The Role of Slack (KCNT1) Channels in the Pathogenesis of Temporal Lobe Epilepsy
Journal: Journal of Clinical Medicine Research DOI: 10.32629/jcmr.v6i2.4057
Abstract
Current therapeutic strategies for epilepsy predominantly focus on seizure frequency control and symptom alleviation. However, approximately 30% of patients progress to drug-resistant epilepsy, particularly temporal lobe epilepsy (TLE), due to the absence of specific therapeutic targets, etiological complexity, and interindividual heterogeneity. Delineating the pathogenic mechanisms of TLE and identifying novel regulatory factors hold critical clinical significance for developing targeted therapies. Notably, in vivo studies have demonstrated that gain-of-function mutations in KCNT1 selectively suppress the excitability of inhibitory interneurons, disrupting excitatory/inhibitory (E/I) balance and promoting epileptogenesis. This evidence suggests a pathological association between KCNT1 dysfunction and epilepsy. A hypothesis arises whether upregulated KCNT1 expression during TLE episodes may predominately localize in inhibitory neurons, exacerbating epileptic progression through functional suppression of these cells. Furthermore, neuroglial cell activation during epileptogenesis triggers massive release of inflammatory mediators (e.g., interleukins, tumor necrosis factors). The NF-κB signaling cascade, activated by seizure-induced oxidative stress and elevated proinflammatory mediators associated with neuronal damage, has been shown to bind specific cis-elements in the KCNT2 promoter to regulate its transcription — a mechanism implicated in neurological pathogenesis. At the same time, some studies have found that mouse NF-κB can specifically bind to the KCNT2 promoter regulatory sequence and up-regulate KCNT2 transcription. Since KCNT1 and KCNT2 have similar structure and function, they interact to form functional channels and cause similar related diseases. So can KCNT1 expression change in response to the occurrence and development of temporal lobe epilepsy and is the mechanism of change related to the NF-κB pathway? This raises a pivotal question: Could inflammatory mediators modulate KCNT1 expression via NF-κB pathway activation during TLE progression? Through systematic investigation, this study aims to address these scientific inquiries, providing mechanistic insights into epileptogenic processes and potential therapeutic targets.
Keywords
Slack channel; Epilepsy; KCNT1; inflammatory mediators; NF-κB pathway.
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[47] Choi J, Koh S. Role of brain inflammation in epileptogenesis[J]. Yonsei Medical Journal, 2008, 49(1): 1-18.
[48] Vishwakarma S, Singh S, Singh T G. Pharmacological modulation of cytokines correlating neuroinflammatory cascades in epileptogenesis[J]. Molecular Biology Reports, 2022, 49(2): 1437-1452.
[49] Sanz P, Garcia-Gimeno M A. Reactive Glia Inflammatory Signaling Pathways and Epilepsy[J]. International Journal of Molecular Sciences, 2020, 21(11): 4096.
[50] Han T, Qin Y, Mou C, et.al. Seizure induced synaptic plasticity alteration in hippocampus is mediated by IL-1β receptor through PI3K/Akt pathway[J]. American Journal of Translational Research, 2016, 8(10): 4499-4509.
[51] Zhang H, Tao J, Zhang S, et.al. LncRNA MEG3 Reduces Hippocampal Neuron Apoptosis via the PI3K/AKT/mTOR Pathway in a Rat Model of Temporal Lobe Epilepsy[J]. Neuropsychiatric Disease and Treatment, 2020, 16: 2519-2528.
[52] Gómez-Chávez F, Correa D, Navarrete-Meneses P, et.al. NF-κB and Its Regulators During Pregnancy[J]. Frontiers in Immunology, 2021, 12: 679106.
[53] Hoffmann A, Natoli G, Ghosh G. Transcriptional regulation via the NF-kappaB signaling module[J]. Oncogene, 2006, 25(51): 6706-6716.
[54] Verma I M, Stevenson J K, Schwarz E M, et.al. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation[J]. Genes & Development, 1995, 9(22): 2723-2735.
