Affinage

KCNT1

Potassium channel subfamily T member 1 · UniProt Q5JUK3

Length
1230 aa
Mass
138.3 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNT1 encodes Slack (Slo2.2/KNa1.1), a sodium-activated potassium channel whose α-subunit alone is sufficient to reconstitute KNa activity in lipid bilayers (PMID:22729647) and which sets neuronal firing properties across brainstem, cortical, sensory, and olfactory neurons (PMID:12442315, PMID:26559620). The channel forms heteromers with the related Slo and Slick (KCNT2) subunits, generating conductances and pharmacology distinct from homomers; heteromerization with Slick requires the Slack-B N-terminus, which also directs surface localization (PMID:10196543, PMID:19403831), and alternative N-terminal splice isoforms (Slack-A vs Slack-B) tune gating to favor rapid adaptation versus rhythmic firing (PMID:18787033). Channel activity is governed largely through its large cytoplasmic C-terminus: intracellular Na+ binding activates the channel and overrides acid/CO2 inhibition (PMID:18082331), PIP2 activates via a proximal C-terminal lysine (PMID:22728883), and Gαq-coupled receptor stimulation increases current through PKC phosphorylation, whereas PKA acts only indirectly by trafficking channels out of the membrane rather than altering gating (PMID:16687497, PMID:19540251, PMID:20962237). The C-terminus serves as a signaling scaffold, binding FMRP (which directly activates the channel) (PMID:20512134, PMID:23115170), the PP1-targeting actin-binding protein Phactr1 (whose channel-stimulation-dependent dissociation is lost in disease mutants) (PMID:27545877, PMID:31914597), and the synaptic scaffold Magi-1 that links Slack to NaV1.8 in sensory neurons (PMID:30860870). De novo gain-of-function mutations clustered in the C-terminus cause severe epilepsy by increasing maximal open probability, sodium sensitivity, cooperative inter-channel gating, and the fraction of channels open at rest, mimicking constitutive PKC activation (PMID:23086397, PMID:25482562, PMID:26725113, PMID:36499459); paradoxically, this hyperexcitability arises because the augmented KNa current preferentially suppresses firing of inhibitory interneurons while enhancing excitatory neuron output, disrupting cortical excitation/inhibition balance (PMID:31350261, PMID:33113364, PMID:38457342). Antisense oligonucleotide silencing of Kcnt1 reduces seizures and extends survival in gain-of-function and sodium-channel epilepsy models (PMID:36173683, PMID:37901435). Beyond epilepsy, Slack regulates nociceptor excitability and itch/pain behavior in coordination with NaV1.8, P2X3, and TRPA1 (PMID:26559620, PMID:30860870, PMID:33401689, PMID:35626730), supports hippocampal-dependent cognitive flexibility and NMDAR/GluN2B-dependent synaptic plasticity (PMID:26077685, PMID:34664085), gates anxiety through BLA-vHPC circuits (PMID:35197318), contributes to prefrontal working memory via an HCN-Slack postsynaptic complex (PMID:37889366), and confers neuroprotection against NMDA excitotoxicity (PMID:33817875).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1998 High

    Establishing that Slack does not act in isolation, the discovery that Slack co-assembles with Slo subunits defined a combinatorial logic for generating channels with distinct conductance and calcium sensitivity.

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

    PMID:10196543

    Open questions at the time
    • Native heteromer stoichiometry not determined
    • Physiological context of Slack/Slo heteromers in neurons not established
  2. 2002 Medium

    Mapping Slack protein to brainstem, olfactory, and cortical neurons distinct from Slo distribution argued for an autonomous role in setting firing properties.

    Evidence Affinity-purified antibody immunohistochemistry and Western blot of rat brain

    PMID:12442315

    Open questions at the time
    • Functional consequence inferred, not tested
    • Subcellular targeting mechanism unknown
  3. 2006 High

    Demonstrating that Gαq-coupled receptors activate Slack via PKC linked the channel to neuromodulatory signaling and distinguished it from the oppositely regulated paralog Slick.

    Evidence Co-expression of channels and receptors in oocytes, PMA application, chimera construction

    PMID:16687497

    Open questions at the time
    • Direct PKC phosphorylation site on Slack not identified in this study
    • In vivo relevance of GqPCR coupling untested
  4. 2006 High

    Pharmacological characterization identified bepridil, quinidine, and bithionol as Slack modulators, providing tools later used to probe disease mutants.

    Evidence Whole-cell and excised-patch recordings in stable HEK line and oocytes with concentration-response curves

    PMID:16876206

    Open questions at the time
    • Binding sites not mapped
    • Selectivity over related channels not fully defined
  5. 2008 High

    Identifying Slack-A and Slack-B splice isoforms with divergent gating showed that alternative N-termini diversify the channel's contribution to adaptation versus rhythmic firing.

