Expression of cardiac inwardly rectifying potassium channels in pentylenetetrazole kindling model of epilepsy in rats

Enes Akyüz; Pınar Mega Tiber; Merve Beker; Fahri Akbaş

doi:10.14715/cmb/2017.64.15.8

Issue

Vol. 64 No. 15: Issue 15

Issue Published : January 1, 2019

The undersigned hereby assign all rights, included but not limited to copyright, for this manuscript to CMB Association upon its submission for consideration to publication on Cellular and Molecular Biology. The rights assigned include, but are not limited to, the sole and exclusive rights to license, sell, subsequently assign, derive, distribute, display and reproduce this manuscript, in whole or in part, in any format, electronic or otherwise, including those in existence at the time this agreement was signed. The authors hereby warrant that they have not granted or assigned, and shall not grant or assign, the aforementioned rights to any other person, firm, organization, or other entity. All rights are automatically restored to authors if this manuscript is not accepted for publication.

Expression of cardiac inwardly rectifying potassium channels in pentylenetetrazole kindling model of epilepsy in rats

https://doi.org/10.14715/cmb/2017.64.15.8

Enes Akyüz

Yozgat Bozok University, Medical Faculty, Department of Biophysics, Erdoğan Akdağ Yerleşkesi, 66100, Yozgat, Turkey

Pınar Mega Tiber

Marmara University, Medical Faculty, Department of Biophysics, Başıbüyük Mah. Maltepe Başıbüyük Yolu Sok. No:9/1. Maltepe, Istanbul, Turkey

Merve Beker

Bezmialem Vakif University, Medical Faculty, Department of Medical Biology, Adnan Menderes Bulvarı Vatan Caddesi 34093 Fatih, Istanbul, Turkey

Fahri Akbaş

Bezmialem Vakif University, Medical Faculty, Department of Medical Biology, Adnan Menderes Bulvarı Vatan Caddesi 34093 Fatih, Istanbul, Turkey

Corresponding Author(s) : Enes Akyüz

enesakyuz25@gmail.com

Cellular and Molecular Biology, Vol. 64 No. 15: Issue 15
Article Published : December 31, 2018

Abstract

Clinical and experimental studies show that epilepsy affects cardiac function; however, the underlying molecular mechanism has not been fully elucidated. Inwardly-rectifying potassium (Kir) channels transport K+ ions into excitable cells such as neurons and cardiomyocytes; they control the cell excitability by acting towards the repolarization phase of cardiac action potential. Kir channel expression has been previously shown to vary in epileptic brains, at the same time seizures are known to affect the autonomic nervous system. Kir channel expression in cardiac tissue is a possible mechanism for the explanation of cardiac pathology in epilepsy. We investigate the expression of Kir channels in epileptic cardiac tissue by using pentylenetetrazole (PTZ)-kindling model in rats. Our molecular analyses showed significant decrease in cardiac Kir channel mRNA and protein expression of PTZ-kindled rats. Interestingly, both Kir2.x, which directs IK1 flux in ventricular tissue and Kir3.x, which is responsible for IKACh in the atria, were observed to decrease significantly. Kir channel expression also differs between females and males. This is the first study to our knowledge in epileptic cardiac tissue showing the expression of Kir channels. Our results show that Kir channels may play a role in cardiac pathology associated with epilepsy.

Keywords

Epilepsy Kir channels Heart Rats Protein and gene expression.

Akyüz, E., Mega Tiber, P., Beker, M., & Akbaş, F. (2018). Expression of cardiac inwardly rectifying potassium channels in pentylenetetrazole kindling model of epilepsy in rats. Cellular and Molecular Biology, 64(15), 47–54. https://doi.org/10.14715/cmb/2017.64.15.8