[55] Ravi R, Bedi A. NF-kappaB in cancer--a friend turned foe[J]. Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy, 2004, 7(1): 53-67.
[56] Tomasello D L, Gancarz-Kausch A M, Dietz D M, et.al. Transcriptional Regulation of the Sodium-activated Potassium Channel SLICK (KCNT2) Promoter by Nuclear Factor-κB[J]. The Journal of Biological Chemistry, 2015, 290(30): 18575-18583.
[57] Legrand-Poels S, Schoonbroodt S, Matroule J Y, et.al. Nf-kappa B: an important transcription factor in photobiology[J]. Journal of Photochemistry and Photobiology. B, Biology, 1998, 45(1): 1-8.
[2] Annegers J F, Rocca W A, Hauser W A. Causes of epilepsy: contributions of the Rochester epidemiology project[J]. Mayo Clinic Proceedings, 1996, 71(6): 570-575.
[3] Ding D, Zhou D, Sander J W, et.al. Epilepsy in China: major progress in the past two decades[J]. The Lancet. Neurology, 2021, 20(4): 316-326.
[4] Bartolini E, Ferrari A R, Lattanzi S, et.al. Drug-resistant epilepsy at the age extremes: Disentangling the underlying etiology[J]. Epilepsy & Behavior: E&B, 2022, 132: 108739.
[5] Arends J B A M. Movement-based seizure detection[J]. Epilepsia, 2018, 59 Suppl 1: 30-35.
[6] Löscher W, Klitgaard H, Twyman R E, et.al. New avenues for anti-epileptic drug discovery and development[J]. Nature Reviews. Drug Discovery, 2013, 12(10): 757-776.
[7] Najm I, Ying Z, Janigro D. Mechanisms of epileptogenesis[J]. Neurologic Clinics, 2001, 19(2): 237-250.
[8] Ransohoff R M. How neuroinflammation contributes to neurodegeneration[J]. Science (New York, N.Y.), 2016, 353(6301): 777-783.
[9] Chen T S, Lai M C, Huang H Y I, et.al. Immunity, Ion Channels and Epilepsy[J]. International Journal of Molecular Sciences, 2022, 23(12): 6446.
[10] Wei F, Yan L M, Su T, et.al. Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy[J]. Neuroscience Bulletin, 2017, 33(4): 455-477.
[11] Gribkoff V K, Winquist R J. Potassium channelopathies associated with epilepsy-related syndromes and directions for therapeutic intervention[J]. Biochemical Pharmacology, 2023, 208: 115413.
[12] Bhattacharjee A, Gan L, Kaczmarek L K. Localization of the Slack potassium channel in the rat central nervous system[J]. The Journal of Comparative Neurology, 2002, 454(3): 241-254.
[13] Budelli G, Hage T A, Wei A, et.al. Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology[J]. Nature Neuroscience, 2009, 12(6): 745-750.
[14] Wallén P, Robertson B, Cangiano L, et.al. Sodium-dependent potassium channels of a Slack-like subtype contribute to the slow afterhyperpolarization in lamprey spinal neurons[J]. The Journal of Physiology, 2007, 585(Pt 1): 75-90.
[15] Kubota M, Saito N. Sodium- and calcium-dependent conductances of neurones in the zebra finch hyperstriatum ventrale pars caudale in vitro[J]. The Journal of Physiology, 1991, 440: 131-142.
[16] Nuwer M O, Picchione K E, Bhattacharjee A. PKA-induced internalization of Slack KNa channels produces dorsal root ganglion neuron hyperexcitability[J]. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 2010, 30(42): 14165-14172.
[17] Wu J, Quraishi I H, Zhang Y, et.al. Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons[J]. Cell reports, 2024, 43(3): 113904.
[18] Gao S bang, Wu Y, Lü C xia, et.al. Slack and Slick KNa channels are required for the depolarizing afterpotential of acutely isolated, medium diameter rat dorsal root ganglion neurons[J]. Acta Pharmacologica Sinica, 2008, 29(8): 899-905.
