Slack Channels as Key Regulators of Neuronal Excitability: Implications for Neural Function and the Link to Epilepsy Pathogenesis

© 2024 by the Authors. Licensee Whioce Publishing, Singapore. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

Download PDF

Cite

XML

HTML

Abstract

The Slack channel encoded by the KCNT1 gene is a sodium-activated potassium channel. By regulating the flow of potassium ions, the Slack channel affects the membrane potential and discharge activity of neurons, thus participating in regulating neuronal excitability. Therefore, it plays a crucial role in maintaining the normal function of the nervous system. Consequently, abnormal Slack channel function is closely linked to various neurological diseases, such as epilepsy. Currently, quinidine-based medication therapy and neuroregulatory therapy are key components of the treatment of epilepsy resulting from Slack channel dysfunction. This article aims to outline the fundamental features of the Slack channel while providing a thorough analysis of the main distinctions and possible connections between Slick and Slack channels. Furthermore, this study focuses on the function of controlling the neuronal excitability of Slack channels while delving deeper into the potential correlation between Slack channels and epilepsy and their treatment strategies.

References

Wallen P, Robertson B, Cangiano L, et al., 2007, Sodium-dependent Potassium Channels of a Slack-like Subtype Contribute to the Slow Afterhyperpolarization in Lamprey Spinal Neurons. The Journal of Physiology, 585(1): 75–90.

Griffin AM, Kahlig KM, Hatch RJ, et al., 2021, Discovery of the First Orally Available, Selective K(Na)1.1 Inhibitor: In Vitro and In Vivo Activity of an Oxadiazole Series. ACS Medicinal Chemistry Letters, 12(4): 593–602.

Mao X, Bruneau N, Gao Q, et al., 2020, The Epilepsy of Infancy with Migrating Focal Seizures: Identification of de novo Mutations of the KCNT2 Gene That Exert Inhibitory Effects on the Corresponding Heteromeric K(Na)1.1/K(Na)1.2 Potassium Channel. Frontiers in Cellular Neuroscience, 2020(14): 1.

Matt L, Pham T, Skrabak D, et al., 2021, The Na(+)-activated K(+) Channel Slack Contributes to Synaptic Development and Plasticity. Cellular and Molecular Life Sciences, 78(23): 7569–7587.

Kessi M, Chen B, Peng J, et al., 2020, Intellectual Disability and Potassium Channelopathies: A Systematic Review. Frontiers in Genetics, 2020(11): 614.

Bausch AE, Dieter R, Nann Y, et al., 2015, The Sodium-Activated Potassium Channel Slack is Required for Optimal Cognitive Flexibility in Mice. Learning & Memory, 22(7): 323–335.

Kuchenbuch M, Barcia G, Chemaly N, et al., 2019, KCNT1 Epilepsy with Migrating Focal Seizures Shows a Temporal Sequence with Poor Outcome, High Mortality, and SUDEP. Brain, 142(10): 2996–3008.

Miziak B, Czuczwar SJ, 2022, Approaches for the Discovery of Drugs That Target K Na 1.1 Channels in KCNT1-associated Epilepsy. Expert Opinion on Drug Discovery, 17(12): 1313–1328.

Lim CX, Ricos MG, Dibbens LM, et al., 2016, KCNT1 Mutations in Seizure Disorders: The Phenotypic Spectrum and Functional Effects. Journal Of Medical Genetics, 53(4): 217–225.

Hussain R, Lim CX, Shaukat Z, et al., 2024, Drosophila Expressing Mutant Human KCNT1 Transgenes Make an Effective Tool for Targeted Drug Screening in a Whole Animal Model of KCNT1-epilepsy. Scientific Reports, 14(1): 3357.

Bhattacharjee A, Kaczmarek LK, 2005, For K+ Channels, Na+ is the New Ca2+. Trends in Neurosciences, 28(8): 422–428.

Zhang Q, Liu Y, Xu J, et al., 2021, The Functional Properties, Physiological Roles, Channelopathy and Pharmacological Characteristics of the Slack (KCNT1) Channel. Advances in Experimental Medicine and Biology, 2021(1349): 387–400.

Ali SR, Malone TJ, Zhang Y, et al., 2020, Phactr1 Regulates Slack (KCNT1) Channels via Protein Phosphatase 1 (PP1). FASEB Journal, 34(1): 1591–601.

Yan Y, Yang Y, Bian S, et al., 2012, Expression, Purification and Functional Reconstitution of Slack Sodium-Activated Potassium Channels. Journal of Membrane Biology, 245(11): 667–674.

