Affinage

KCNT1

Potassium channel subfamily T member 1 · UniProt Q5JUK3

Length
1230 aa
Mass
138.3 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNT1 encodes the sodium-activated potassium channel Slack (KNa1.1), a central regulator of neuronal excitability that shapes afterhyperpolarization, action potential threshold, and firing patterns across sensory, cortical, and brainstem circuits. The channel is intrinsically activated by intracellular Na⁺ and further modulated by PIP2, intracellular pH, and PKC-mediated phosphorylation of its C-terminal RCK domains; its C-terminus also scaffolds FMRP (which directly activates the channel) and the Phactr1–PP1 phosphatase complex (which suppresses it through dephosphorylation) (PMID:20512134, PMID:27545877, PMID:31914597). Gain-of-function mutations cause epileptic encephalopathies (including EIMFS and ADNFLE) by increasing Na⁺ sensitivity and cooperative inter-channel gating, with a selective impact on inhibitory neuron excitability that drives cortical hyperexcitability and seizures (PMID:23086397, PMID:25482562, PMID:33113364). Slack also forms functional partnerships with HCN channels at prefrontal cortical dendritic spines to regulate working memory, attenuates NMDA-mediated excitotoxicity via K⁺ efflux-dependent neuroprotection, and undergoes PKA-dependent internalization in nociceptors to modulate pain signaling (PMID:37889366, PMID:33817875, PMID:20962237).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Establishing that Slack forms functional K⁺ channels — both as homomers and as heteromers with Slo — resolved the molecular identity of a sodium-activated potassium conductance and revealed its capacity for heteromeric assembly.

    Evidence Heterologous co-expression in Xenopus oocytes with single-channel recordings

    PMID:10196543

    Open questions at the time
    • Na⁺ activation mechanism at the structural level not defined
    • physiological role in native neurons unknown
    • stoichiometry of heteromeric assembly not determined
  2. 2006 High

    Demonstrating that PKC directly activates Slack (while inhibiting Slick) downstream of Gαq-coupled receptors established the first signaling pathway controlling Slack and identified the C-terminal region as the regulatory locus, while identification of splice variants with distinct gating kinetics explained how a single gene produces divergent firing patterns.

    Evidence Oocyte co-expression with GPCRs, PKC activator application, chimera construction; RT-PCR, CHO/oocyte single-channel recordings of Slack-A and Slack-B isoforms

    PMID:16687497 PMID:18787033

    Open questions at the time
    • Specific PKC phosphorylation site(s) on Slack not mapped
    • in vivo relevance of splice-variant-specific firing patterns not tested
  3. 2008 High

    Showing that Slack/Slick heteromers have distinct trafficking, conductance, and PKC responses — dependent on the Slack-B N-terminus — and that native KNa currents in DRG neurons require Na⁺ and Cl⁻ for full activation established the heteromeric channel as a physiologically relevant entity with dual ionic regulation.

    Evidence Co-immunoprecipitation, single-channel electrophysiology, immunocytochemistry in heterologous cells; patch-clamp of rat DRG neurons with TTX blockade

    PMID:18664322 PMID:19403831

    Open questions at the time
    • Cl⁻ binding site not identified
    • relative abundance of homomers vs. heteromers in vivo unknown
  4. 2010 High

    Discovery that FMRP directly binds and activates Slack through its C-terminus linked a major intellectual disability protein to potassium channel function, while demonstration that PKA triggers Slack internalization (not gating modulation) in DRG nociceptors revealed a trafficking-based mechanism for pain sensitization.

    Evidence Co-immunoprecipitation, pulldown, electrophysiology for FMRP–Slack; cultured DRG neurons, RNAi, trafficking assays for PKA-dependent internalization

    PMID:20512134 PMID:20962237

    Open questions at the time
    • FMRP binding domain on Slack C-terminus not mapped to residue level
    • whether FMRP regulation is altered by disease mutations unknown
    • PKA internalization mechanism (adaptor proteins, endocytic pathway) not defined
  5. 2012 High

    Identification of de novo gain-of-function KCNT1 mutations in severe epilepsies, combined with purified protein reconstitution confirming intrinsic Na⁺-activated K⁺ channel sufficiency and PIP2 as a direct activator, established KCNT1 as a disease gene and defined its core biophysical regulatory inputs.

    Evidence Exome sequencing with functional electrophysiology of mutants; purified Slack reconstituted in planar bilayers; mutagenesis of PIP2-binding lysine in oocytes

    PMID:22728883 PMID:22729647 PMID:23086397

    Open questions at the time
    • Structure of disease-mutant channels not resolved
    • non-conducting signaling functions of the C-terminus not characterized at molecular level
  6. 2014 High

    Mechanistic dissection of 12 disease mutations revealed that gain-of-function arises primarily from increased Na⁺ sensitivity and enhanced cooperative gating between channels rather than altered intrinsic open probability, fundamentally reframing how mutations produce hyperactivity; quinidine was shown to partially reverse gain-of-function.

