İçeri Doğrultucu Potasyum Kanalları ve Epilepsi

Abstract

İçeri doğrultucu potasyum kanalları “inwardly rectifying potassium channels” (Kir kanalları), aksiyon potansiyelinde hücre içine K+ iyonu taşıyarak, aksiyon potansiyelini membran dinlenim potansiyeline stabilize etmekle görevlidir. Yakın dönemde yapılan fonksiyonel çalışmalarda, başta epilepsi olmak üzere çeşitli nörolojik hastalıklarda ilişkisi olduğu belirlenen Kir kanallarının alt ailelerinden olan Kir4.1 kanalının fonksiyon bozukluğuna bağlı olarak hücre içine K+ iyonu taşıyamadığı görülmüştür. Bu veriyi destekleyen araştırmalarda ise, ekstraselüler ortamda glutamat ile K+ iyonu dengesinin bozulması sonucu hücrenin hiperaktiviteye gidebileceği düşünülmüştür. 7 alt aileye sahip Kir kanallarının epilepsi mekanizmasındaki rolü üzerine yapılan araştırmalarda şimdiye kadar Kir2.x, Kir3.x, Kir4.1 ve Kir6.2 kanallarının fonksiyonel olarak değişebileceği gösterilmiştir. Klinik ve deneysel araştırmalardan elde edilen kanıtların epilepsinin kardiyak fonksiyonu etkileyebileceğini göstermektedir, fakat bunun moleküler mekanizması henüz tam olarak bilinmemektedir. Bu nedenle, ayrıca kardiyak Kir kanalları da ele alınmıştır. 

Keywords

• Kir kanalları,K+ iyonu,hiperaktivite,disfonksiyon,epilepsi

Inwardly Rectifying Potassium Channels and Epilepsy

Abstract

Inwardly rectifying potassium channels (Kir channels) are responsible for restraining the action potential of the membrane by stabilizing the membrane potential for relaxation by transporting K+ ions into the cell. Recent functional studies have shown that the Kir4.1 channel, a subset of the Kir channels, which is associated with various neurological disorders, primarily epilepsy, cannot carry K+ ions into the cell due to dysfunction. In studies supporting this data, it was thought that the glutamate and K+ ion unbalance in the extracellular medium could result in hyperactivity of the cell. Investigations into the role of Kir channels with 7 subfamilies in the mechanism of epilepsy have shown that the Kir2.x, Kir3.x, Kir4.1 and Kir6.2 channels functionally may change. Evidence obtained from clinical and experimental studies show that epilepsy could affect cardiac function; however, the molecular mechanism underlying has not been fully understood yet. For this reason, cardiac Kir channels are also considered. 

Keywords

• Kir channels,K+ ion,hyperactivity,dysfunction,epilepsy

References

1. 1. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev. 2010;90(1):291-366.
2. 2. Butt AM, Kalsi A. Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions. J Cell Mol Med. 2006;10(1):33-44.
3. 3. Bond CT, Pessia M, Xia XM, Lagrutta A, Kavanaugh MP, Adelman JP. Cloning and expression of a family of inward rectifier potassium channels. Receptors Channels. 1994;2(3):183-91.
4. 4. Gonzalez C, Baez-Nieto D, Valencia I, Oyarzun I, Rojas P, Naranjo D, et al. K(+) channels: functionstructural overview. Compr Physiol. 2012;2(3):2087-149.
5. 5. Lopatin AN, Makhina EN, Nichols CG. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification. Nature. 1994;372(6504):366-9.
6. 6. Lu Z, MacKinnon R. Electrostatic tuning of Mg2+ affinity in an inward-rectifier K+ channel. Nature. 1994;371(6494):243-6.
7. 7. Young CC, Stegen M, Bernard R, Muller M, Bischofberger J, Veh RW, et al. Upregulation of inward rectifier K+ (Kir2) channels in dentate gyrus granule cells in temporal lobe epilepsy. J Physiol. 2009;587(Pt 17):4213- 33.
8. 8. Rodriguez-Menchaca AA, Arechiga-Figueroa IA, Sanchez-Chapula JA. The molecular basis of chloroethylclonidine block of inward rectifier (Kir2.1 and Kir4.1) K(+) channels. Pharmacol Rep. 2016;68(2):383-9.