    Evidence Promoter identification, RT-PCR, single-channel recordings, numerical simulation, immunohistochemistry

    PMID:18787033

    Open questions at the time
    • Cell-type-specific isoform usage incompletely mapped
    • Structural basis of N-terminal gating control unresolved
  6. 2009 High

    Showing that Slack-B's N-terminus is required for Slick heteromerization and surface localization mechanistically explained how native KNa channel diversity and trafficking are achieved.

    Evidence Co-expression in HEK/oocytes, single-channel electrophysiology, domain-deletion analysis, immunocytochemistry

    PMID:19403831

    Open questions at the time
    • Heteromer subunit ratio in vivo unknown
    • Trafficking partners mediating surface delivery not identified
  7. 2010 High

    The discovery that FMRP binds the Slack C-terminus and activates the channel established a direct molecular link between a fragile-X protein and KNa channel gating.

    Evidence Co-immunoprecipitation and electrophysiology in heterologous systems and mouse neurons

    PMID:20512134

    Open questions at the time
    • FMRP binding site on Slack not mapped at residue level
    • Whether FMRP regulates channel translation versus gating not disentangled
  8. 2010 High

    Distinguishing PKA-driven channel internalization from gating modulation clarified that nociceptor hyperexcitability arises from Slack surface removal, while a parallel study showed PKA does not directly gate Slack.

    Evidence Trafficking/biotinylation assays, RNAi knockdown, and patch clamp in DRG and HEK-Slack; mutagenesis of consensus PKA site

    PMID:19540251 PMID:20962237

    Open questions at the time
    • Trafficking machinery executing internalization unidentified
    • Link between PKA and the trafficking step mechanistically incomplete
  9. 2012 High

    Demonstrating that the purified Slack α-subunit alone reconstitutes KNa activity proved the channel is intrinsically sodium-gated without obligate accessory subunits.

    Evidence Protein purification and reconstitution in planar bilayers and membrane vesicles

    PMID:22729647

    Open questions at the time
    • Atomic structure of the Na+ sensor not resolved here
    • Lipid dependence of reconstituted activity not detailed
  10. 2012 High

    Linking de novo C-terminal KCNT1 mutations to constitutive gain-of-function that mimics PKC phosphorylation defined the founding disease mechanism for KCNT1 epilepsy.

    Evidence Exome sequencing and functional electrophysiology of mutant channels

    PMID:23086397

    Open questions at the time
    • How gain-of-function K+ current produces seizures left unexplained at this stage
    • Non-conducting C-terminal partner identities not defined
  11. 2012 High

    Reciprocal FMRP-Slack interaction and PIP2 activation studies extended C-terminal regulation, showing FMRP directly increases channel opening and PIP2 activates via proximal C-terminal K339.

    Evidence Reciprocal Co-IP, intracellular FMRP injection, inside-out patches, siRNA; oocyte voltage clamp with K339 mutagenesis

    PMID:22728883 PMID:23115170

    Open questions at the time
    • Integration of PIP2 and FMRP regulation not addressed
    • Physiological PIP2 dynamics controlling Slack in vivo unknown
  12. 2014 High

    Resolving that disease mutants increase current mainly through enhanced positive cooperative gating between channels, and that quinidine reduces this gain, identified a novel mechanism and a candidate therapeutic.

    Evidence Single-channel cooperative-gating analysis across 9 mutants; automated oocyte voltage clamp with quinidine across ADNFLE/EIMFS mutants

    PMID:24591078 PMID:25482562

    Open questions at the time
    • Molecular basis of inter-channel cooperativity unknown
    • Quinidine concentrations effective in vitro exceed clinically tolerable levels
  13. 2015 High

    Single-channel dissection of 12 mutants established increased sodium sensitivity and maximal open probability as the predominant gain-of-function mechanism.

    Evidence Single-channel patch clamp with Na+ concentration-response analysis

    PMID:26725113

    Open questions at the time
    • Why elevated K+ conductance causes hyperexcitability not yet resolved here
    • Structural location of altered Na+ sensor not mapped
  14. 2015 High

    Genetic knockout and behavioral studies assigned native Slack functions in DRG firing brake and nociception, olfactory current compensation, and hippocampal-dependent cognitive flexibility.

    Evidence Kcnt1 knockout mice, DRG patch clamp, itch/pain assays; RNAi in Kv1.3-/- olfactory neurons; KO behavioral battery

    PMID:20393063 PMID:26077685 PMID:26559620

    Open questions at the time
    • Circuit basis of cognitive flexibility deficit not defined
    • Compensatory upregulation mechanism unspecified
  15. 2016 High

    Showing that channel stimulation triggers Phactr1/PP1 dissociation from wild-type but not mutant Slack revealed a non-conducting signaling output disrupted by disease mutations.