    Evidence Systematic single-channel patch-clamp recordings with controlled Na⁺; automated voltage clamp in oocytes with quinidine rescue

    PMID:24591078 PMID:25482562 PMID:26725113

    Open questions at the time
    • Molecular basis of cooperative gating unknown
    • quinidine mechanism of action on Slack not defined
    • clinical efficacy of quinidine not established by these studies
  7. 2016 High

    Discovery that Phactr1 recruits PP1 to dephosphorylate the Slack C-terminus and suppress channel activity — and that channel activation triggers Phactr1 dissociation — revealed a bidirectional phosphorylation-dependent signaling switch at the channel; disease mutants failed to trigger this dissociation, linking defective non-conducting signaling to intellectual disability.

    Evidence Optical biosensor assay, co-immunoprecipitation, mutant analysis in neuronal and transfected cells

    PMID:27545877

    Open questions at the time
    • Downstream targets of dissociated Phactr1–PP1 complex not identified
    • whether Phactr1 signaling defect contributes to seizures vs. cognitive phenotype not separated
  8. 2019 High

    The Phactr1–PP1–Slack regulatory axis was further defined by showing PP1-binding and PKC-site (S407) dependence of current suppression, while a Magi-1 scaffold was found to physically couple Slack with NaV1.8 in DRG neurons, and iPSC-derived human neurons carrying P924L showed cell-autonomous hyperexcitability with paradoxically increased firing, validating the gain-of-function mechanism in human cells.

    Evidence Co-IP, mutagenesis, patch-clamp for Phactr1–PP1; Co-IP and DRG-specific knockdown for Magi-1; whole-cell patch clamp and network recording of human iPSC neurons

    PMID:30860870 PMID:31350261 PMID:31914597

    Open questions at the time
    • Magi-1 interaction validated only by Co-IP; reciprocal functional coupling of NaV1.8 and Slack not demonstrated
    • iPSC neuron subtypes not resolved for differential sensitivity
  9. 2020 High

    Cell-type-specific electrophysiology in KCNT1-Y796H knock-in mice demonstrated that gain-of-function selectively impairs inhibitory (non-fast-spiking) neuron excitability while sparing excitatory neurons, providing the circuit-level explanation for cortical hyperexcitability and seizures; Kcnt1 knockout revealed roles in motor learning, cognitive flexibility, and anxiety via BLA-to-vHPC projections.

    Evidence Knock-in and knockout mouse models, cell-type specific patch-clamp, EEG, circuit-specific viral rescue, behavioral testing

    PMID:32081855 PMID:33113364 PMID:35197318

    Open questions at the time
    • Why non-fast-spiking inhibitory neurons are selectively vulnerable is mechanistically unexplained
    • whether excitatory neuron sparing generalizes across all mutations unknown
  10. 2021 High

    Slack was shown to attenuate NMDA-mediated excitotoxic cell death by mediating K⁺ efflux following NMDAR activation and upregulating TrkB/TrkC/Erk pro-survival signaling, establishing a neuroprotective function beyond excitability control.

    Evidence Kcnt1 KO mice, intrastriatal NMDA injection, primary cerebellar granule cell cultures, real-time K⁺ monitoring, RT-PCR

    PMID:33817875

    Open questions at the time
    • Whether neuroprotection is a direct consequence of K⁺ efflux or requires the non-conducting C-terminal signaling scaffold is unresolved
    • relevance to chronic neurodegeneration not tested
  11. 2023 High

    Demonstrating that HCN channels provide Na⁺ to activate Slack at PFC dendritic spines — with functional coupling confirmed by co-immunoprecipitation and ultrastructural colocalization — revealed a novel ion channel partnership that regulates prefrontal working memory.

    Evidence Co-immunoprecipitation, immunoelectron microscopy, patch-clamp of pyramidal neurons, HCN pharmacological blockade, in vivo working memory task

    PMID:37889366

    Open questions at the time
    • Whether HCN–Slack coupling is disrupted by disease mutations not tested
    • molecular basis of physical interaction not mapped
  12. 2024 High

    Analysis of Slack-R455H knock-in mice revealed that gain-of-function mutations secondarily upregulate NaV1.6 expression and lengthen axon initial segments in both excitatory and inhibitory neurons, yet the functional outcome diverges by cell type — enhancing excitatory but suppressing inhibitory neuron firing — uncovering a homeostatic maladaptation that compounds circuit imbalance.