[19] Ruffin V A, Gu X Q, Zhou D, et.al. The sodium-activated potassium channel Slack is modulated by hypercapnia and acidosis[J]. Neuroscience, 2008, 151(2): 410-418.
[20] Kim G E, Kaczmarek L K. Emerging role of the KCNT1 Slack channel in intellectual disability[J]. Frontiers in Cellular Neuroscience, 2014, 8: 209.
[21] Gertler T, Bearden D, Bhattacharjee A, et al. KCNT1-Related Epilepsy. 2018 Sep 20. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Kaczmarek
[22] Noebels J. Precision physiology and rescue of brain ion channel disorders[J]. The Journal of General Physiology, 2017, 149(5): 533-546.
[23] Sandhiya S, Dkhar SA. Potassium channels in health, disease & development of channel modulators. Indian J Med Res. 2009 Mar;129(3):223-32.
[24] Brown M R, Kronengold J, Gazula V R, et.al. Amino-termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation[J]. The Journal of Physiology, 2008, 586(21): 5161-5179.
[25] Yuan A, Santi C M, Wei A, et al. The sodium-activated potassium channel is encoded by a member of the Slo gene family[J]. Neuron, 2003, 37(5): 765-773.
[26] Salkoff L, Butler A, Ferreira G, et al. High-conductance potassium channels of the SLO family[J]. Nature Reviews. Neuroscience, 2006, 7(12): 921-931.
[27] Joiner W J, Tang M D, Wang L Y, et al. Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits[J]. Nature Neuroscience, 1998, 1(6): 462-469.
[28] Hite R K, MacKinnon R. Structural Titration of Slo2.2, a Na+-Dependent K+ Channel[J]. Cell, 2017, 168(3): 390-399.e11.
[29] Hite R K, Yuan P, Li Z, et al. Cryo-electron microscopy structure of the Slo2.2 Na(+)-activated K(+) channel[J]. Nature, 2015, 527(7577): 198-203.
[30] Kaczmarek L K. Slack, Slick and Sodium-Activated Potassium Channels[J]. ISRN neuroscience, 2013, 2013(2013): 354262.
[31] Bhattacharjee A, Kaczmarek L K. For K+ channels, Na+ is the new Ca2+[J]. Trends in Neurosciences, 2005, 28(8): 422-428.
[32] Zhang Z, Rosenhouse-Dantsker A, Tang Q Y, et al. The RCK2 domain uses a coordination site present in Kir channels to confer sodium sensitivity to Slo2.2 channels[J]. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 2010, 30(22): 7554-7562.
[33] X L, L S L. Sodium-activated potassium conductance participates in the depolarizing afterpotential following a single action potential in rat hippocampal CA1 pyramidal cells[J]. Brain research, 2004, 1023(2).
[34] Ohba C, Kato M, Takahashi N, et.al. De novo KCNT1 mutations in early-onset epileptic encephalopathy[J]. Epilepsia, 2015, 56(9): e121-128.
[35] Sukenik N, Vinogradov O, Weinreb E, et.al. Neuronal circuits overcome imbalance in excitation and inhibition by adjusting connection numbers[J]. Proceedings of the National Academy of Sciences of the United States of America, 2021, 118(12): e2018459118.
[36] Shirani F, Choi H. On the physiological and structural contributors to the overall balance of excitation and inhibition in local cortical networks[J]. bioRxiv: The Preprint Server for Biology, 2023: 2023.01.10.523489.
[37] Matsui A, Spangler C, Elferich J, et.al. Cryo-electron tomographic investigation of native hippocampal glutamatergic synapses[J]. eLife, 2024, 13: RP98458.
[38] Sallard E, Letourneur D, Legendre P. Electrophysiology of ionotropic GABA receptors[J]. Cellular and molecular life sciences: CMLS, 2021, 78(13): 5341-5370.
[39] Qian X, Zhao X, Yu L, et.al. Current status of GABA receptor subtypes in analgesia[J]. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 2023, 168: 115800.