Download Citation

References

Ficker, D.M., et al., Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology, 1998. 51(5): p. 1270-4.
Lhatoo, S.D. and J.W. Sander, Sudden unexpected death in epilepsy. Hong Kong Med J, 2002. 8(5): p. 354-8.
Leestma, J.E., Forensic considerations in sudden unexpected death in epilepsy. Epilepsia, 1997. 38(11 Suppl): p. S63-6.
Hesdorffer, D.C., et al., Estimating risk for developing epilepsy: a population-based study in Rochester, Minnesota. Neurology, 2011. 76(1): p. 23-7.
Feely, M., Fortnightly review: drug treatment of epilepsy. BMJ, 1999. 318(7176): p. 106-9.
Laxer, K.D., et al., The consequences of refractory epilepsy and its treatment. Epilepsy Behav, 2014. 37: p. 59-70.
Nei, M., R.T. Ho, and M.R. Sperling, EKG abnormalities during partial seizures in refractory epilepsy. Epilepsia, 2000. 41(5): p. 542-8.
Tomson, T., et al., Heart rate variability in patients with epilepsy. Epilepsy Res, 1998. 30(1): p. 77-83.
Lotufo, P.A., et al., A systematic review and meta-analysis of heart rate variability in epilepsy and antiepileptic drugs. Epilepsia, 2012. 53(2): p. 272-82.
Devinsky, O., Effects of Seizures on Autonomic and Cardiovascular Function. Epilepsy Curr, 2004. 4(2): p. 43-46.
Moseley, B., et al., Autonomic epileptic seizures, autonomic effects of seizures, and SUDEP. Epilepsy Behav, 2013. 26(3): p. 375-85.
Dlouhy, B.J., B.K. Gehlbach, and G.B. Richerson, Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention. J Neurol Neurosurg Psychiatry, 2016. 87(4): p. 402-13.
Hibino, H., et al., Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev, 2010. 90(1): p. 291-366.
Bond, C.T., et al., Cloning and expression of a family of inward rectifier potassium channels. Receptors Channels, 1994. 2(3): p. 183-91.
Villa, C. and R. Combi, Potassium Channels and Human Epileptic Phenotypes: An Updated Overview. Front Cell Neurosci, 2016. 10: p. 81.
Pattnaik, B.R., et al., Genetic defects in the hotspot of inwardly rectifying K(+) (Kir) channels and their metabolic consequences: a review. Mol Genet Metab, 2012. 105(1): p. 64-72.
Anumonwo, J.M. and A.N. Lopatin, Cardiac strong inward rectifier potassium channels. J Mol Cell Cardiol, 2010. 48(1): p. 45-54.
Day, M., et al., Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci, 2005. 25(38): p. 8776-87.
Gonzalez, C., et al., K(+) channels: function-structural overview. Compr Physiol, 2012. 2(3): p. 2087-149.
Brenner, R. and K.S. Wilcox, Potassium Channelopathies of Epilepsy, in Jasper's Basic Mechanisms of the Epilepsies, J.L. Noebels, et al., Editors. 2012: Bethesda (MD).
Gross, G.J. and J.A. Auchampach, Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res, 1992. 70(2): p. 223-33.
D'Adamo, M.C., et al., K(+) channelepsy: progress in the neurobiology of potassium channels and epilepsy. Front Cell Neurosci, 2013. 7: p. 134.
Karschin, C. and A. Karschin, Ontogeny of gene expression of Kir channel subunits in the rat. Mol Cell Neurosci, 1997. 10(3-4): p. 131-48.
D'Avanzo, N., et al., Expression and purification of recombinant human inward rectifier K+ (KCNJ) channels in Saccharomyces cerevisiae. Protein Expr Purif, 2010. 71(1): p. 115-21.
Humphries, E.S. and C. Dart, Neuronal and Cardiovascular Potassium Channels as Therapeutic Drug Targets: Promise and Pitfalls. J Biomol Screen, 2015. 20(9): p. 1055-73.
Racine, R.J., Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972. 32(3): p. 281-94.
Jansen, K. and L. Lagae, Cardiac changes in epilepsy. Seizure, 2010. 19(8): p. 455-60.
Lee, J. and O. Devinsky, The role of autonomic dysfunction in sudden unexplained death in epilepsy patients. Rev Neurol Dis, 2005. 2(2): p. 61-9.
Goldman, A.M., et al., Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci Transl Med, 2009. 1(2): p. 2ra6.
Glasscock, E., et al., Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J Neurosci, 2010. 30(15): p. 5167-75.
Powell, K.L., et al., HCN channelopathy and cardiac electrophysiologic dysfunction in genetic and acquired rat epilepsy models. Epilepsia, 2014. 55(4): p. 609-20.
Snyders, D.J., Structure and function of cardiac potassium channels. Cardiovasc Res, 1999. 42(2): p. 377-90.
Grandi, E., et al., Potassium channels in the heart: structure, function and regulation. J Physiol, 2017. 595(7): p. 2209-2228.
Lopatin, A.N. and C.G. Nichols, Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol, 2001. 33(4): p. 625-38.
Zaritsky, J.J., et al., Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation. Circ Res, 2000. 87(2): p. 160-6.
McLerie, M. and A.N. Lopatin, Dominant-negative suppression of I(K1) in the mouse heart leads to altered cardiac excitability. J Mol Cell Cardiol, 2003. 35(4): p. 367-78.
Young, C.C., et al., Upregulation of inward rectifier K+ (Kir2) channels in dentate gyrus granule cells in temporal lobe epilepsy. J Physiol, 2009. 587(Pt 17): p. 4213-33.
Xu, L., et al., Tenidap, an agonist of the inwardly rectifying K+ channel Kir2.3, delays the onset of cortical epileptiform activity in a model of chronic temporal lobe epilepsy. Neurol Res, 2013. 35(6): p. 561-7.
Haruna, Y., et al., Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome. Hum Mutat, 2007. 28(2): p. 208.
Priori, S.G., et al., A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res, 2005. 96(7): p. 800-7.
Dobrev, D., et al., The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation. Circulation, 2005. 112(24): p. 3697-706.
Yang, Y., et al., Identification of a Kir3.4 mutation in congenital long QT syndrome. Am J Hum Genet, 2010. 86(6): p. 872-80.
Mazarati, A., et al., Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: The effects of subtype-selective agonists and the role of G-protein-mediated signaling. J Pharmacol Exp Ther, 2006. 318(2): p. 700-8.
Kaufmann, K., et al., ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice. ACS Chem Neurosci, 2013. 4(9): p. 1278-86.
Steinhauser, C., M. Grunnet, and G. Carmignoto, Crucial role of astrocytes in temporal lobe epilepsy. Neuroscience, 2016. 323: p. 157-69.
Michalak, Z., et al., Neuropathology of SUDEP: Role of inflammation, blood-brain barrier impairment, and hypoxia. Neurology, 2017. 88(6): p. 551-561.
Haider, S., et al., Focus on Kir6.2: a key component of the ATP-sensitive potassium channel. J Mol Cell Cardiol, 2005. 38(6): p. 927-36.
Ravindran, K., et al., The pathophysiology of cardiac dysfunction in epilepsy. Epilepsy Res, 2016. 127: p. 19-29.
Rivero, A. and A.B. Curtis, Sex differences in arrhythmias. Current Opinion in Cardiology, 2010. 25(1): p. 8-15.
Bhave, G., et al., Small-molecule modulators of inward rectifier K+ channels: recent advances and future possibilities. Future Med Chem, 2010. 2(5): p. 757-74.