    Evidence Knock-in mouse, cell-type specific patch-clamp, NaV subunit immunostaining, AIS length measurement

    PMID:38457342

    Open questions at the time
    • Mechanism of NaV1.6 upregulation (transcriptional vs. post-translational) not determined
    • whether NaV changes are reversible with Slack normalization unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Critical open questions include the high-resolution structural basis of Na⁺-dependent gating and cooperative channel interactions, the molecular identity of non-conducting C-terminal signaling targets in development, and whether therapeutic Slack inhibition can rescue both seizure and cognitive phenotypes without compromising neuroprotective functions.
  • No cryo-EM or X-ray structure of full-length Slack in open/closed states
  • non-conducting developmental signaling partners not identified
  • cell-type-specific therapeutic targeting strategies not developed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 3
Partners
FMR1HCN1KCNMA1KCNT2MAGI1PHACTR1PPP1CA
Complex memberships
Slack homotetramerSlack-HCN complexSlack-Slick heteromerSlack-Slo heteromer

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Slack (KCNT1) subunits co-assemble with Slo subunits to form heteromeric intermediate-conductance calcium-activated potassium channels (~60–180 pS) distinct from either homomeric channel; Slack homomers show ~25–65 pS conductance and are inhibited by intracellular calcium. Heterologous co-expression in Xenopus oocytes, single-channel recordings Nature neuroscience High 10196543
2002 Slack (KCNT1) protein is localized in rat brain neurons predominantly in brainstem nuclei (trigeminal, reticular formation, vestibular, oculomotor, auditory), olfactory bulb, and frontal cortex, with both cell body and axonal fiber distribution; subcellular distribution differs from Slo channel, suggesting an autonomous role. Affinity-purified antibody immunohistochemistry and Western blot on rat brain membranes The Journal of comparative neurology High 12442315
2006 Slack (KCNT1/Slo2.2) activity is strongly activated (while Slick/Slo2.1 is inhibited) by Gαq protein-coupled receptor stimulation (M1 muscarinic and mGluR1) via protein kinase C (PKC); PKC activator PMA increases Slo2.2 currents; a chimera study identified that the distal carboxyl region of Slo2.1 controls sensitivity to PMA. Xenopus oocyte co-expression with GPCRs, two-electrode voltage clamp, PKC activator application, chimera construction, immunocytochemistry The Journal of neuroscience High 16687497
2006 Quinidine and bepridil inhibit Slack currents in a concentration-dependent manner (bepridil IC50 ~1 µM in HEK cells) and reduce channel activity in excised patches; bithionol acts as a robust activator of Slack currents directly on the extracellular face of excised patches. Stable HEK cell line expressing Slack, Xenopus oocyte expression, patch-clamp electrophysiology, pharmacological dose-response Neuropharmacology High 16876206
2007 Slack channel open probability decreases dose-dependently with decreased pH or increased CO2 in low intracellular Na+ conditions; in high intracellular Na+, open probability increases even in the presence of decreased pH, indicating that intracellular Na+ and H+/CO2 have opposing modulatory effects on Slack gating. Inside-out patch recordings from Xenopus oocytes expressing Slack channel, varied CO2 and pH conditions Neuroscience Medium 18082331
2007 A Slack-like KNa channel contributes to the slow afterhyperpolarization (sAHP) in lamprey spinal neurons; this non-Ca2+-dependent sAHP component is Na+-dependent and blocked by quinidine; Slack immunoreactivity was detected in lamprey spinal cord neurons. Electrophysiology (Na+ replacement with Li+, quinidine block), immunofluorescence with anti-Slack antibody in lamprey spinal cord The Journal of physiology Medium 17884929
2008 Alternative splicing of Slack generates distinct isoforms (Slack-A and Slack-B) driven by independent promoters; Slack-A activates rapidly with multiple subconductance states and brief openings (promoting rapid adaptation), while Slack-B activates slowly (promoting rhythmic firing); Slack-A is enriched in brainstem and olfactory bulb. RT-PCR, CHO cell expression, single-channel recordings in Xenopus oocytes, immunohistochemistry, numerical simulations The Journal of physiology High 18787033
2008 Slack and Slick KNa channels are required for depolarizing afterpotential (DAP) in medium-diameter rat DRG neurons; native KNa channels show 201 pS conductance and Na+-dependent activation (EC50 ~35 mM) with additional Cl−-dependent activation; TTX abolishes inward Na+ currents and subsequent KNa currents. Inside-out and whole-cell patch-clamp, RT-PCR, TTX blockade in rat DRG neurons Acta pharmacologica Sinica Medium 18664322
2009 Slick and Slack-B subunits co-assemble into heteromeric KNa channels with distinct unitary conductance, kinetic behavior, subcellular localization, and PKC response; heteromer formation requires the N-terminal domain of Slack-B; this N-terminal domain facilitates trafficking of heteromeric channels to the plasma membrane. Co-immunoprecipitation, heterologous expression, single-channel electrophysiology, immunocytochemistry The Journal of neuroscience High 19403831
2009 PKA does not directly modulate Slack channel gating: neither PKA catalytic subunit applied to inside-out patches, 8-bromo-cAMP, forskolin (via cAMP), nor mutation of the consensus PKA phosphorylation site between RCK domains affected Slack open probability or current amplitude. HEK-293 stable cell line with nystatin-perforated patch clamp, inside-out patches, mutagenesis, PKA catalytic subunit application Neuropharmacology Medium 19540251