9. 9. Pattnaik BR, Asuma MP, Spott R, Pillers DA. Genetic defects in the hotspot of inwardly rectifying K(+) (Kir) channels and their metabolic consequences: a review. Mol Genet Metab. 2012;105(1):64-72.
10. 10. Loscher W. Current status and future directions in the pharmacotherapy of epilepsy. Trends Pharmacol Sci. 2002;23(3):113-8.
11. 11. Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of epilepsy: a systematic review and meta-analysis. Neurology. 2011;77(10):1005-12.
12. 12. Dichter MA. Basic mechanisms of epilepsy: targets for therapeutic intervention. Epilepsia. 1997;38 Suppl 9:S2-6.
13. 13. Leestma JE, Annegers JF, Brodie MJ, Brown S, Schraeder P, Siscovick D, et al. Sudden unexplained death in epilepsy: observations from a large clinical development program. Epilepsia. 1997;38(1):47-55.
14. 14. Rugg-Gunn FJ, Simister RJ, Squirrell M, Holdright DR, Duncan JS. Cardiac arrhythmias in focal epilepsy: a prospective long-term study. Lancet. 2004;364(9452):2212-9.
15. 15. Bae EK, Park K, Kim H, Jung KH, Lee ST, Chu K, et al. Ictal asystole and eating reflex seizures with temporal lobe epilepsy. Epilepsy Behav. 2011;20(2):404-6.
16. 16. Irsel Tezer F, Saygi S. The association of cardiac asystole with partial seizures: does it result from ictal or interictal activity? Epilepsy Res. 2011;96(1-2):180-4.
17. 17. Moseley BD, Wirrell EC, Nickels K, Johnson JN, Ackerman MJ, Britton J. Electrocardiographic and oximetric changes during partial complex and generalized seizures. Epilepsy Res. 2011;95(3):237-45.
18. 18. Nei M, Zangaladze AT, Sharan A, Ho RT. Interictal epileptiform discharges and asystole. Epilepsy Res. 2011;93(2-3):204-7.
19. 19. Karschin C, Dissmann E, Stuhmer W, Karschin A. IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain. J Neurosci. 1996;16(11):3559-70.
20. 20. Mongiat LA, Esposito MS, Lombardi G, Schinder AF. Reliable activation of immature neurons in the adult hippocampus. PLoS One. 2009;4(4):e5320.
21. 21. Bordey A, Sontheimer H. Properties of human glial cells associated with epileptic seizure foci. Epilepsy Res. 1998;32(1-2):286-303.
22. 22. Jabs R, Seifert G, Steinhauser C. Astrocytic function and its alteration in the epileptic brain. Epilepsia. 2008;49 Suppl 2:3-12.
23. 23. Chever O, Djukic B, McCarthy KD, Amzica F. Implication of Kir4.1 channel in excess potassium clearance: an in vivo study on anesthetized glialconditional Kir4.1 knock-out mice. J Neurosci. 2010;30(47):15769-77.
24. 24. Lopatin AN, Nichols CG. Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol. 2001;33(4):625-38.
25. 25. McLerie M, Lopatin AN. Dominant-negative suppression of I(K1) in the mouse heart leads to altered cardiac excitability. J Mol Cell Cardiol. 2003;35(4):367-78.
26. 26. Noujaim SF, Pandit SV, Berenfeld O, Vikstrom K, Cerrone M, Mironov S, et al. Up-regulation of the inward rectifier K+ current (I K1) in the mouse heart accelerates and stabilizes rotors. J Physiol. 2007;578(Pt 1):315-26.
27. 27. Anumonwo JM, Lopatin AN. Cardiac strong inward rectifier potassium channels. J Mol Cell Cardiol. 2010;48(1):45-54.
28. 28. Mi H, Deerinck TJ, Jones M, Ellisman MH, Schwarz TL. Inwardly rectifying K+ channels that may participate in K+ buffering are localized in microvilli of Schwann cells. J Neurosci. 1996;16(8):2421-9.
29. 29. Krapivinsky G, Gordon EA, Wickman K, Velimirovic B, Krapivinsky L, Clapham DE. The Gprotein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Nature. 1995;374(6518):135-41.