    Evidence Label-free optical biosensor mass-redistribution assay and Co-IP with mutant controls

    PMID:27545877

    Open questions at the time
    • Downstream PP1 targets following dissociation not identified
    • Physiological consequence of failed dissociation in neurons untested
  16. 2017 Medium

    Identifying F932I as a trafficking-defective loss-of-function variant showed that not all KCNT1 mutations are gain-of-function, expanding the disease mechanism spectrum.

    Evidence Mutagenesis, patch clamp, and membrane-versus-total Western blot fractionation

    PMID:28366665

    Open questions at the time
    • Single variant; broader loss-of-function landscape unknown
    • Trafficking defect mechanism not resolved
  17. 2019 High

    Phactr1 was shown to tether Slack to actin and require PP1 binding plus the S407 PKC site to reduce current, defining the scaffold-phosphatase module controlling channel amplitude.

    Evidence Reciprocal Co-IP, patch clamp, S407 mutagenesis, Phactr1 domain mutants

    PMID:31914597

    Open questions at the time
    • Dynamics of actin coupling during activity not measured
    • Interplay with FMRP and Magi-1 scaffolding unresolved
  18. 2019 High

    Human iPSC neurons and a Magi-1 scaffold study together showed that Slack gain-of-function causes cell-autonomous hyperexcitability and that Slack forms a Magi-1/NaV1.8 sensory macrocomplex.

    Evidence iPSC-derived neuron patch/MEA recordings and simulation; Magi-1 Co-IP with DRG-specific knockdown and behavior

    PMID:30860870 PMID:31350261

    Open questions at the time
    • Paradoxical hyperexcitability from K+ current not yet explained mechanistically at this stage
    • Magi-1 macrocomplex stoichiometry undefined
  19. 2020 High

    Knock-in mouse models resolved the central paradox: gain-of-function KNa current preferentially impairs inhibitory interneuron firing, producing network hyperexcitability and seizures.

    Evidence Y796H and R455H knock-in mice, cell-type-specific patch clamp, MEA recordings, EEG, behavior, connectivity analysis

    PMID:32081855 PMID:33113364

    Open questions at the time
    • Why subthreshold KNa increase is interneuron-selective not fully mechanistic
    • Developmental timing of circuit rewiring unclear
  20. 2021 Medium

    Knockout studies linked Slack to NMDAR/GluN2B-dependent synaptic plasticity and to neuroprotection against excitotoxicity, broadening its role beyond firing control.

    Evidence Slack KO hippocampal LTP/LTD slice electrophysiology with GluN2B/GluA1/Rab4 Western blots; intrastriatal NMDA lesion model with K+ monitoring; P2X3 co-localization and injury model

    PMID:33401689 PMID:33817875 PMID:34664085

    Open questions at the time
    • Single-lab findings for each role
    • Molecular link between channel activity and GluN2B/TrkB signaling indirect
  21. 2022 High

    ASO silencing of Kcnt1 reduced seizures, improved behavior, and extended survival in gain-of-function mice, providing therapeutic proof-of-concept; additional studies defined anxiety and resting-open-probability severity relationships.

    Evidence P924L knock-in ASO treatment with EEG/behavior/survival; circuit-specific BLA KO and rescue; HEK mutagenesis correlating resting Po with severity; TRPA1 co-localization conditional KO

    PMID:35197318 PMID:35626730 PMID:36173683 PMID:36499459

    Open questions at the time
    • Long-term ASO efficacy and safety not established
    • Mechanistic link between resting open probability and clinical severity correlational
  22. 2023 High

    Discovery of an HCN-Slack postsynaptic complex in PFC and extended ASO efficacy across sodium-channel epilepsies established new physiological and therapeutic dimensions for KCNT1.

    Evidence Reciprocal Co-IP, immunoEM co-localization, patch clamp, Ca2+ reporter and in vivo working-memory pharmacology; ASO survival studies in Scn1a/Scn8a mutants

    PMID:37889366 PMID:37901435

    Open questions at the time
    • How HCN-driven Na+ influx is spatially coupled to Slack at spines not detailed
    • Generality of KCNT1 as cross-epilepsy modifier untested in humans
  23. 2024 High

    Cell-type-specific analysis of R455H knock-in cortex revealed coordinate upregulation of NaV1.6 alongside KNa, with opposing firing effects in excitatory versus inhibitory neurons, refining the excitation/inhibition imbalance model.

