Ukr.Biochem.J. 2020; Volume 92, Issue 5, Sep-Oct, pp. 5-14


ATP-sensitive potassium transport in rat brain mitochondria is highly sensitive to mK(ATP) channels openers: a light scattering study

O. V. Akopova*, L. I. Kolchinskaya, V. I. Nosar,
A. N. Smirnov, L. V. Bratus

Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv;

Received: 17 January 2020; Accepted: 25 June 2020

The aspects of ATP-sensitive K+ transport regulation by mitochondrial K+,ATP-sensitive (mKATP) channels openers are important for understanding the properties of these channels. The effect of KATP channels openers (KCOs) diazoxide and pinacidil on ATP-sensitive K+ transport in isolated brain mitochondria was studied in the absence and the presence of MgATP using light scattering technique. Without MgATP we observed high sensitivity of ATP-sensitive K+ transport to both drugs with full activation at ≤ 0.5 µM. ATP-sensitive K+ transport was specifically blocked by ATP in the presence of Mg2+. Neither Mg2+ nor ATP affected Vmax of ATP-sensitive K+ transport activated by KCOs, but MgATP shifted the activation curve to micromolar scale. The blockage of ATP-sensitive K+ transport by KATP channels blockers glibenclamide and 5-hydroxydecanoate in the absence and the presence of MgATP proved the sensitivity of ATP-sensitive K+ transport to the blockers of mKATP channel. Full activation of mKATP channel by diazoxide and pinacidil on sub-micromolar scale in the absence of MgATP was shown. The sensitivity of ATP-sensitive K+ transport to the known modulators of mKATP channel (diazoxide, pinacidil, glibenclamide, 5-HD and MgATP) proved the identity of ATP-sensitive K+ transport with mKATP channel activity. Based on our studies, we hypothesized that mKATP channel might comprise high affinity sites for KCOs binding screened by MgATP. The results of this work reveal novel not described earlier aspects of the regulation of ATP-sensitive K+ transport by mKATP channels openers, important for understanding of mKATP channel properties.