[40] Sarlo G L, Holton K F. Brain concentrations of glutamate and GABA in human epilepsy: A review[J]. Seizure, 2021, 91: 213-227.
[41] Hu Y T, Tan Z L, Hirjak D, et.al. Brain-wide changes in excitation-inhibition balance of major depressive disorder: a systematic review of topographic patterns of GABA- and glutamatergic alterations[J]. Molecular Psychiatry, 2023, 28(8): 3257-3266.
[42] Burnyasheva A O, Stefanova N A, Kolosova N G, et.al. Changes in the Glutamate/GABA System in the Hippocampus of Rats with Age and during Alzheimer’s Disease Signs Development[J]. Biochemistry. Biokhimiia, 2023, 88(12): 1972-1986.
[43] McTague A, Nair U, Malhotra S, et.al. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy[J]. Neurology, 2018, 90(1): e55-e66.
[44] Shore A N, Colombo S, Tobin W F, et.al. Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy[J]. Cell Reports, 2020, 33(4): 108303.
[45] Foresti M L, Arisi G M, Shapiro L A. Role of glia in epilepsy-associated neuropathology, neuroinflammation and neurogenesis[J]. Brain Research Reviews, 2011, 66(1-2): 115-122. [67] Mikati M A, Jiang Y H, Carboni M, et al. Quinidine in the treatment of KCNT1-positive epilepsies[J]. Annals of Neurology, 2015, 78(6): 995-999.
[46] Zoicas I, Kornhuber J. The Role of Metabotropic Glutamate Receptors in Social Behavior in Rodents[J]. International Journal of Molecular Sciences, 2019, 20(6): 1412.
[47] Choi J, Koh S. Role of brain inflammation in epileptogenesis[J]. Yonsei Medical Journal, 2008, 49(1): 1-18.
[48] Vishwakarma S, Singh S, Singh T G. Pharmacological modulation of cytokines correlating neuroinflammatory cascades in epileptogenesis[J]. Molecular Biology Reports, 2022, 49(2): 1437-1452.
[49] Sanz P, Garcia-Gimeno M A. Reactive Glia Inflammatory Signaling Pathways and Epilepsy[J]. International Journal of Molecular Sciences, 2020, 21(11): 4096.
[50] Han T, Qin Y, Mou C, et.al. Seizure induced synaptic plasticity alteration in hippocampus is mediated by IL-1β receptor through PI3K/Akt pathway[J]. American Journal of Translational Research, 2016, 8(10): 4499-4509.
[51] Zhang H, Tao J, Zhang S, et.al. LncRNA MEG3 Reduces Hippocampal Neuron Apoptosis via the PI3K/AKT/mTOR Pathway in a Rat Model of Temporal Lobe Epilepsy[J]. Neuropsychiatric Disease and Treatment, 2020, 16: 2519-2528.
[52] Gómez-Chávez F, Correa D, Navarrete-Meneses P, et.al. NF-κB and Its Regulators During Pregnancy[J]. Frontiers in Immunology, 2021, 12: 679106.
[53] Hoffmann A, Natoli G, Ghosh G. Transcriptional regulation via the NF-kappaB signaling module[J]. Oncogene, 2006, 25(51): 6706-6716.
[54] Verma I M, Stevenson J K, Schwarz E M, et.al. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation[J]. Genes & Development, 1995, 9(22): 2723-2735.
[55] Ravi R, Bedi A. NF-kappaB in cancer--a friend turned foe[J]. Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy, 2004, 7(1): 53-67.
[56] Tomasello D L, Gancarz-Kausch A M, Dietz D M, et.al. Transcriptional Regulation of the Sodium-activated Potassium Channel SLICK (KCNT2) Promoter by Nuclear Factor-κB[J]. The Journal of Biological Chemistry, 2015, 290(30): 18575-18583.
[57] Legrand-Poels S, Schoonbroodt S, Matroule J Y, et.al. Nf-kappa B: an important transcription factor in photobiology[J]. Journal of Photochemistry and Photobiology. B, Biology, 1998, 45(1): 1-8.
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