    Evidence R455H knock-in mice, cell-type-specific patch clamp, NaV subunit expression and axon initial segment immunostaining

    PMID:38457342

    Open questions at the time
    • Signal driving coordinate KNa/NaV co-regulation unknown
    • Causal contribution of NaV upregulation to seizures not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structural basis for how disease mutations alter the Na+ sensor and produce cooperative inter-channel gating, and how this translates to interneuron-selective dysfunction, remains to be defined.
  • No atomic structure of mutant channels linking residue changes to gating
  • Molecular basis of inter-channel cooperativity unresolved
  • Mechanism of interneuron-selective vulnerability incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0005198 structural molecule activity 2 GO:0060089 molecular transducer activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
FMR1HCNKCNT2MAGI1P2RX3PHACTR1SCN10ATRPA1
Complex memberships
HCN-Slack postsynaptic complexSlack-Magi-1-NaV1.8 sensory macrocomplexSlack/Slick (KCNT1/KCNT2) heteromeric KNa channelSlack/Slo heteromeric KNa channel

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Slack channel subunits co-assemble with Slo subunits to form heteromeric intermediate-conductance (~60–180 pS) calcium-activated potassium channels that differ pharmacologically and biophysically from either Slack or Slo homomers alone. Slack homomers rectify outwardly (~25–65 pS) and are inhibited by intracellular calcium, whereas Slack/Slo heteromers are activated by cytoplasmic calcium. Heterologous co-expression in Xenopus oocytes, single-channel recordings Nature neuroscience High 10196543
2002 Slack protein is localized predominantly in brainstem neurons (trigeminal system, reticular formation, vestibular/oculomotor nuclei, medial nucleus of the trapezoid body), olfactory bulb, red nucleus, deep cerebellar nuclei, and frontal cortex, with subcellular distribution in both cell bodies and axonal fibers—distinct from the Slo channel distribution—suggesting an autonomous role in regulating neuronal firing properties. Affinity-purified antibody, immunohistochemistry of rat brain slices, Western blot The Journal of comparative neurology Medium 12442315
2006 Slack (Slo2.2) currents are strongly activated by Gαq-protein coupled receptor (GqPCR) stimulation (M1 muscarinic and mGluR1 receptors) via protein kinase C (PKC); PKC activator PMA increases Slack currents. This is opposite to the effect on Slick (Slo2.1), which is inhibited. The distal C-terminal region of Slo2.1 controls PMA sensitivity in that paralog. Co-expression of channels and receptors in Xenopus oocytes, whole-cell voltage clamp, PMA application, chimera construction The Journal of neuroscience High 16687497
2006 Slack channels are inhibited by bepridil (IC50 ~1.0 µM) and quinidine in a concentration-dependent manner; bithionol activates Slack currents by acting relatively directly on the channel from the extracellular face of excised patches. Stable HEK cell line expressing Slack, whole-cell patch clamp, excised inside-out patch recordings in Xenopus oocytes Neuropharmacology High 16876206
2007 Slack channel open probability is decreased by reduced pH or increased CO2 in a dose-dependent manner at low intracellular Na+; however, at high intracellular Na+ (45 mM), Slack open probability increases even in the presence of decreased pH, indicating that intracellular Na+ level overrides acid inhibition. Inside-out patch recordings of Slack expressed in Xenopus oocytes under varied pH and CO2 conditions Neuroscience Medium 18082331
2007 In lamprey spinal neurons, a Slack-like KNa channel contributes to the slow afterhyperpolarization (sAHP) following action potentials; this component is Na+-dependent (blocked by Li+ substitution), quinidine-sensitive, and Slack immunoreactivity is present in medium and large spinal cord neurons. Electrophysiology (intracellular recordings), ion substitution, quinidine pharmacology, immunofluorescence The Journal of physiology Medium 17884929
2008 Alternative RNA splicing from independent promoters produces at least five Slack isoforms differing in cytoplasmic N-termini (Slack-A and Slack-B). Slack-A channels activate rapidly upon depolarization with multiple subconductance states and brief openings; Slack-B activates slowly (hundreds of ms) with longer fully-open state (~6× longer). In numerical simulations, Slack-A promotes rapid adaptation while Slack-B promotes rhythmic firing. Promoter identification, RT-PCR, CHO cell expression, single-channel recordings in Xenopus oocytes, numerical simulations, immunohistochemistry The Journal of physiology High 18787033
2008 Slack and Slick KNa channels are required for the depolarizing afterpotential (DAP) in medium-diameter rat dorsal root ganglion neurons; KNa channels in these cells have ~201 pS unitary conductance, are activated by cytoplasmic Na+ (EC50 ~35 mM), and also show Cl−-dependent activation. Inside-out and whole-cell patch clamp, RT-PCR for Slack/Slick expression in DRG neurons Acta pharmacologica Sinica Medium 18664322
2009 Slick and Slack subunits co-assemble to form heteromeric KNa channels with unitary conductance, kinetics, subcellular localization, and PKC response different from homomers. Heteromer formation requires the N-terminal domain of Slack-B; this N-terminal domain also facilitates localization of heteromeric channels to the plasma membrane. Slick and Slack-B are co-expressed in many central neurons. Co-expression in HEK cells and Xenopus oocytes, single-channel electrophysiology, immunocytochemistry, domain-deletion analysis The Journal of neuroscience High 19403831