Keywords: , , , ,


  1.  Garlid KD, Costa ADT, Quinlan CL, Pierre SV, Dos Santos P. Cardioprotective signaling to mitochondria. J Mol Cell Cardiol. 2009;46(6):858-866. PubMedPubMed, CrossRef
  2. Correia SC, Cardoso S, Santos RX, Carvalho C, Santos MS, Perry G, Smith MA, Moreira PI. New insights into the mechanisms of mitochondrial preconditioning-triggered neuroprotection. Curr Pharm Des. 2011;17(31):3381-3389.  PubMed, CrossRef
  3. Salgado-Puga K, Rodríguez-Colorado J, Prado-Alcalá RA, Peña-Ortega F. Subclinical Doses of ATP-Sensitive Potassium Channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β. J Alzheimers Dis. 2017;57(1):205-226. PubMed, CrossRef
  4. Busija DW, Gaspar T, Domoki F, Katakam PV, Bari F. Mitochondrial-mediated suppression of ROS production upon exposure of neurons to lethal stress: mitochondrial targeted preconditioning. Adv Drug Deliv Rev. 2008;60(13-14):1471-1477. PubMed, PubMedCentral, CrossRef
  5. Abe E, Fujiki M, Nagai Y, Shiqi K, Kubo T, Ishii K, Abe T, Kobayashi H.  The phosphatidylinositol-3 kinase/Akt pathway mediates geranylgeranylacetone-induced neuroprotection against cerebral infarction in rats. Brain Res. 2010;1330:151-157. PubMed, CrossRef
  6. Zhang F, Cui J , Lv B, Yu B. Nicorandil protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis. Int J Mol Med. 2015;36(2):415-423. PubMed, PubMedCentral, CrossRef
  7. Laskowski M , Augustynek B, Kulawiak B, Koprowski P, Bednarczyk P, Jarmuszkiewicz W, Szewczyk A. What do we not know about mitochondrial potassium channels? Biochim Biophys Acta. 2016;1857(8):1247-1257. PubMed, CrossRef DOI: 10.1016/j.bbabio.2016.03.007
  8. Ye Z, Guo Q, Wang N, Xia P, Yuan Y, Wang E. Delayed neuroprotection induced by sevoflurane via opening mitochondrial ATP-sensitive potassium channels and p38 MAPK phosphorylation. Neurol Sci. 2012;33(2):239-249. PubMed, CrossRef
  9. Garlid  KD, Paucek P, Yarov-Yarovoy V, Sun X, Schindler PA. The mitochondrial KATP channel as a receptor for potassium channel openers. J Biol Chem. 1996;271(15):8796-8799. PubMed, CrossRef
  10. Jabůrek M, Yarov-Yarovoy V, Paucek P, Garlid KD. State-dependent inhibition of the mitochondrial KATP channel by glyburide and 5-hydroxydecanoate. J Biol Chem. 1998;273(22):13578-13582.  PubMed
  11. Holmuhamedov EL, Jovanović S, Dzeja PP, Jovanović A, Terzic A. Mitochondrial ATP-sensitive K+ channels modulate cardiac mitochondrial function. Am J Physiol. 1998;275(5):H1567-H1576. PubMed, CrossRef
  12. Riess ML , Camara AKS, Heinen A, Eells JT, Henry MM, Stowe DF. KATP channel openers have opposite effects on mitochondrial respiration under different energetic conditions. J Cardiovasc Pharmacol. 2008;51(5):483-491. PubMed, PubMedCentral, CrossRef
  13. Kopustinskiene DM, Liobikas J, Skemiene K, Malinauskas F, Toleikis A. Direct effects of K(ATP) channel openers pinacidil and diazoxide on oxidative phosphorylation of mitochondria in situ. Cell Physiol Biochem. 2010;25(2-3):181-186. PubMed, CrossRef
  14. Garlid KD, Paucek P. Mitochondrial potassium transport: the K(+) cycle. Biochim Biophys Acta. 2003;1606(1-3):23-41. PubMed, CrossRef
  15. Akopova OV, Nosar VI, Bouryi VA, Mankovskaya IN, Sagach VF.  Influence of ATP-dependent K(+)-channel opener on K(+)-cycle and oxygen consumption in rat liver mitochondria. Biochemistry (Mosc). 2010;75(9):1139-1147. PubMed, CrossRef
  16. 16. Gelband CH, Ishikawa T, Post JM, Keef KD, Hume JR. Intracellular divalent cations block smooth muscle K+ channels. Circ Res. 1993;73(1):24-34.
    PubMed, CrossRef
  17. Beavis AD. Upper and lower limits of the charge translocation stoichiometry of mitochondrial electron transport. J Biol Chem. 1987;262(13):6165-6173.  PubMed
  18. Mironova GD, Negoda AE, Marinov BS, Paucek P, Costa ADT, Grigoriev SM, Skarga YuYu, Garlid KD. Functional distinctions between the mitochondrial ATP-dependent K+ channel (mitoKATP) and its inward rectifier subunit (mitoKIR). J Biol Chem. 2004;279(31):32562-32568. PubMed, CrossRef
  19. Wojtovich AP, Urciuoli WR, Chatterjee S, Fisher AB, Nehrke K, Brookes PS. Kir6.2 is not the mitochondrial KATP channel but is required for cardioprotection by ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2013;304(11):H1439-H1445. PubMed, PubMedCentral, CrossRef
  20. Henn MC, Janjua MB, Kanter EM, Makepeace CM, Schuessler RB, Nichols CG, Lawton JS. Adenosine Triphosphate-Sensitive Potassium Channel Kir Subunits Implicated in Cardioprotection by Diazoxide. J Am Heart Assoc. 2015;4(8):e002016. PubMed, PubMedCentral, CrossRef
  21. Paggio A, Checchetto V, Campo A, Menabò R, Di Marco G, Di Lisa  F, Szabo I, Rizzuto R, De Stefani D. Identification of an ATP-sensitive potassium channel in mitochondria. Nature. 2019;572(7771):609-613. PubMed, PubMedCentral, CrossRef
  22. Foster DB, Ho AS, Rucker J, Garlid AO, Chen L, Sidor A, Garlid KD, O’Rourke B. Mitochondrial ROMK channel is a molecular component of mitoK(ATP). Circ Res. 2012;111(4):446-454. PubMed, PubMedCentral, CrossRef
  23. Laskowski M, Augustynek B,  Bednarczyk P,  Żochowska M, Kalisz J,  O’Rourke B,  Szewczyk A, Kulawiak B. Single-Channel Properties of the ROMK-Pore-Forming Subunit of the Mitochondrial ATP-Sensitive Potassium Channel. Int J Mol Sci. 2019;20(21):5323. PubMed, PubMedCentral, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.