2010 FMRP (Fragile X mental retardation protein) binds directly to the C-terminus of the Slack (KCNT1) sodium-activated potassium channel and activates the channel, increasing its opening; this interaction was demonstrated biochemically and electrophysiologically in mouse. Co-immunoprecipitation, pulldown, electrophysiological recordings in heterologous expression system Nature neuroscience High 20512134
2010 PKA-induced internalization of Slack KNa channels from the plasma membrane of DRG neurons underlies nociceptor hyperexcitability; PKA does not modulate Slack at the level of channel gating but reduces membrane-resident channels; siRNA knockdown of Slack mimics PKA-induced loss of firing accommodation. Cultured DRG neurons, whole-cell patch clamp, PKA activation, RNA interference, channel trafficking assay The Journal of neuroscience High 20962237
2010 Loss of Kv1.3 in olfactory neurons produces a compensatory upregulation of Slack-B protein and increased Na+-activated K+ currents; RNA interference of Slack suppresses ~75% of net outward current in Kv1.3−/− neurons, linking Slack expression to olfactory neuron excitability compensation. Western blot, voltage-clamp of olfactory bulb slices, RNAi knockdown, elevated intracellular sodium application Journal of neurophysiology Medium 20393063
2012 FMRP and Slack are colocalized at the periphery of Aplysia bag cell neurons and reciprocally co-immunoprecipitate; intracellular injection of FMRP enhances a slowly activating Slack-like outward current and narrows action potentials; Slack channels are required for recovery from prolonged neuronal inhibition that also requires new protein synthesis. Immunocytochemistry, co-immunoprecipitation, intracellular injection, inside-out patch, siRNA knockdown, current-clamp recordings The Journal of neuroscience High 23115170
2012 De novo gain-of-function mutations in the C-terminal domain of KCNT1 cause constitutive channel activation, mimicking PKC phosphorylation of the C-terminal domain; the C-terminus of KCNT1 interacts with cytoplasmic proteins involved in developmental signaling pathways (non-conducting function). Exome sequencing, functional electrophysiology, PKC phosphorylation comparison Nature genetics High 23086397
2012 Slack (KCNT1) channel is required for functional reconstitution of Na+-activated potassium channel activity; the Slack α-subunit alone is sufficient for Na+-activated K+ channel activity when purified and reconstituted into planar bilayer membranes and membrane vesicles. Protein purification, planar bilayer reconstitution, membrane vesicle electrophysiology The Journal of membrane biology High 22729647
2012 PIP2 directly activates Slack channels; the activating effect requires lysine 339 in Slack's proximal C-terminus; endogenous PIP2 also modulates Slack channel activity. Two-electrode voltage clamp in Xenopus oocytes, mutagenesis of PIP2-binding lysine, exogenous PIP2 application Biochemical and biophysical research communications Medium 22728883
2014 Nine disease-causing KCNT1 mutations produce large increases in current amplitude not accountable by changes in intrinsic open probability of individual channels; instead, the mutations greatly increase cooperative gating interactions between multiple channels in a patch (channel-channel interactions). Single-channel patch-clamp recordings, cooperative gating analysis, nine mutant channels characterized Cell reports High 25482562
2014 KCNT1 epilepsy mutations increase channel gain-of-function primarily by increasing Na+ sensitivity (maximal open probability); seven of 12 mutations increase Na+ sensitivity and two show channel over-activity only at high intracellular Na+ (~80 mM); all 12 mutants increase maximal open probability. Single-channel patch-clamp, inside-out recordings with controlled intracellular Na+ in heterologous expression Cell reports High 26725113
2014 KCNT1 gain-of-function mutations associated with ADNFLE and EIMFS show significantly different magnitudes of increased channel activity in Xenopus oocyte assays; quinidine (100–300 µM) significantly reduces gain-of-function for all mutations studied. Automated two-electrode voltage clamp in Xenopus laevis oocytes, quantitative RT-PCR for developmental expression Annals of neurology High 24591078
2015 Genetic knockout of Slo2.2 (Kcnt1) abolishes KNa current in small-diameter DRG neurons, increases action potential firing and decreases AP threshold in isolectin B4+ neurons, and enhances itch and pain responses; KNa activation acts as a brake to initiation of the first depolarization-elicited action potential. Genetic knockout of Kcnt1, whole-cell patch clamp of DRG neurons, behavioral itch/pain assays eLife High 26559620
2016 Stimulation of Slack channels (by pharmacological activators or PKC phosphorylation of C-terminal residue) triggers dissociation of the PP1-targeting protein Phactr-1 from the channel, resulting in loss of mass near the plasma membrane detected by optical biosensor; disease-causing Slack mutants associated with intellectual disability fail to trigger this mass change; Phactr-1 dissociation is specific to wild-type Slack and not observed with related K+ channels. Optical biosensor assay, co-immunoprecipitation, neuronal and transfected cell studies, Slack mutant analysis Cell reports High 27545877