2009 cAMP-dependent kinase (PKA) does not acutely modulate Slack channel function or gating kinetics; forskolin inhibition of Slack currents was replicated by inactive analog 1,9-dideoxyforskolin (off-target effect), direct PKA catalytic subunit application to inside-out patches did not affect open probability, and mutation of a consensus PKA phosphorylation site (S→E) had no effect on current kinetics. Nystatin-perforated patch whole-cell clamp in HEK-Slack stable line, inside-out patch recordings, site-directed mutagenesis Neuropharmacology Medium 19540251
2010 FMRP binds directly to the C terminus of the Slack sodium-activated potassium channel and activates the channel; this interaction was demonstrated biochemically and electrophysiologically in mouse neurons. Co-immunoprecipitation, electrophysiology in heterologous expression system and mouse neurons Nature neuroscience High 20512134
2010 PKA activation internalizes Slack KNa channels from DRG neuron plasma membranes (trafficking, not direct gating modulation), reducing KNa current and causing loss of firing accommodation analogous to PKA-induced nociceptor hyperexcitability. Slack knockdown by RNAi produces the same accommodation loss. Whole-cell patch clamp in cultured DRG neurons, RNAi knockdown, surface biotinylation/trafficking assays The Journal of neuroscience High 20962237
2010 Loss of Kv1.3 in olfactory bulb mitral cells produces a compensatory increase in Slack-B protein and Na+-activated K+ currents; RNAi knockdown of Slack suppresses ~75% of net outward current in Kv1.3-/- neurons but only ~25% in wildtype neurons. Western blot, voltage-clamp recordings of OB slices, RNAi in primary olfactory neuron cultures Journal of neurophysiology Medium 20393063
2012 De novo gain-of-function mutations in the C-terminal domain of KCNT1 cause constitutive activation of the channel, mimicking the effects of PKC phosphorylation of the C-terminal domain. The C terminus of KCNT1 also interacts with cytoplasmic proteins involved in developmental signaling pathways (non-conducting function). Exome sequencing, functional electrophysiology in heterologous expression systems, PKC phosphorylation mimicry Nature genetics High 23086397
2012 FMRP and Slack are colocalized at the periphery of isolated Aplysia bag cell neurons, can be reciprocally co-immunoprecipitated, and FMRP injection rapidly induces a slowly-activating sustained outward current matching native Slack KNa current. FMRP addition to inside-out patches containing Aplysia Slack channels increases channel opening. Slack channels are required for recovery from post-discharge inhibition in a protein-synthesis-dependent manner. Immunolocalization, reciprocal co-immunoprecipitation, intracellular FMRP injection, inside-out patch recordings, siRNA knockdown, current-clamp recordings The Journal of neuroscience High 23115170
2012 The Slack α-subunit alone is sufficient for Na+-activated potassium channel activity when reconstituted in planar bilayer membranes and membrane vesicles after purification from expression systems. Protein purification, functional reconstitution in planar lipid bilayers and membrane vesicles The Journal of membrane biology High 22729647
2012 PIP2 activates both Slick and Slack channels expressed in Xenopus oocytes via direct interaction; the activating effect involves lysine 339 at the proximal C-terminus of Slack. Endogenous PIP2 also modulates Slack channels. Two-electrode voltage clamp in Xenopus oocytes, exogenous PIP2 application, site-directed mutagenesis of K339 Biochemical and biophysical research communications Medium 22728883
2014 Nine KCNT1 epilepsy-associated mutations produce greatly increased current amplitude not explained by increases in intrinsic single-channel open probability of individual channels, but rather by increased positive cooperative interactions between multiple channels in a membrane patch. The degree of cooperative gating is much greater for all mutant channels than wild-type. Single-channel patch clamp recordings, analysis of cooperative gating in excised patches Cell reports High 25482562
2014 KCNT1 gain-of-function mutations associated with ADNFLE and EIMFS cause significantly different magnitudes of current increase when expressed in Xenopus oocytes; quinidine (100–300 µM) significantly reduces gain of function for all mutations tested. Automated two-electrode voltage clamp in Xenopus oocytes, pharmacological testing with quinidine Annals of neurology High 24591078
2015 Seven of 12 KCNT1 epilepsy-associated mutations increase channel sodium sensitivity (EC50 shift), while one decreases it. All 12 mutants increase maximal open probability (Po) as revealed by single-channel recordings. Channel over-activity in two mutants occurs only at ~80 mM intracellular Na+. The predominant disease mechanism is increased ability of sodium binding to activate the channel. Single-channel patch clamp recordings, dose-response analysis of intracellular Na+ concentration Cell reports High 26725113
