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Impairment of Brain Mitochondrial Charybdotoxin- and ATP-Insensitive BK Channel Activities in Diabetes

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Abstract

Existing evidence indicates an impairment of mitochondrial functions and alterations in potassium channel activities in diabetes. Because mitochondrial potassium channels have been involved in several mitochondrial functions including cytoprotection, apoptosis and calcium homeostasis, a study was carried out to consider whether the gating behavior of the mitochondrial ATP- and ChTx-insensitive Ca2+-activated potassium channel (mitoBKCa) is altered in a streptozotocin (STZ) model of diabetes. Using ion channel incorporation of brain mitochondrial inner membrane into the bilayer lipid membrane, we provide in this work evidence for modifications of the mitoBKCa ion permeation properties with channels from vesicles preparations coming from diabetic rats characterized by a significant decrease in conductance. More importantly, the open probability of channels from diabetic rats was reduced 1.5–2.5 fold compared to control, the most significant decrease being observed at depolarizing potentials. Because BKCa β4 subunit has been documented to left shift the BKCa channel voltage dependence curve in high Ca2+ conditions, a Western blot analysis was undertaken where the expression of mitoBKCa α and β4 subunits was estimated using of anti-α and β4 subunit antibodies. Our results indicated a significant decrease in mitoBKCa β4 subunit expression coupled to a decrease in the expression of α subunit, an observation compatible with the observed decrease in Ca2+ sensitivity. Our results thus demonstrate a modification in the mitoBKCa channel gating properties in membrane preparations coming from STZ model of diabetic rats, an effect potentially linked to a change in mitoBKCa β4 and α subunits expression and/or to an increase in reactive oxygen species production in high glucose conditions.

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References

  • Ashley, R. H. (1995). Ion channels, a practical approach. In A. J. Williams (Ed.), The measurement of the function of ion channels reconstituted into artificial membranes (pp. 55–57). Oxford: IRL Press.

    Google Scholar 

  • Bednarczyk, P. (2009). Potassium channels in brain mitochondria. Acta Biochimica Polonica, 56(3), 385–392.

    CAS  PubMed  Google Scholar 

  • Brenner, R., Chen, Q. H., Vilaythong, A., Toney, G. M., Noebels, J. L., & Aldrich, R. W. (2005). BK channel beta4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Nature Neuroscience, 8(12), 1752–1759.

    Article  CAS  PubMed  Google Scholar 

  • Cardoso, A. R., Queliconi, B. B., & Kowaltowski, A. J. (2010). Mitochondrial ion transport pathways: Role in metabolic diseases. Biochimica et Biophysica Acta, 1797(6–7), 832–838.

    Article  CAS  PubMed  Google Scholar 

  • Da Cruz, S., Xenarios, I., Langridge, J., Vilbois, F., Parone, P. A., & Martinou, J. C. (2003). Proteomic analysis of the mouse liver mitochondrial inner membrane. Journal of Biological Chemistry, 278(42), 41566–41571.

    Article  PubMed  Google Scholar 

  • Douglas, R. M., Lai, J. C., Bian, S., Cummins, L., Moczydlowski, E., & Haddad, G. G. (2006). The calcium-sensitive large-conductance potassium channel (BK/MAXI K) is present in the inner mitochondrial membrane of rat brain. Neuroscience, 139(4), 1249–1261.

    Article  CAS  PubMed  Google Scholar 

  • Fahanik-Babaei, J., Eliassi, A., Jafari, A., Sauve, R., Salari, S., & Saghiri, R. (2011a). Electro-pharmacological profile of a mitochondrial inner membrane big-potassium channel from rat brain. Biochimica et Biophysica Acta, 1808(1), 454–460.

    Article  CAS  PubMed  Google Scholar 

  • Fahanik-Babaei, J., Eliassi, A., & Saghiri, R. (2011b). How many types of large conductance Ca+2-activated potassium channels exist in brain mitochondrial inner membrane: evidence for a new mitochondrial large conductance Ca2+-activated potassium channel in brain mitochondria. Neuroscience, 199, 125–132.

    Article  CAS  PubMed  Google Scholar 

  • Gustafsson, A. B., & Gottlieb, R. A. (2008). Heart mitochondria: Gates of life and death. Cardiovascular Research, 77(2), 334–343.

    Article  CAS  PubMed  Google Scholar 

  • Heller, A., Brockhoff, G., & Goepferich, A. (2012). Targeting drugs to mitochondria. European Journal of Pharmaceutics and Biopharmaceutics, 82(1), 1–18.

    Article  CAS  PubMed  Google Scholar 

  • Islam, M. S., & Choi, H. (2007). Nongenetic model of type 2 diabetes: A comparative study. Pharmacology, 79(4), 243–249.

