Affinage

KCNT2

Potassium channel subfamily T member 2 · UniProt Q6UVM3

Length
1135 aa
Mass
130.5 kDa
Annotated
2026-04-28
57 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNT2 (Slick/Slo2.1) encodes a high-conductance, weakly voltage-dependent potassium channel activated by intracellular Na⁺ (sensed via a single residue, D757, in the C-terminus) and Cl⁻, and modulated by PIP2, cell volume, and PKC-mediated inhibition downstream of Gαq-coupled receptors (PMID:14684870, PMID:25903137, PMID:22728883, PMID:16687497). Gating occurs at the selectivity filter rather than the S6 bundle crossing, with hydrophobic contacts between S5 and the pore helix (notably Phe240) stabilizing the closed state (PMID:24166878, PMID:26724206). KCNT2 co-assembles with KCNT1 (Slack) into heteromeric channels with distinct conductance and regulation, forms a functional complex with NALCN in smooth muscle, limits nociceptor and heat-sensor excitability in sensory neurons via Na⁺-dependent feedback downstream of TRPM3, mediates anesthetic preconditioning-induced cardioprotection, and regulates store-operated calcium entry in cardiac fibroblasts to control post-infarction fibrosis (PMID:19403831, PMID:34746693, PMID:39744124, PMID:26845140, PMID:41842949). Pathogenic KCNT2 variants cause developmental and epileptic encephalopathy through gain- or loss-of-function mechanisms, including altered ion selectivity (PMID:29069600, PMID:37062836).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2003 High

    Cloning of KCNT2 established it as a Na⁺- and Cl⁻-activated K⁺ channel, defining the gene's primary molecular identity and placing it in the Slo2 subfamily alongside Slack.

    Evidence Cloning from brain cDNA with heterologous expression electrophysiology and ATP-binding site mutagenesis in Xenopus oocytes

    PMID:14684870

    Open questions at the time
    • Original ATP inhibition claim was later contradicted
    • No structural data at this stage
    • Physiological activating Na⁺ concentration in native cells unknown
  2. 2005 High

    Mapping Slick expression across the rat CNS and modeling its spike-frequency adaptation function answered where and how KCNT2 shapes neuronal firing patterns.

    Evidence In situ hybridization, immunohistochemistry across rat brain, and computational simulation of spike adaptation

    PMID:15717307

    Open questions at the time
    • No loss-of-function validation of computational predictions
    • Species-specific differences not yet addressed
  3. 2006 High

    Discovery that Gαq-coupled receptor signaling inhibits Slick via PKC (opposite to Slack activation) revealed a key regulatory divergence between the two Slo2 paralogs.

    Evidence Xenopus oocyte coexpression with M1/mGluR1, PMA pharmacology, chimeric channel analysis mapping sensitivity to distal C-terminus

    PMID:16687497

    Open questions at the time
    • PKC phosphorylation site(s) on Slick not identified
    • In vivo relevance of differential GqPCR modulation not tested
  4. 2008 Medium

    Identification of Slick/Slack as contributors to the depolarizing afterpotential in DRG neurons established their role in somatosensory physiology.

    Evidence Inside-out and whole-cell patch-clamp with RT-PCR in medium-diameter rat DRG neurons

    PMID:18664322

    Open questions at the time
    • Relative contributions of Slick vs. Slack homomers vs. heteromers not resolved
    • No genetic loss-of-function in this study
  5. 2009 High

    Demonstration that Slick and Slack co-assemble into heteromeric channels requiring the Slack-B N-terminal domain explained how native KNa channel diversity arises and how subunit composition controls trafficking and pharmacological properties.

    Evidence Co-immunoprecipitation, single-channel recording, N-terminal deletion/fusion in Xenopus oocytes and mammalian cells

    PMID:19403831

    Open questions at the time
    • Stoichiometry of heteromeric channels not determined
    • In vivo heteromer prevalence unknown
  6. 2010 High

    Identification of fenamate activation independent of Na⁺ and mapping of weak voltage dependence to R190 in the S4-S5 linker separated pharmacological and physiological gating pathways.

    Evidence Xenopus oocyte voltage-clamp with systematic mutagenesis of S1-S4 and S4-S5 linker

    PMID:20176855

    Open questions at the time
    • Fenamate binding site not structurally resolved
    • Physiological relevance of voltage dependence unclear
  7. 2012 High

    PIP2 was identified as a direct activator of Slick via K306, and fenamate structure-activity analysis with A278R mutagenesis localized separate extracellular activation and intracellular pore-block sites, expanding the pharmacological framework.

    Evidence Xenopus oocyte electrophysiology with exogenous PIP2, mutagenesis (K306, A278R), and systematic SAR of N-phenylanthranilic acid derivatives

    PMID:22728883 PMID:22851714

    Open questions at the time
    • PIP2 interaction not validated structurally
    • Whether PIP2 and Na⁺ activation are synergistic or independent not fully resolved
  8. 2013 High

    Demonstrating that the selectivity filter—not the S6 bundle crossing—gates Slo2.1 fundamentally reframed the channel's gating mechanism, with Phe240 in the pore helix acting as a critical gating switch.

    Evidence Alanine-scanning mutagenesis of S5/S6/pore helix, intragenic rescue, verapamil probing in Xenopus oocytes

    PMID:24166878

    Open questions at the time
    • No cryo-EM or crystal structure to confirm predicted conformational changes
    • Coupling pathway from Na⁺ sensor to selectivity filter unknown
  9. 2014 High

    Refutation of the original ATP-inhibition claim through three orthogonal approaches corrected a foundational error, while cell volume sensitivity was shown to be a Slick-selective property independent of cytoskeletal signaling.