References

Ficker, D.M., et al., Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology, 1998. 51(5): p. 1270-4.

Lhatoo, S.D. and J.W. Sander, Sudden unexpected death in epilepsy. Hong Kong Med J, 2002. 8(5): p. 354-8.

Leestma, J.E., Forensic considerations in sudden unexpected death in epilepsy. Epilepsia, 1997. 38(11 Suppl): p. S63-6.

Hesdorffer, D.C., et al., Estimating risk for developing epilepsy: a population-based study in Rochester, Minnesota. Neurology, 2011. 76(1): p. 23-7.

Feely, M., Fortnightly review: drug treatment of epilepsy. BMJ, 1999. 318(7176): p. 106-9.

Laxer, K.D., et al., The consequences of refractory epilepsy and its treatment. Epilepsy Behav, 2014. 37: p. 59-70.

Nei, M., R.T. Ho, and M.R. Sperling, EKG abnormalities during partial seizures in refractory epilepsy. Epilepsia, 2000. 41(5): p. 542-8.

Tomson, T., et al., Heart rate variability in patients with epilepsy. Epilepsy Res, 1998. 30(1): p. 77-83.

Lotufo, P.A., et al., A systematic review and meta-analysis of heart rate variability in epilepsy and antiepileptic drugs. Epilepsia, 2012. 53(2): p. 272-82.

Devinsky, O., Effects of Seizures on Autonomic and Cardiovascular Function. Epilepsy Curr, 2004. 4(2): p. 43-46.

Moseley, B., et al., Autonomic epileptic seizures, autonomic effects of seizures, and SUDEP. Epilepsy Behav, 2013. 26(3): p. 375-85.

Dlouhy, B.J., B.K. Gehlbach, and G.B. Richerson, Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention. J Neurol Neurosurg Psychiatry, 2016. 87(4): p. 402-13.

Hibino, H., et al., Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev, 2010. 90(1): p. 291-366.

Bond, C.T., et al., Cloning and expression of a family of inward rectifier potassium channels. Receptors Channels, 1994. 2(3): p. 183-91.

Villa, C. and R. Combi, Potassium Channels and Human Epileptic Phenotypes: An Updated Overview. Front Cell Neurosci, 2016. 10: p. 81.

Pattnaik, B.R., et al., Genetic defects in the hotspot of inwardly rectifying K(+) (Kir) channels and their metabolic consequences: a review. Mol Genet Metab, 2012. 105(1): p. 64-72.

Anumonwo, J.M. and A.N. Lopatin, Cardiac strong inward rectifier potassium channels. J Mol Cell Cardiol, 2010. 48(1): p. 45-54.

Day, M., et al., Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci, 2005. 25(38): p. 8776-87.

Gonzalez, C., et al., K(+) channels: function-structural overview. Compr Physiol, 2012. 2(3): p. 2087-149.