    Article  CAS  PubMed  Google Scholar 

  • Joseph, A. M., Joanisse, D. R., Baillot, R. G., Hood, D. A. (2012). Mitochondrial dysregulation in the pathogenesis of diabetes: Potential for mitochondrial biogenesis-mediated interventions. Experimental Diabetes Research, (642038).

  • Kohro, S., Hogan, Q. H., Nakae, Y., Yamakage, M., & Bosnjak, Z. J. (2001). Anesthetic effects on mitochondrial ATP-sensitive K channel. Anesthesiology, 95(6), 1435–1440.

    Article  CAS  PubMed  Google Scholar 

  • Kulawiak, B., Kudin, A. P., Szewczyk, A., & Kunz, W. S. (2008). BK channel openers inhibit ROS production of isolated rat brain mitochondria. Experimental Neurology, 212(2), 543–547.

    Article  CAS  PubMed  Google Scholar 

  • Latorre, R., Morera, F. J., & Zaelzer, C. (2010). Allosteric interactions and the modular nature of the voltage- and Ca2+-activated (BK) channel. The Journal of Physiology, 588(Pt 17), 3141–3148.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li, S., Deng, Z., Wei, L., Liang, L., Ai, W., Shou, X., et al. (2011). Reduction of large-conductance Ca2+ activated K+ channel with compensatory increase of nitric oxide in insulin resistant rats. Diabetes/Metabolism Research and Reviews, 27(5), 461–469.

    Article  CAS  PubMed  Google Scholar 

  • Lu, T., He, T., Katusic, Z. S., & Lee, H. C. (2006). Molecular mechanisms mediating inhibition of human large conductance Ca2+-activated K+ channels by high glucose. Circulation Research, 99(6), 607–616.

    Article  CAS  PubMed  Google Scholar 

  • Lu, T., Ye, D., He, T., Wang, X. L., Wang, H. L., & Lee, H. C. (2008). Impaired Ca2+-dependent activation of large-conductance Ca2+-activated K+ channels in the coronary artery smooth muscle cells of Zucker Diabetic Fatty rats. Biophysical Journal, 95(11), 5165–5177.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maechler, P., Carobbio, S., & Rubi, B. (2006). In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion. The International Journal of Biochemistry & Cell Biology, 38(5–6), 696–709.

    Article  CAS  Google Scholar 

  • McGahon, M. K., Dash, D. P., Arora, A., Wall, N., Dawicki, J., Simpson, D. A., et al. (2007). Diabetes downregulates large-conductance Ca2+-activated potassium beta 1 channel subunit in retinal arteriolar smooth muscle. Circulation Research, 100(5), 703–711.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Meera, P., Wallner, M., & Toro, L. (2000). A neuronal beta subunit (KCNMB4) makes the large conductance, voltage- and Ca2+-activated K+ channel resistant to charybdotoxin and iberiotoxin. Proceedings of the National Academy of Sciences of the United States of America, 97(10), 5562–5567.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Morino, K., Petersen, K. F., Dufour, S., Befroy, D., Frattini, J., Shatzkes, N., et al. (2005). Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. Journal of Clinical Investigation, 115(12), 3587–3593.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Piwonska, M., Wilczek, E., Szewczyk, A., & Wilczynski, G. M. (2008). Differential distribution of Ca2+-activated potassium channel beta4 subunit in rat brain: Immunolocalization in neuronal mitochondria. Neuroscience, 153(2), 446–460.

    Article  CAS  PubMed  Google Scholar 

  • Qian, X., Niu, X., & Magleby, K. L. (2006). Intra- and intersubunit cooperativity in activation of BK channels by Ca2+. The Journal of General Physiology, 128(4), 389–404.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rieusset, J. (2011). Mitochondria and endoplasmic reticulum: Mitochondria-endoplasmic reticulum interplay in type 2 diabetes pathophysiology. International Journal of Biochemistry & Cell Biology, 43(9), 1257–1262.

    Article  CAS  Google Scholar 

  • Rosenthal, R. E., Hamud, F., Fiskum, G., Varghese, P. J., & Sharpe, S. (1987). Cerebral ischemia and reperfusion: Prevention of brain mitochondrial injury by lidoflazine. Journal of Cerebral Blood Flow and Metabolism, 7(6), 752–758.

    Article  CAS  PubMed  Google Scholar 

  • Shruti, S., Urban-Ciecko, J., Fitzpatrick, J. A., Brenner, R., Bruchez, M. P., & Barth, A. L. (2012). The brain-specific Beta4 subunit downregulates BK channel cell surface expression. PLoS One, 7(3), e33429.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Siemen, D., Loupatatzis, C., Borecky, J., Gulbins, E., & Lang, F. (1999). Ca2+-activated K channel of the BK-type in the inner mitochondrial membrane of a human glioma cell line. Biochemical and Biophysical Research Communications, 257(2), 549–554.