2017 The p.Phe932Ile KCNT1 mutation produces a loss-of-function phenotype (reduced channel current); membrane expression of the mutant Slack protein is substantially reduced despite unchanged total protein levels; the Slack opener loxapine fails to restore current, suggesting impaired membrane trafficking. Heterologous expression of analogous rat Slack mutation, patch-clamp electrophysiology, Western blot (total vs. membrane fractionation), pharmacological testing Neuroscience Medium 28366665
2019 Phactr1 links PP1 (protein phosphatase 1) to the Slack (KCNT1) channel C-terminus: Phactr1 co-immunoprecipitates with Slack and is required to link the channel to actin; co-expression of Phactr1 reduces Slack current amplitude in a PP1-binding-dependent and PKC phosphorylation site (S407)-dependent manner. Co-immunoprecipitation, patch-clamp electrophysiology, Phactr1 mutant disrupting PP1 binding, PKC phosphorylation site mutagenesis FASEB journal High 31914597
2019 Magi-1 scaffold protein directly binds both NaV1.8 and Slack (KCNT1) channels in DRG neurons, forming a macrocomplex; DRG-specific knockdown of Magi-1 attenuates thermal nociception and reduces NaV1.8 protein expression. Co-immunoprecipitation, DRG-specific knockdown, behavioral nociception assays, Western blot FASEB journal Medium 30860870
2019 A KCNT1 gain-of-function mutation (P924L) expressed in human iPSC-derived neurons increases Na+-dependent K+ currents several-fold, shortens action potential duration, increases afterhyperpolarization amplitude, and paradoxically increases action potential firing rates and network burst intensity — demonstrating a cell-autonomous hyperexcitability mechanism. Human iPSC-derived neurons with homozygous P924L KCNT1 mutation, whole-cell patch clamp, network activity recording, numerical simulations The Journal of neuroscience High 31350261
2020 The KCNT1-Y796H gain-of-function variant increases KNa current across subthreshold voltages specifically in inhibitory non-fast-spiking cortical neurons (but not excitatory neurons), impairing inhibitory neuron excitability and AP generation, leading to motor cortex hyperexcitability, network hypersynchronicity, and early-onset seizures in mice. Knock-in mouse model, multiplatform electrophysiology (patch clamp of cortical neuron subtypes), EEG, synaptic connectivity analysis Cell reports High 33113364
2020 Loss of Kcnt1 in mice produces deficits in motor skill learning and cognitive flexibility but normal working memory; heterozygous Kcnt1+/R455H mice show persistent interictal spikes, spontaneous seizures, and reduced seizure threshold; homozygous Kcnt1R455H/R455H is embryonic lethal. Kcnt1 knockout and Kcnt1R455H knock-in mouse models, behavioral testing, video-EEG monitoring, PTZ-induced seizure threshold Scientific reports High 32081855
2021 Slack K+ channels attenuate NMDA-induced excitotoxic neuronal cell death; Slack KO neurons show excessive cell death after NMDA/glutamate exposure; NMDAR-evoked K+ signals (monitored in real-time) are significantly reduced in Slack KO cerebellar granule cells; TrkB/TrkC/Erk pro-survival pathway transcripts are elevated in NMDA-exposed Slack-proficient cells, suggesting Slack-dependent neuroprotection. Kcnt1 KO mice, intrastriatal NMDA microinjection, primary cerebellar granule cell cultures, pharmacological dissection (MK-801, NBQX), real-time K+ monitoring, RT-PCR FASEB journal High 33817875
2022 Antisense oligonucleotide (ASO) gene-silencing targeting Kcnt1 in a mouse model (KCNT1 p.P924L knock-in) significantly reduces seizure frequency, improves behavioral abnormalities, and extends survival after single intracerebroventricular injection, providing proof-of-concept for ASO therapy. Knock-in mouse model, intracerebroventricular ASO injection, video-EEG seizure monitoring, behavioral assays, survival analysis JCI insight High 36173683
2022 Slack channel deletion in basolateral amygdala (BLA) glutamatergic neurons is sufficient to cause anxious behaviors; Slack channel reduces BLA glutamatergic neuron excitability; restoration of KCNT1 expression in the BLA-to-ventral hippocampus (vHPC) projection reverses anxiety in Slack KO mice. Slack KO and gain-of-function (Y777H) mice, electrophysiology of BLA neurons, circuit-specific viral vector rescue, behavioral tests (elevated plus maze, open field) The Journal of neuroscience High 35197318
2023 HCN channels and Slack KNa channels co-immunoprecipitate in cortical extracts and colocalize at postsynaptic spines of PFC pyramidal neurons by immunoelectron microscopy; Na+ influx through HCN channels activates Slack channels to hyperpolarize PFC pyramidal neurons; blocking HCN reduces KNa current in neurons co-expressing both channels but not in HEK cells with Slack alone; Slack inhibition in rat PFC improves working memory performance. Co-immunoprecipitation, immunoelectron microscopy, patch-clamp of pyramidal neurons, pharmacological HCN blockade, in vivo pharmacology with working memory task Molecular neurobiology High 37889366
2024 In cortical neurons of Slack-R455H knock-in mice, KNa and voltage-dependent Na+ (NaV) currents are both increased in excitatory and inhibitory neurons; however, increased currents enhance firing in excitatory neurons while suppressing firing in inhibitory neurons; NaV1.6 subunit expression is upregulated and axon initial segment length is increased in both neuron types. Knock-in mouse model, patch-clamp electrophysiology of cortical neuron subtypes, NaV subunit immunostaining, axon initial segment length measurement Cell reports High 38457342