2015 Genetic knockout of Slo2.2 (Kcnt1) abolishes KNa current in small-diameter DRG neurons and increases action potential firing frequency and lowers AP threshold in IB4+ neurons; Slo2.2 KO but not Slo2.1 KO enhances itch and pain responses. KNa activation acts as a brake on the first depolarization-evoked AP with no discernible effect on afterhyperpolarizations. Genetic knockout, whole-cell patch clamp in dissociated DRG neurons, behavioral assays (itch/pain) eLife High 26559620
2015 Slack channel deletion in mice results in impaired cognitive flexibility (reversal learning) and adaptation to novel environments, while working memory, reference memory, and cerebellar motor function are normal, indicating a specific requirement for Slack in hippocampal-dependent cognitive flexibility. Kcnt1 null mouse behavioral battery (Morris water maze, reversal learning, open field, rotarod) Learning & memory Medium 26077685
2016 Stimulation of Slack channels (by pharmacological activators or PKC phosphorylation of the C-terminal domain) causes dissociation of the PP1-targeting protein Phactr1 from the channel, detected as loss of mass near the plasma membrane. KCNT1 epilepsy mutants fail to trigger this dissociation. Phactr1 dissociation is specific to wild-type Slack and not observed for related K+ channels. Optical biosensor (label-free, mass redistribution) assay in neurons and transfected cells, co-immunoprecipitation Cell reports High 27545877
2017 The p.Phe932Ile (F932I) mutation in KCNT1 produces a loss-of-function phenotype (reduced membrane expression without change in total protein), not gain-of-function. The Slack opener loxapine has no effect on this mutant, consistent with trafficking defect preventing membrane insertion. Site-directed mutagenesis, whole-cell patch clamp in Xenopus oocytes/HEK cells, Western blot of membrane vs. total fractions Neuroscience Medium 28366665
2019 Phactr1, an actin-binding protein that recruits PP1, binds to the C-terminus of Slack and is required to link the channel to actin. Co-expression of Phactr1 with wild-type Slack reduces current amplitude in a manner dependent on the conserved PKC phosphorylation site S407; a Phactr1 mutant that disrupts PP1 binding but not actin binding fails to alter Slack currents. Co-immunoprecipitation, whole-cell patch clamp, site-directed mutagenesis of S407, Phactr1 domain mutants FASEB journal High 31914597
2019 In human iPSC-derived neurons bearing homozygous P924L KCNT1 mutation, Na+-dependent K+ currents are increased several-fold. The increased KNa current shortens action potential duration, increases afterhyperpolarization amplitude, and paradoxically increases AP firing rates and network burst frequency—demonstrating a cell-autonomous mechanism by which Slack gain-of-function causes neuronal hyperexcitability. iPSC-derived neuron engineering, whole-cell patch clamp, current-clamp recordings, MEA network recordings, numerical simulations The Journal of neuroscience High 31350261
2019 Magi-1 scaffolds Slack KNa channels (via direct binding) together with NaV1.8 channels in DRG neurons, forming a macrocomplex that regulates DRG excitability and nociceptive behaviors. Co-immunoprecipitation (Magi-1 with Slack), DRG-specific Magi-1 knockdown, behavioral assays FASEB journal Medium 30860870
2020 In a KCNT1-Y796H gain-of-function knock-in mouse, KNa currents are increased in both excitatory and inhibitory cortical neurons, but the increase in KNa current across subthreshold voltages occurs specifically in inhibitory neurons (particularly non-fast-spiking), causing inhibitory-neuron-specific impairments in excitability and AP generation, network hyperexcitability, and synaptic rewiring with increased homotypic connectivity. Knock-in mouse model, whole-cell patch clamp of cortical neurons, multi-electrode array recordings, synaptic connectivity analysis Cell reports High 33113364
2020 Loss of Kcnt1 produces deficits in open-field behavior and motor skill learning, and protects from death after maximum electroshock-induced seizures. Heterozygous Kcnt1+/R455H mice show persistent interictal spikes, spontaneous seizures, and decreased PTZ threshold, while homozygous Kcnt1R455H/R455H mice are embryonic lethal. Kcnt1 null and R455H knock-in mouse models, video-EEG monitoring, PTZ/MES seizure threshold testing, behavioral tasks Scientific reports High 32081855
2021 Slack-deficient neurons are more susceptible to NMDA-induced excitotoxicity; Slack KO increases NMDA-induced brain lesion size and neuronal cell death in cerebellar granule cell cultures. NMDAR-evoked KNa current contributes to intracellular K+ maintenance, and Slack-proficient neurons show elevated TrkB/TrkC transcripts and Erk pathway activation after NMDA exposure, suggesting a neuroprotective mechanism. Intrastriatal NMDA microinjection in Slack KO mice, primary cerebellar granule cell cultures, MK-801/NBQX pharmacology, real-time K+ monitoring, RT-PCR FASEB journal Medium 33817875
2021 Slack-/- mice lack hippocampal LTD and LTP in infancy (P6-P14) due to impaired NMDAR signaling: GluN2B levels and NMDAR-mediated EPSPs are reduced. Slack-/- also lack mGluR-LTD associated with upregulation of Rab4 (recycling endosome GTPase), possibly accelerating AMPAR recycling. GluA1-S845 dephosphorylation after chemical LTD is also reduced. LTP and mGluR-LTD are restored in adult Slack-/-. Kcnt1 knockout mice, hippocampal slice electrophysiology (LTP/LTD), Western blot of GluN2B/GluA1/Rab4, pharmacological inhibition with Ro 25-6981 Cellular and molecular life sciences Medium 34664085