Xu J, Lv YT, Zhao XY, et al., 2023, Identification of Sodium- and Chloride-Sensitive Sites in the Slack Channel. Journal of Neuroscience, 43(15): 2665–2681.

Fleming MR, Brown MR, Kronengold J, et al., 2016, Stimulation of Slack K(+) Channels Alters Mass at the Plasma Membrane by Triggering Dissociation of a Phosphatase-Regulatory Complex. Cell Reports, 16(9): 2281–2288.

Cole BA, Kalli AC, Pilati N, et al., 2024, A Molecular Switch in RCK2 Triggers Sodium-dependent Activation of K(Na)1.1 (KCNT1) Potassium Channels. Biophysical Journal, 123(14): 2145–2153.

Malone TJ, Wu J, Zhang Y, et al., 2024, Neuronal Potassium Channel Activity Triggers Initiation of mRNA Translation through Binding of Translation Regulators. bioRxiv, PMC10871293.

Bausch AE, Ehinger R, Straubinger J, et al., 2018, Loss of Sodium-Activated Potassium Channel Slack and FMRP Differentially Affect Social Behavior in Mice. Neuroscience, 2018(384): 361–374.

Cioclu MC, Mosca I, Ambrosino P, et al., 2023, KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties. Annals of Neurology, 94(2): 332–349.

Jackson A, Banka S, Stewart H, et al., 2021, Recurrent KCNT2 Missense Variants Affecting p.Arg190 Result in a Recognizable Phenotype. American Journal of Medical Genetics, 185(10): 3083–3091.

Liu R, Sun L, Shi X, et al., 2024, Increased Expression of K(Na)1.2 Channel by MAPK Pathway Regulates Neuronal Activity Following Traumatic Brain Injury. Neurochemical Research, 49(2): 427–440.

Cui F, Wulan T, Zhang Q, et al., 2024, Identification of a Novel KCNT2 Variant in a Family with Developmental and Epileptic Encephalopathies: A Case Report and Literature Review. Frontiers in Genetics, 2024(15): 1371282.

Lee JH, Kang M, Park S, et al., 2019, The Local Translation of K(Na) in Dendritic Projections of Auditory Neurons and the Roles of K(Na) in the Transition from Hidden to Overt Hearing Loss. Aging (Albany NY), 11(23): 11541–1164.

Rizzi S, Knaus HG, Schwarzer C, 2016, Differential Distribution of the Sodium-activated Potassium Channels Slick and Slack in Mouse Brain. Journal of Comparative Neurology, 524(10): 2093–2116.

Li P, Halabi CM, Stewart R, et al., 2019, Sodium-activated Potassium Channels Moderate Excitability in Vascular Smooth Muscle. The Journal of Physiology, 597(20): 5093–5108.

Alagoz M, Kherad N, Bozkurt S, et al., 2020, New Mutations in KCNT2 Gene Causing Early Infantile Epileptic Encephalopathy Type 57: Case Study and Literature Review. Acta Biochimica Polonica, 67(3): 431–434.

Bhattacharjee A, Joiner WJ, Wu M, et al., 2003, Slick (Slo2.1), A Rapidly-gating Sodium-activated Potassium Channel Inhibited by ATP. The Journal of Neuroscience, 23(37): 11681–1191.

Bhattacharjee A, Von Hehn CA, Mei X, et al., 2005, Localization of the Na+-activated K+ Channel Slick in the Rat Central Nervous System. The Journal of Comparative Neurology, 484(1): 80–92.

Tejada MA, Hashem N, Calloe K, et al., 2017, Heteromeric Slick/Slack K+ Channels show Graded Sensitivity to Cell Volume Changes. PLoS One, 12(2): e0169914.

Budelli G, Hage TA, Wei A, et al., 2009, Na+-activated K+ Channels Express a Large Delayed Outward Current in Neurons during Normal Physiology. Nature Neuroscience, 12(6): 745–750.

Bonardi CM, Heyne HO, Fiannacca M, et al., 2021, KCNT1-related Epilepsies and Epileptic Encephalopathies: Phenotypic and Mutational Spectrum. Brain, 144(12): 3635–3650.

Skrabak D, Bischof H, Pham T, et al., 2023, Slack K(+) Channels Limit Kainic Acid-induced Seizure Severity in Mice by Modulating Neuronal Excitability and Firing. Communications Biology, 6(1): 1029.

Wu J, Quraishi IH, Zhang Y, et al., 2023, Disease-causing Slack Potassium Channel Mutations Produce Opposite Effects on Excitability of Excitatory and Inhibitory Neurons. bioRxiv.

Hill SF, Jafar-Nejad P, Rigo F, et al., 2023, Reduction of Kcnt1 is Therapeutic in Mouse Models of SCN1A and SCN8A Epilepsy. Frontiers in Neuroscience, 2023(17): 1282201.