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nature genetics 371 23086397
2012 Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nature genetics 303 23086396
2010 Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nature neuroscience 210 20512134
2014 KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Annals of neurology 207 24591078
2002 Localization of the Slack potassium channel in the rat central nervous system. The Journal of comparative neurology 161 12442315
1998 Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nature neuroscience 145 10196543
1988 Granulomatous variants of cutaneous T-cell lymphoma. The histopathology of granulomatous mycosis fungoides and granulomatous slack skin. The American journal of surgical pathology 136 3257655
2015 Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia 120 26122718
2008 Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization For Research and Treatment of Cancer (EORTC). Archives of dermatology 120 19075143
2017 Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology 99 29196579
2012 Regulation of neuronal excitability by interaction of fragile X mental retardation protein with slack potassium channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 98 23115170
2014 Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell reports 97 25482562
2015 De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia 94 26140313
2017 Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine. Neurology 93 29196578
1987 Granulomatous slack skin: clonal rearrangement of the T-cell receptor beta gene is evidence for the lymphoproliferative nature of a cutaneous elastolytic disorder. The Journal of investigative dermatology 91 3496402
2006 Opposite regulation of Slick and Slack K+ channels by neuromodulators. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 16687497
2016 KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. Journal of medical genetics 81 26740507
2006 Pharmacological activation and inhibition of Slack (Slo2.2) channels. Neuropharmacology 78 16876206
2015 Knockout of Slo2.2 enhances itch, abolishes KNa current, and increases action potential firing frequency in DRG neurons. eLife 77 26559620
2019 An Epilepsy-Associated KCNT1 Mutation Enhances Excitability of Human iPSC-Derived Neurons by Increasing Slack KNa Currents. The Journal of neuroscience : the official journal of the Society for Neuroscience 76 31350261
2013 A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene 74 24029078
2015 Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms. Cell reports 67 26725113
2014 Emerging role of the KCNT1 Slack channel in intellectual disability. Frontiers in cellular neuroscience 67 25120433
2009 The N-terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium-activated potassium channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 67 19403831
2021 KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum. Brain : a journal of neurology 66 34114611
2008 Amino-termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation. The Journal of physiology 66 18787033
2019 Treatment Responsiveness in KCNT1-Related Epilepsy. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 65 31054119
2007 Sodium-dependent potassium channels of a Slack-like subtype contribute to the slow afterhyperpolarization in lamprey spinal neurons. The Journal of physiology 65 17884929
2020 Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy. Cell reports 61 33113364
2018 Early Treatment with Quinidine in 2 Patients with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) Due to Gain-of-Function KCNT1 Mutations: Functional Studies, Clinical Responses, and Critical Issues for Personalized Therapy. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 58 30112700
1998 Granulomatous slack skin. Report of three patients with an updated review of the literature. Dermatology (Basel, Switzerland) 58 9669112
2015 Differential distribution of the sodium-activated potassium channels slick and slack in mouse brain. The Journal of comparative neurology 52 26587966
2022 Antisense oligonucleotide therapy for KCNT1 encephalopathy. JCI insight 51 36173683
2018 Lack of response to quinidine in KCNT1-related neonatal epilepsy. Epilepsia 51 30182418
2013 Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy. Pediatric neurology 51 24120652
2010 PKA-induced internalization of slack KNa channels produces dorsal root ganglion neuron hyperexcitability. The Journal of neuroscience : the official journal of the Society for Neuroscience 51 20962237