2021 Slack channels are closely associated with P2X3 purinergic receptors in sensory neurons; Slack-mediated IKNa is reduced after peripheral nerve injury and can be bidirectionally modulated in response to P2X3 activation in vitro. Slack KO mice show altered nocifensive responses to P2X3 stimulation. Whole-cell patch clamp, co-localization immunostaining, peripheral nerve injury model, behavioral assays International journal of molecular sciences Medium 33401689
2022 Antisense oligonucleotide (ASO) gene silencing targeting Kcnt1 in a P924L knock-in mouse model significantly reduces seizure frequency, improves behavioral abnormalities, and extends survival after intracerebroventricular injection, providing proof-of-concept for ASO-based therapy in KCNT1 encephalopathy. Knock-in mouse model, intracerebroventricular ASO injection, video-EEG monitoring, behavioral assays, survival analysis JCI insight High 36173683
2022 Slack channel deletion in BLA glutamatergic neurons is sufficient to cause enhanced anxiety-like avoidance behaviors; Slack KO reduces BLA glutamatergic neuron excitability. Re-expression of KCNT1 in BLA or BLA-vHPC glutamatergic projections rescues anxiety behaviors in Slack KO mice. Slack Y777H gain-of-function mice show anxiolytic behaviors with decreased BLA neuron excitability. Circuit-specific Slack KO (viral approach), whole-cell patch clamp of BLA neurons, behavioral tests (elevated plus maze, open field), Kcnt1 viral re-expression in BLA projections The Journal of neuroscience Medium 35197318
2022 Multiple KCNT1 epilepsy-associated mutations increase KCNT1 current amplitude and/or shift voltage dependence of channel opening, increasing the proportion of channels open at resting membrane potential. The T314A mutation does not affect current amplitude but abolishes voltage dependence. Positive correlation between channel open probability at resting membrane potential and neurological disorder severity was observed. Site-directed mutagenesis, whole-cell patch clamp in HEK293T cells International journal of molecular sciences Medium 36499459
2022 TRPA1 co-localizes extensively with Slack in sensory neurons; Slack-dependent KNa currents are modulated in a TRPA1-dependent manner in sensory neurons and HEK cells co-transfected with TRPA1 and Slack. Conditional Slack KO in sensory neurons increases TRPA1-mediated (but not TRPV1-mediated) pain behavior. In situ hybridization, immunostaining, whole-cell patch clamp in sensory neurons and HEK cells, conditional KO behavioral assays Cells Medium 35626730
2023 HCN and Slack channels co-immunoprecipitate in cortical extracts and co-localize at postsynaptic spines of PFC pyramidal neurons by immunoelectron microscopy. ZD7288 (HCN blocker) reduces KNa current in pyramidal cells expressing both HCN and Slack but not in HEK cells expressing Slack alone, indicating that HCN activation drives Na+ influx that activates Slack. cAMP-induced HCN activation elevates cytoplasmic Ca2+ but this is reversed by co-expression with Slack. Pharmacological Slack blockade in rat PFC improves working memory performance. Co-immunoprecipitation, immunoelectron microscopy, whole-cell patch clamp, Ca2+ reporter assay, in vivo pharmacology in rat PFC working memory task Molecular neurobiology High 37889366
2023 Reducing Kcnt1 expression with an antisense oligonucleotide prolongs survival in both Scn1a and Scn8a mutant mice (models of Dravet syndrome and SCN8A epilepsy), implicating KCNT1 as a modulatory therapeutic target for balancing excitation/inhibition in sodium channel epilepsies. ASO treatment of Scn1a and Scn8a mutant mice, survival analysis Frontiers in neuroscience Medium 37901435
2024 In Slack-R455H knock-in mice, both KNa and NaV currents are increased in excitatory and inhibitory cortical neurons; however, the increased currents enhance firing in excitatory neurons but suppress firing in inhibitory neurons. NaV1.6 subunit expression and axon initial segment length/NaV immunostaining are upregulated in both neuron types, demonstrating coordinate regulation of KNa and NaV channel expression. Knock-in mouse model, whole-cell patch clamp of cortical neuron subtypes, NaV channel subunit expression analysis, immunostaining of axon initial segments 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 377 23086397
2012 Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nature genetics 306 23086396
2010 Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nature neuroscience 215 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 162 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 122 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 122 19075143
2017 Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology 102 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 100 23115170
2015 De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia 99 26140313
2014 Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell reports 97 25482562
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
2016 KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. Journal of medical genetics 84 26740507
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
2006 Pharmacological activation and inhibition of Slack (Slo2.2) channels. Neuropharmacology 79 16876206
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 77 31350261
2015 Knockout of Slo2.2 enhances itch, abolishes KNa current, and increases action potential firing frequency in DRG neurons. eLife 77 26559620
