ within nanomolar concentration range, when using DZ without Mg·ATP, another novel non-specific side effect of this drug was observed, i.e., the activation of ATP-insensitive potassium transport in line with ATP-sensitive one [55]. Unlike mK ATP channel, ATP-insensitive potassium transport in our work was suppressed by Mg2+, and could not be restored by DZ.…”

Section: Appraisal Of Functional Consequences Of K Atp Channels Openimentioning

confidence: 95%

“…However, conventional use of Mg·ATP complex for monitoring mK ATP channel opening hinder the direct studies of DZ effect on K+ cycle because of severe suppression of K+/H+ exchanger by Mg2+ ions [68,72]. Indeed, based on our observations as well, Mg2+ and Mg·ATP completely inhibited K +/H+ exchanger, while Mg2+ chelating with EDTA permitted to observe the activation of K+/H+ exchange by DZ in liver mitochondria in the same concentration range where full activation of mK ATP channel was reached (≤500 nM) [55]. So, using combined polarographic and light absorbance studies, in our works we found high sensitivity of liver mK ATP channel to DZ in the absence of Mg·ATP, and developed an approach to the direct study of bioenergetic effects ensuing from the activation of potassium cycle avoiding both off-target effects of high concentrations of this mK ATP channel opener and the suppression of K+-cycle by Mg·ATP.…”

Section: Appraisal Of Functional Consequences Of K Atp Channels Openimentioning

confidence: 98%

“…While the nature of this ATP-insensitive potassium transport remained unclear, for the estimation of bioenergetic effects of mK ATP channel opening in mitochondria (mitochondrial uncoupling, depolarization, suppression of ATP synthesis and ROS production), we applied polarographic approach based on the estimation of a partial share of mK ATP channel in total potassium transport, using stoichiometric ratios between the cation transport and state 4 oxygen consumption. Thus we established partial shares of both ATP-sensitive and ATP-insensitive constituents in potassium transport, and have shown that respiratory stimulation by DZ in liver mitochondria directly ensued from the activation of potassium cycle, eventually resulting in mitochondrial uncoupling [55].…”

Section: Appraisal Of Functional Consequences Of K Atp Channels Openimentioning

confidence: 99%

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Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

Акопова¹

2017

J Drug Metab Toxicol

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Diazoxide (DZ) is a well-known cardioprotective drug capable of mimicking ischemic preconditioning. Being primarily a pharmacological opener of mitochondrial ATP-sensitive potassium channels (mK ATP channels), DZ is known to produce multiple side effects because of its interactions with different cellular targets (such as plasma membrane K ATP channels, F 0 F 1 ATP synthase, succinate dehydrogenase and others), capable of confounding an understanding of direct bioenergetic effects of mK ATP channels opening in mitochondria. In this review direct and offtarget effects of DZ were discussed. The emphasis was made on molecular basis of DZ interaction with K ATP channels and different K ATP channels isoforms sensitivity to this drug. The present knowledge on DZ interaction with mK ATP channels is outlined as well as DZ interactions with other molecular targets affecting mitochondrial functions and bioenergetics. Conclusion was reached that high sensitivity of mK ATP channel to DZ allows for avoiding offtarget effects of this drug in studies on isolated mitochondria, which makes it a useful tool in an appraisal of diverse functional effects of mK ATP channel opening.

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Section: Mkatp Channels As the Target Of Diazoxidementioning

confidence: 58%

Section: Appraisal Of Functional Consequences Of K Atp Channels Openimentioning

confidence: 83%

Section: Appraisal Of Functional Consequences Of K Atp Channels Openimentioning

confidence: 95%

Section: Appraisal Of Functional Consequences Of K Atp Channels Openimentioning

confidence: 98%

Section: Appraisal Of Functional Consequences Of K Atp Channels Openimentioning

confidence: 99%

See 3 more Smart Citations

Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

Акопова¹

2017

J Drug Metab Toxicol

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The effect of atp-dependent potassium uptake on mitochondrial functions under acute hypoxia

Акопова

Nosar

Gavenauskas

et al. 2016

J Bioenerg Biomembr

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The opening of mitochondrial K(+) АТР-channel (mtK(+) АТР-channel) is supposed to be important in the modulation of mitochondrial functions under hypoxia, but the underlying mechanisms have not been clarified yet. The aim of this work was to study the effect of acute hypoxia on mtK(+) АТР-channel activity and to estimate the contribution of the channel in the modulation of mitochondrial functions. MtK(+) АТР-channel activity was assessed polarographically from the rate of State 4 respiration and by potentiometric monitoring of potassium efflux from deenergized mitochondria. It was shown that hypoxia reliably increased mtK(+) АТР-channel activity, which resulted in the changes of respiration rates (increase of State 4 and suppression of State 3 respiration), uncoupling (the decrease of respiratory control ratio) and suppression of phosphorylation. These effects were well mimicked by mtK(+) АТР-channel opener diazoxide (DZ) in isolated rat liver mitochondria. MtK(+) АТР-channel opening in vitro suppressed phosphorylation too, but increased phosphorylation efficiency, while mtK(+) АТР-channel blockers reduced it dramatically. The correlation was established between mtK(+) АТР-channel activity and the endurance of the rats to physical training under hypoxia. Hypoxia improved physical endurance, but treatment by mtK(+) АТР-channel blockers glibenklamide and 5-hydroxydecanoate (5-HD) prior to hypoxia strongly reduced both the channel activity and the endurance limits. This was in accord with the observation that under glibenklamide and 5-HD administration hypoxia failed to restore mtK(+) АТР-channel activity. Based on the experiments, we came to the conclusion that mtK(+) АТР-channel opening played a decisive role in the regulation of energy metabolism under acute hypoxia via the modulation of phosphorylation system in mitochondria.

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Effect of potential-dependent potassium uptake on calcium accumulation in rat brain mitochondria

Акопова

Kolchinskaya

Nosar

et al. 2013

Biochemistry Moscow

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The effect of potential-dependent potassium uptake at 0-120 mM K+ on matrix Ca2+ accumulation in rat brain mitochondria was studied. An increase in oxygen consumption and proton extrusion rates as well as increase in matrix pH with increase in K+ content in the medium was observed due to K+ uptake into the mitochondria. The accumulation of Ca2+ was shown to depend on K+ concentration in the medium. At K+ concentration ≤30 mM, Ca2+ uptake is decreased due to K+-induced membrane depolarization, whereas at higher K+ concentrations, up to 120 mM K+, Ca2+ uptake is increased in spite of membrane depolarization caused by matrix alkalization due to K+ uptake. Mitochondrial K+(ATP)-channel blockers (glibenclamide and 5-hydroxydecanoic acid) diminish K+ uptake as well as K+-induced depolarization and matrix alkalization, which results in attenuation of the potassium-induced effects on matrix Ca2+ uptake, i.e. increase in Ca2+ uptake at low K+ content in the medium due to the smaller membrane depolarization and decrease in Ca2+ uptake at high potassium concentrations because of restricted rise in matrix pH. The results show the importance of potential-dependent potassium uptake, and especially the K+(ATP) channel, in the regulation of calcium accumulation in rat brain mitochondria.

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Influence of ATP-dependent K+-channel opener on K+-cycle and oxygen consumption in rat liver mitochondria

Cited by 18 publications

References 17 publications

Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

The effect of atp-dependent potassium uptake on mitochondrial functions under acute hypoxia

Effect of potential-dependent potassium uptake on calcium accumulation in rat brain mitochondria

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