30. 30. Slesinger PA, Reuveny E, Jan YN, Jan LY. Identification of structural elements involved in G protein gating of the GIRK1 potassium channel. Neuron. 1995;15(5):1145-56.
31. 31. Whorton MR, MacKinnon R. X-ray structure of the mammalian GIRK2-betagamma G-protein complex. Nature. 2013;498(7453):190-7.
32. 32. Signorini S, Liao YJ, Duncan SA, Jan LY, Stoffel M. Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2. Proc Natl Acad Sci U S A. 1997;94(3):923-7.
33. 33. Patil N, Cox DR, Bhat D, Faham M, Myers RM, Peterson AS. A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation. Nat Genet. 1995;11(2):126-9.
34. 34. Slesinger PA, Patil N, Liao YJ, Jan YN, Jan LY, Cox DR. Functional effects of the mouse weaver mutation on G protein-gated inwardly rectifying K+ channels. Neuron. 1996;16(2):321-31.
35. 35. Tucker SJ, Pessia M, Moorhouse AJ, Gribble F, Ashcroft FM, Maylie J, et al. Heteromeric channel formation and Ca(2+)-free media reduce the toxic effect of the weaver Kir 3.2 allele. FEBS Lett. 1996;390(3):253-7.
36. 36. Takahashi T, Takahashi I, Komatsu M, Sawaishi Y, Higashi K, Nishimura G, et al. Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin Genet. 2001;60(6):447- 51.
37. 37. Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P. Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci. 2001;21(15):5429-38.
38. 38. Buono RJ, Lohoff FW, Sander T, Sperling MR, O'Connor MJ, Dlugos DJ, et al. Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility. Epilepsy Res. 2004;58(2- 3):175-83.
39. 39. Inyushin M, Kucheryavykh LY, Kucheryavykh YV, Nichols CG, Buono RJ, Ferraro TN, et al. Potassium channel activity and glutamate uptake are impaired in astrocytes of seizure-susceptible DBA/2 mice. Epilepsia. 2010;51(9):1707-13.
40. 40. Ferraro TN, Golden GT, Smith GG, Martin JF, Lohoff FW, Gieringer TA, et al. Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene. Mamm Genome. 2004;15(4):239-51.
41. 41. Shang L, Lucchese CJ, Haider S, Tucker SJ. Functional characterisation of missense variations in the Kir4.1 potassium channel (KCNJ10) associated with seizure susceptibility. Brain Res Mol Brain Res. 2005;139(1):178-83.
42. 42. Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, et al. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med. 2009;360(19):1960-70.
43. 43. Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD. Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J Neurosci. 2007;27(42):11354-65.
44. 44. Higashimori H, Sontheimer H. Role of Kir4.1 channels in growth control of glia. Glia. 2007;55(16):1668- 79.
45. 45. Sharman JL, Mpamhanga CP, Spedding M, Germain P, Staels B, Dacquet C, et al. IUPHAR-DB: new receptors and tools for easy searching and visualization of pharmacological data. Nucleic Acids Res. 2011;39(Database issue):D534-8.
46. 46. Haider S, Antcliff JF, Proks P, Sansom MS, Ashcroft FM. Focus on Kir6.2: a key component of the ATP-sensitive potassium channel. J Mol Cell Cardiol. 2005;38(6):927-36.
47. 47. Kane GC, Liu XK, Yamada S, Olson TM, Terzic A. Cardiac KATP channels in health and disease. J Mol Cell Cardiol. 2005;38(6):937-43.
48. 48. Yellen G. Ketone bodies, glycolysis, and KATP channels in the mechanism of the ketogenic diet. Epilepsia. 2008;49 Suppl 8:80-2.
49. 49. Cooper EC, Pan Z. Putting an end to DEND: a severe neonatal-onset epilepsy is treatable if recognized early. Neurology. 2007;69(13):1310-1.
50. 50. Yamada K, Ji JJ, Yuan H, Miki T, Sato S, Horimoto N, et al. Protective role of ATP-sensitive potassium channels in hypoxia-induce