    Article  CAS  PubMed  Google Scholar 

  • Singleton, W. S., Gray, M. S., Brown, M. L., & White, J. L. (1965). Chromatographically homogeneous lecithin from egg phospholipids. Journal of the American Oil Chemists’ Society, 42, 53–56.

    Article  CAS  PubMed  Google Scholar 

  • Skalska, J., Bednarczyk, P., Piwonska, M., Kulawiak, B., Wilczynski, G., Dolowy, K., et al. (2009). Calcium ions regulate K+ uptake into brain mitochondria: The evidence for a novel potassium channel. International Journal of Molecular Sciences, 10(3), 1104–1120.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stowe, D. F., Aldakkak, M., Camara, A. K., Riess, M. L., Heinen, A., Varadarajan, S. G., et al. (2006). Cardiac mitochondrial preconditioning by big Ca2+-sensitive K+ channel opening requires superoxide radical generation. American Journal of Physiology Heart and Circulatory Physiology, 290(1), H434–H440.

    Article  CAS  PubMed  Google Scholar 

  • Szabo, I., Leanza, L., Gulbins, E., & Zoratti, M. (2012). Physiology of potassium channels in the inner membrane of mitochondria. Pflugers Archiv, 463(2), 231–246.

    Article  CAS  PubMed  Google Scholar 

  • Szabo, I., & Zoratti, M. (2014). Mitochondrial channels: Ion fluxes and more. Physiological Reviews, 94(2), 519–608.

    Article  CAS  PubMed  Google Scholar 

  • Wang, B., Rothberg, B. S., & Brenner, R. (2006). Mechanism of beta4 subunit modulation of BK channels. Journal of General Physiology, 127(4), 449–465.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang, R. X., Shi, H. F., Chai, Q., Wu, Y., Sun, W., Ji, Y., et al. (2012). Molecular mechanisms of diabetic coronary dysfunction due to large conductance Ca2+-activated K+ channel impairment. Chinese Medical Journal, 125(14), 2548–2555.

    CAS  PubMed  Google Scholar 

  • Weiger, T. M., Holmqvist, M. H., Levitan, I. B., Clark, F. T., Sprague, S., Huang, W. J., et al. (2000). A novel nervous system beta subunit that downregulates human large conductance calcium-dependent potassium channels. The Journal of neuroscience, 20(10), 3563–3570.

    CAS  PubMed  Google Scholar 

  • Xu, W., Liu, Y., Wang, S., McDonald, T., Van Eyk, J. E., Sidor, A., et al. (2002). Cytoprotective role of Ca2+-activated K+ channels in the cardiac inner mitochondrial membrane. Science, 298(5595), 1029–1033.

    Article  CAS  PubMed  Google Scholar 

  • Zaugg, M., Lucchinetti, E., Spahn, D. R., Pasch, T., & Schaub, M. C. (2002). Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial K(ATP) channels via multiple signaling pathways. Anesthesiology, 97(1), 4–14.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the Neuroscience Research Center of Shahid Beheshti University of Medical Sciences. We thank Dr. F. Khodagholi and Dr. M. Hedayati for their assistance.

Conflict of interest

The authors confirm that there is no conflict of interest.

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Authors and Affiliations

  1. Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    E. Noursadeghi & A. Eliassi

  2. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    E. Noursadeghi

  3. Department of Physiology, Medical School, Guilan University of Medical Sciences, Rasht, Iran

    A. Jafari

  4. Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran

    R. Saghiri

  5. Membrane Protein Research Group, Department of Molecular and Integrative Physiology, Université de Montréal, Montréal, QC, H3C 3J7, Canada

    R. Sauve

  6. Department of Physiology, Medical School, Shahid Beheshti University of Medical Sciences, 1985717443, Evin, Tehran, Iran

    A. Eliassi

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  1. E. Noursadeghi
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  2. A. Jafari
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  3. R. Saghiri
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  4. R. Sauve
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  5. A. Eliassi
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Correspondence to A. Eliassi.

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Noursadeghi, E., Jafari, A., Saghiri, R. et al. Impairment of Brain Mitochondrial Charybdotoxin- and ATP-Insensitive BK Channel Activities in Diabetes. Neuromol Med 16, 862–871 (2014). https://doi.org/10.1007/s12017-014-8334-6

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  • DOI: https://doi.org/10.1007/s12017-014-8334-6

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