2017 Does age affect response to quinidine in patients with KCNT1 mutations? Report of three new cases and review of the literature. Seizure 44 29291456
2020 Impaired motor skill learning and altered seizure susceptibility in mice with loss or gain of function of the Kcnt1 gene encoding Slack (KNa1.1) Na+-activated K+ channels. Scientific reports 41 32081855
1994 Granulomatous slack skin: report of a case associated with Hodgkin's disease and a review of the literature. The British journal of dermatology 41 7917995
2019 KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP. Brain : a journal of neurology 40 31532509
2015 The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice. Learning & memory (Cold Spring Harbor, N.Y.) 40 26077685
1992 Granulomatous slack skin: a clinicopathological and immunohistochemical study of three cases. The British journal of dermatology 35 1531613
2016 Stimulation of Slack K(+) Channels Alters Mass at the Plasma Membrane by Triggering Dissociation of a Phosphatase-Regulatory Complex. Cell reports 33 27545877
2019 Epilepsy with migrating focal seizures: KCNT1 mutation hotspots and phenotype variability. Neurology. Genetics 32 31872048
2018 Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations. Annals of clinical and translational neurology 32 30847371
2019 Quinidine Therapy for Lennox-Gastaut Syndrome With KCNT1 Mutation. A Case Report and Literature Review. Frontiers in neurology 31 30804880
2010 The slack sodium-activated potassium channel provides a major outward current in olfactory neurons of Kv1.3-/- super-smeller mice. Journal of neurophysiology 31 20393063
2017 A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures. Brain & development 30 29037447
2017 The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype. Neuroscience 28 28366665
2008 Slack and Slick KNa channels are required for the depolarizing afterpotential of acutely isolated, medium diameter rat dorsal root ganglion neurons. Acta pharmacologica Sinica 28 18664322
2021 Targeting KNa1.1 channels in KCNT1-associated epilepsy. Trends in pharmacological sciences 27 34074526
2012 Granulomatous slack skin disease: a review, in comparison with mycosis fungoides. Journal of the European Academy of Dermatology and Venereology : JEADV 27 22435618
1997 Granulomatous slack skin in childhood. Pediatric dermatology 27 9192413
2017 Slack KNa Channels Influence Dorsal Horn Synapses and Nociceptive Behavior. Molecular pain 23 28604221
2022 Precision therapy with quinidine of KCNT1-related epileptic disorders: A systematic review. British journal of clinical pharmacology 22 35940594
2006 Vitamin D-mediated hypercalcemia in slack skin disease: evidence for involvement of extrarenal 25-hydroxyvitamin D 1alpha-hydroxylase. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 22 16939409
1996 Cutaneous T-cell lymphoma associated with granulomatous slack skin. Dermatology (Basel, Switzerland) 22 8726653
2024 Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons. Cell reports 21 38457342
2021 Slack K+ channels attenuate NMDA-induced excitotoxic brain damage and neuronal cell death. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 33817875
1999 Granulomatous mycosis fungoides: report of a case with some histopathologic features of granulomatous slack skin. The American Journal of dermatopathology 20 10218676
2023 Interaction Between HCN and Slack Channels Regulates mPFC Pyramidal Cell Excitability in Working Memory Circuits. Molecular neurobiology 19 37889366
2013 Gene-wide tagging study of the association between KCNT1 polymorphisms and the susceptibility and efficacy of genetic generalized epilepsy in Chinese population. CNS neuroscience & therapeutics 19 24279416
2007 The sodium-activated potassium channel Slack is modulated by hypercapnia and acidosis. Neuroscience 19 18082331
1994 Granulomatous slack skin. Histopathology 19 7959645
2000 Granulomatous slack skin: successful treatment with recombinant interferon-gamma. The British journal of dermatology 18 10730774
2023 Spatial transcriptomics reveals heterogeneity of macrophages in the tumor microenvironment of granulomatous slack skin. The Journal of pathology 17 37550813
2022 The Slack Channel Regulates Anxiety-Like Behaviors via Basolateral Amygdala Glutamatergic Projections to Ventral Hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 35197318