2013 A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene 76 24029078
2021 KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum. Brain : a journal of neurology 72 34114611
2019 Treatment Responsiveness in KCNT1-Related Epilepsy. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 68 31054119
2014 Emerging role of the KCNT1 Slack channel in intellectual disability. Frontiers in cellular neuroscience 68 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 68 19403831
2015 Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms. Cell reports 67 26725113
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
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
2022 Antisense oligonucleotide therapy for KCNT1 encephalopathy. JCI insight 56 36173683
2015 Differential distribution of the sodium-activated potassium channels slick and slack in mouse brain. The Journal of comparative neurology 53 26587966
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
2019 KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP. Brain : a journal of neurology 43 31532509
2015 The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice. Learning & memory (Cold Spring Harbor, N.Y.) 42 26077685
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
1992 Granulomatous slack skin: a clinicopathological and immunohistochemical study of three cases. The British journal of dermatology 35 1531613
2019 Epilepsy with migrating focal seizures: KCNT1 mutation hotspots and phenotype variability. Neurology. Genetics 34 31872048
2016 Stimulation of Slack K(+) Channels Alters Mass at the Plasma Membrane by Triggering Dissociation of a Phosphatase-Regulatory Complex. Cell reports 34 27545877
2018 Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations. Annals of clinical and translational neurology 33 30847371
2019 Quinidine Therapy for Lennox-Gastaut Syndrome With KCNT1 Mutation. A Case Report and Literature Review. Frontiers in neurology 32 30804880
2017 A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures. Brain & development 31 29037447
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
2021 Targeting KNa1.1 channels in KCNT1-associated epilepsy. Trends in pharmacological sciences 29 34074526
2017 The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype. Neuroscience 29 28366665
2012 Granulomatous slack skin disease: a review, in comparison with mycosis fungoides. Journal of the European Academy of Dermatology and Venereology : JEADV 28 22435618
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
1997 Granulomatous slack skin in childhood. Pediatric dermatology 27 9192413
2024 Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons. Cell reports 24 38457342
2022 Precision therapy with quinidine of KCNT1-related epileptic disorders: A systematic review. British journal of clinical pharmacology 24 35940594
2017 Slack KNa Channels Influence Dorsal Horn Synapses and Nociceptive Behavior. Molecular pain 24 28604221
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
2023 Interaction Between HCN and Slack Channels Regulates mPFC Pyramidal Cell Excitability in Working Memory Circuits. Molecular neurobiology 20 37889366
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
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
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 18 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 18 30860870
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
2018 Quantitative analysis and EEG markers of KCNT1 epilepsy of infancy with migrating focal seizures. Epilepsia 17 30525185
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
2024 Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review. Epilepsia open 16 39093319
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
2022 Functional Effects of Epilepsy Associated KCNT1 Mutations Suggest Pathogenesis via Aberrant Inhibitory Neuronal Activity. International journal of molecular sciences 15 36499459
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
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 14 36437393
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
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
2023 Reduction of Kcnt1 is therapeutic in mouse models of SCN1A and SCN8A epilepsy. Frontiers in neuroscience 12 37901435
2012 Granulomatous slack skin. Histopathology diagnosis preceding clinical manifestations by 12 years. Journal of dermatological case reports 12 23329989
2011 Slack brain in meningioma surgery through lateral supraorbital approach. Surgical neurology international 12 22145086
2023 Design, synthesis, and biological evaluation of a novel series of 1,2,4-oxadiazole inhibitors of SLACK potassium channels: Identification of in vitro tool VU0935685. Bioorganic & medicinal chemistry 11 37812884
2022 Small-molecule inhibitors of Slack potassium channels as potential therapeutics for childhood epilepsies. Pharmaceutical patent analyst 11 35369761
2022 Slack Potassium Channels Modulate TRPA1-Mediated Nociception in Sensory Neurons. Cells 11 35626730
2021 The Na+-activated K+ channel Slack contributes to synaptic development and plasticity. Cellular and molecular life sciences : CMLS 11 34664085
2020 Cardiac phenotypic spectrum of KCNT1 mutations. Cardiology in the young 11 32883383
2012 Expression, purification and functional reconstitution of slack sodium-activated potassium channels. The Journal of membrane biology 11 22729647

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