Rychkov GY, Shaukat Z, Lim CX, et al., 2022, Functional Effects of Epilepsy Associated KCNT1 Mutations Suggest Pathogenesis via Aberrant Inhibitory Neuronal Activity. International Journal of Molecular Sciences, 23(23): 15133.

Quraishi IH, Stern S, Mangan KP, et al., 2019, An Epilepsy-Associated KCNT1 Mutation Enhances Excitability of Human iPSC-Derived Neurons by Increasing Slack K(Na) Currents. The Journal of Neuroscience, 39(37): 7438–7449.

Brown MR, Kronengold J, Gazula VR, et al., 2008, Amino-termini Isoforms of the Slack K+ Channel, Regulated by Alternative Promoters, Differentially Modulate Rhythmic Firing and Adaptation. The Journal of Physiology, 586(21): 5161–5179.

Ruffin VA, Gu XQ, Zhou D, et al., 2008, The Sodium-activated Potassium Channel Slack is Modulated by Hypercapnia and Acidosis. Neuroscience, 151(2): 410–418.

Cole BA, Clapcote SJ, Muench SP, et al., 2021, Targeting K(Na)1.1 Channels in KCNT1-associated Epilepsy. Trends in Pharmacological Sciences, 42(8): 700–713.

Gribkoff VK, Winquist RJ, 2023, Potassium Channelopathies Associated with Epilepsy-related Syndromes and Directions for Therapeutic Intervention. Biochemical Pharmacology, 2023(208): 115413.

Powell SK, Shea OC, Townsley K, et al., 2023, Induction of Dopaminergic Neurons for Neuronal Subtype-specific Modeling of Psychiatric Disease Risk. Molecular Psychiatry, 28(5): 1970–1982.

Catterall WA, Lenaeus MJ, Gamal El-Din TM, 2020, Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels. Annual Review of Pharmacology and Toxicology, 2020(60): 133–154.

Neri S, Mastroianni G, Gardella E, et al., 2022, Epilepsy in Neurodegenerative Diseases. Epileptic Disorders, 24(2): 249–273.

Hansen N, Widman G, Hattingen E, et al., 2017, Mesial Temporal Lobe Epilepsy Associated with KCNT1 Mutation. Seizure, 2017(45): 181–183.

Alsaleem M, Carrion V, Weinstock A, et al., 2019, Infantile Refractory Seizures due to de novo KCNT 1 Mutation. BMJ Case Reports, 12(10): e231178.

Ishii A, Shioda M, Okumura A, et al., 2013, A Recurrent KCNT1 Mutation in Two Sporadic Cases with Malignant Migrating Partial Seizures in Infancy. Gene, 531(2): 467–471.

Ehinger R, Kuret A, Matt L, et al., 2021, Slack K(+) Channels Attenuate NMDA-induced Excitotoxic Brain Damage and Neuronal Cell Death. Faseb Journal, 35(5): e21568.

Fiori S, Staudt M, Boyd RN, et al., 2019, Neural Plasticity after Congenital Brain Lesions. Neural Plasticity, 2019: 9154282.

Shore AN, Colombo S, Tobin WF, et al., 2020, Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy. Cell Reports, 33(4): 108303.

Rizzo F, Ambrosino P, Guacci A, et al., 2016, Characterization of two de novoKCNT1 Mutations in Children with Malignant Migrating Partial Seizures in Infancy. Molecular and Cellular Neurosciences, 2016(72): 54–63.

Milligan CJ, Li M, Gazina EV, et al., 2014, KCNT1 Gain of Function in 2 Epilepsy Phenotypes is Reversed by Quinidine. Annals of Neurology, 75(4): 581–590.

Qunies MA, Emmitte AK, 2022, Small-molecule Inhibitors of Slack Potassium Channels as Potential Therapeutics for Childhood Epilepsies. Pharmaceutical Patent Analyst, 11(2): 45–56.

Liu R, Sun L, Wang Y, et al., 2023, New Use for an Old Drug: Quinidine in KCNT1-related Epilepsy Therapy. Neurological Sciences, 44(4): 1201–1206.

Jannati A, Oberman LM, Rotenberg A, et al., 2023, Assessing the Mechanisms of Brain Plasticity by Transcranial Magnetic Stimulation. Neuropsychopharmacology, 48(1): 191–208.

Wang SW, Gao C, Zheng YM, et al., 2022, Current Applications and Future Perspective of CRISPR/Cas9 Gene Editing in Cancer. Molecular Cancer, 21(1): 57.

Previous article in this issue

Next article in this issue