2019 Magi-1 scaffolds NaV1.8 and Slack KNa channels in dorsal root ganglion neurons regulating excitability and pain. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 30860870
2014 Cell volume changes regulate slick (Slo2.1), but not slack (Slo2.2) K+ channels. PloS one 17 25347289
2009 cAMP-dependent kinase does not modulate the Slack sodium-activated potassium channel. Neuropharmacology 17 19540251
2001 Granulomatous slack skin: a distinct disorder or a variant of mycosis fungoides? Acta dermato-venereologica 17 11411914
1994 Granulomatous slack skin: cytogenetic and molecular analyses. Cancer genetics and cytogenetics 17 8143283
2018 Quantitative analysis and EEG markers of KCNT1 epilepsy of infancy with migrating focal seizures. Epilepsia 16 30525185
2017 Lethal digenic mutations in the K+ channels Kir4.1 (KCNJ10) and SLACK (KCNT1) associated with severe-disabling seizures and neurodevelopmental delay. Journal of neurophysiology 16 28747464
2007 Granulomatous slack skin. European journal of dermatology : EJD 16 17673389
2004 Granulomatous slack skin without evidence of a clonal T-cell proliferation. Journal of the American Academy of Dermatology 16 14726855
2021 Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing. International journal of molecular sciences 15 33401689
2012 Is slack an intrinsic seizure terminator? The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 15 22645110
2012 PIP₂ modulation of Slick and Slack K⁺ channels. Biochemical and biophysical research communications 15 22728883
2023 Functional evaluation of epilepsy-associated KCNT1 variants in multiple cellular systems reveals a predominant gain of function impact on channel properties. Epilepsia 14 37177976
2019 Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14 31914597
2018 Loss of Sodium-Activated Potassium Channel Slack and FMRP Differentially Affect Social Behavior in Mice. Neuroscience 14 29859980
2009 Granulomatous slack skin responds to UVA1 phototherapy. Dermatology (Basel, Switzerland) 14 19546523
2009 Use of optical biosensors to detect modulation of Slack potassium channels by G protein-coupled receptors. Journal of receptor and signal transduction research 14 19640220
2002 A case of primary cutaneous CD30+ T-cell lymphoproliferative disorder with features of granulomatous slack skin disease. The British journal of dermatology 14 12410714
2024 Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review. Epilepsia open 13 39093319
2022 New use for an old drug: quinidine in KCNT1-related epilepsy therapy. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 13 36437393
2022 Functional Effects of Epilepsy Associated KCNT1 Mutations Suggest Pathogenesis via Aberrant Inhibitory Neuronal Activity. International journal of molecular sciences 13 36499459
2019 Concurrent Quinidine and Phenobarbital in the Treatment of a Patient with 2 KCNT1 Mutations. Current therapeutic research, clinical and experimental 13 31388363
2014 A novel KCNT1 mutation in a Japanese patient with epilepsy of infancy with migrating focal seizures. Human genome variation 13 27081515
2003 Granulomatous slack skin disease--disease features and response to pentostatin. British journal of haematology 13 14531912
2011 Slack brain in meningioma surgery through lateral supraorbital approach. Surgical neurology international 12 22145086
2023 Reduction of Kcnt1 is therapeutic in mouse models of SCN1A and SCN8A epilepsy. Frontiers in neuroscience 11 37901435
2022 Small-molecule inhibitors of Slack potassium channels as potential therapeutics for childhood epilepsies. Pharmaceutical patent analyst 11 35369761
2020 Cardiac phenotypic spectrum of KCNT1 mutations. Cardiology in the young 11 32883383
2019 Two South Indian Children with KCNT1-Related Malignant Migrating Focal Seizures of Infancy - Clinical Characteristics and Outcome of Targeted Treatment with Quinidine. Annals of Indian Academy of Neurology 11 31359944
2012 Expression, purification and functional reconstitution of slack sodium-activated potassium channels. The Journal of membrane biology 11 22729647
2012 Granulomatous slack skin. Histopathology diagnosis preceding clinical manifestations by 12 years. Journal of dermatological case reports 11 23329989
2024 Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine-Independent and Chronic Itch. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10 38350720
2015 Granulomatous Lymphoproliferative Disorders: Granulomatous Slack Skin and Lymphomatoid Granulomatosis. Dermatologic clinics 10 26143428