Brenner, R. and K.S. Wilcox, Potassium Channelopathies of Epilepsy, in Jasper's Basic Mechanisms of the Epilepsies, J.L. Noebels, et al., Editors. 2012: Bethesda (MD).

Gross, G.J. and J.A. Auchampach, Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res, 1992. 70(2): p. 223-33.

D'Adamo, M.C., et al., K(+) channelepsy: progress in the neurobiology of potassium channels and epilepsy. Front Cell Neurosci, 2013. 7: p. 134.

Karschin, C. and A. Karschin, Ontogeny of gene expression of Kir channel subunits in the rat. Mol Cell Neurosci, 1997. 10(3-4): p. 131-48.

D'Avanzo, N., et al., Expression and purification of recombinant human inward rectifier K+ (KCNJ) channels in Saccharomyces cerevisiae. Protein Expr Purif, 2010. 71(1): p. 115-21.

Humphries, E.S. and C. Dart, Neuronal and Cardiovascular Potassium Channels as Therapeutic Drug Targets: Promise and Pitfalls. J Biomol Screen, 2015. 20(9): p. 1055-73.

Racine, R.J., Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972. 32(3): p. 281-94.

Jansen, K. and L. Lagae, Cardiac changes in epilepsy. Seizure, 2010. 19(8): p. 455-60.

Lee, J. and O. Devinsky, The role of autonomic dysfunction in sudden unexplained death in epilepsy patients. Rev Neurol Dis, 2005. 2(2): p. 61-9.

Goldman, A.M., et al., Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci Transl Med, 2009. 1(2): p. 2ra6.

Glasscock, E., et al., Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J Neurosci, 2010. 30(15): p. 5167-75.

Powell, K.L., et al., HCN channelopathy and cardiac electrophysiologic dysfunction in genetic and acquired rat epilepsy models. Epilepsia, 2014. 55(4): p. 609-20.

Snyders, D.J., Structure and function of cardiac potassium channels. Cardiovasc Res, 1999. 42(2): p. 377-90.

Grandi, E., et al., Potassium channels in the heart: structure, function and regulation. J Physiol, 2017. 595(7): p. 2209-2228.

Lopatin, A.N. and C.G. Nichols, Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol, 2001. 33(4): p. 625-38.

Zaritsky, J.J., et al., Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation. Circ Res, 2000. 87(2): p. 160-6.

McLerie, M. and A.N. Lopatin, Dominant-negative suppression of I(K1) in the mouse heart leads to altered cardiac excitability. J Mol Cell Cardiol, 2003. 35(4): p. 367-78.

Young, C.C., et al., Upregulation of inward rectifier K+ (Kir2) channels in dentate gyrus granule cells in temporal lobe epilepsy. J Physiol, 2009. 587(Pt 17): p. 4213-33.

Xu, L., et al., Tenidap, an agonist of the inwardly rectifying K+ channel Kir2.3, delays the onset of cortical epileptiform activity in a model of chronic temporal lobe epilepsy. Neurol Res, 2013. 35(6): p. 561-7.

Haruna, Y., et al., Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome. Hum Mutat, 2007. 28(2): p. 208.

Priori, S.G., et al., A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res, 2005. 96(7): p. 800-7.

Dobrev, D., et al., The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation. Circulation, 2005. 112(24): p. 3697-706.

Yang, Y., et al., Identification of a Kir3.4 mutation in congenital long QT syndrome. Am J Hum Genet, 2010. 86(6): p. 872-80.

Mazarati, A., et al., Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: The effects of subtype-selective agonists and the role of G-protein-mediated signaling. J Pharmacol Exp Ther, 2006. 318(2): p. 700-8.

Kaufmann, K., et al., ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice. ACS Chem Neurosci, 2013. 4(9): p. 1278-86.

Steinhauser, C., M. Grunnet, and G. Carmignoto, Crucial role of astrocytes in temporal lobe epilepsy. Neuroscience, 2016. 323: p. 157-69.

Michalak, Z., et al., Neuropathology of SUDEP: Role of inflammation, blood-brain barrier impairment, and hypoxia. Neurology, 2017. 88(6): p. 551-561.

Haider, S., et al., Focus on Kir6.2: a key component of the ATP-sensitive potassium channel. J Mol Cell Cardiol, 2005. 38(6): p. 927-36.

Ravindran, K., et al., The pathophysiology of cardiac dysfunction in epilepsy. Epilepsy Res, 2016. 127: p. 19-29.

Rivero, A. and A.B. Curtis, Sex differences in arrhythmias. Current Opinion in Cardiology, 2010. 25(1): p. 8-15.

Bhave, G., et al., Small-molecule modulators of inward rectifier K+ channels: recent advances and future possibilities. Future Med Chem, 2010. 2(5): p. 757-74.

Author biographies is not available.