    Evidence Excised inside-out patches with direct ATP, metabolic depletion, ATP-site mutagenesis; hypo/hypertonic oocyte swelling assay

    PMID:25214519 PMID:25347289

    Open questions at the time
    • Molecular determinants of volume sensitivity not identified
    • Mechanism by which volume change reaches the channel unknown
  10. 2015 High

    Identification of D757 as the single intracellular Na⁺ sensor, together with S5–pore helix hydrophobic contacts stabilizing the closed state, completed the core gating model from sensor to gate.

    Evidence D757R mutagenesis abolishing Na⁺ activation; systematic S5 alanine scanning identifying L209–F240 contact; Xenopus oocyte and HEK293 electrophysiology

    PMID:25903137 PMID:26724206

    Open questions at the time
    • How Na⁺ binding at D757 propagates conformational change to the selectivity filter is unknown
    • Structural basis of Na⁺/Cl⁻ synergy unresolved
  11. 2015 High

    NF-κB was established as a transcriptional regulator of KCNT2, with ChIP confirming promoter binding and hypoxia-dependent activity, revealing a transcriptional control layer relevant to pathological states.

    Evidence ChIP, luciferase reporter with promoter mutagenesis, RT-qPCR in primary neurons under hypoxia

    PMID:26100633

    Open questions at the time
    • Whether NF-κB-driven Slick upregulation is neuroprotective or maladaptive in vivo not tested
    • Other transcriptional regulators not surveyed
  12. 2015 Medium

    Proteomic analysis of native brain complexes identified beta-synuclein, TMEM263, DPP10, and SAP102 as interactors of Slick/Slack complexes, suggesting a macromolecular signaling assembly.

    Evidence Co-immunoprecipitation with mass spectrometry from mouse brain lysates, double immunofluorescence

    PMID:29124216

    Open questions at the time
    • Interactions not validated by reciprocal Co-IP or reconstitution
    • Functional significance of each interactor for Slick gating or trafficking unknown
    • Single lab, no independent replication
  13. 2016 High

    Knockout studies in heart showed that Slick, but not Slack, is required for volatile anesthetic-stimulated K⁺ transport and anesthetic preconditioning-induced cardioprotection, establishing a specific cardiac role.

    Evidence Global Slo2.1 KO, Slo2.2 KO, and double KO mice with perfused heart ischemia-reperfusion and fluorescent K⁺ flux

    PMID:26845140

    Open questions at the time
    • Molecular mechanism of volatile anesthetic activation of Slick unknown
    • Mitochondrial vs. plasma membrane Slick contribution not dissected
  14. 2017 High

    A de novo F240L variant causing epileptic encephalopathy was shown to reverse Cl⁻ sensitivity and abolish K⁺ selectivity, establishing KCNT2 as a disease gene and pinpointing Phe240 as a dual gating/selectivity determinant.

    Evidence Exome sequencing, heterologous and primary neuron electrophysiology demonstrating altered ion selectivity and hyperexcitability

    PMID:29069600

    Open questions at the time
    • Whether quinidine or other drugs rescue F240L channels not tested in this study
    • Mechanism of reversed Cl⁻ modulation not structurally explained
  15. 2017 High

    Discovery that Slick resides on large dense-core vesicles in CGRP⁺ nociceptors and translocates to the membrane upon stimulation revealed a regulated trafficking mechanism controlling channel density and pain sensitivity.

    Evidence Immunocytochemistry and live-cell imaging of LDCV translocation, Slick KO mouse behavioral phenotyping (thermal hyperalgesia)

    PMID:28943756

    Open questions at the time
    • Molecular signals triggering LDCV-to-membrane translocation not identified
    • Whether LDCV pool is replenished and on what timescale unknown
  16. 2018 High

    In myometrial smooth muscle, oxytocin receptor–Gαq–PKC signaling inhibits tonically active SLO2.1, causing depolarization and Ca²⁺ influx that drives uterine contraction, establishing SLO2.1 as a resting-potential determinant in non-neuronal excitable cells.

    Evidence Patch-clamp in human myometrial smooth muscle cells, PKC inhibitor pharmacology, calcium imaging

    PMID:30334255

    Open questions at the time
    • PKC phosphorylation site(s) still not mapped
    • Relative contribution of Slick vs. other K⁺ channels to resting potential in myometrium not quantified
  17. 2020 High

    Truncating KCNT2 variants in epilepsy patients were shown to reduce heteromeric KNa1.1/KNa1.2 current density, establishing that loss-of-function of KCNT2 also causes epileptic encephalopathy, not only gain-of-function.

    Evidence Whole-cell patch-clamp of homomeric and heteromeric channels in CHO cells expressing patient variants

    PMID:32038177

    Open questions at the time
    • In vivo consequences of reduced heteromeric current not modeled
    • Whether LoF variants affect Slack homomeric current indirectly not tested
  18. 2021 High

    Functional coupling of SLO2.1 with NALCN was demonstrated in myometrial cells: Na⁺ entering through NALCN directly activates adjacent SLO2.1 channels, establishing a paired ion-channel signaling module that sets membrane potential.

    Evidence Proximity ligation assay, patch-clamp, pharmacological channel blockade, Ca²⁺ imaging in human MSMCs

    PMID:34746693

    Open questions at the time
    • Direct physical interaction (co-IP or structural) between NALCN and Slick not demonstrated
    • Whether NALCN-Slick coupling operates in neurons or other tissues unknown
  19. 2022 High

    Conditional knockouts dissected Slick's cell-type-specific roles in spinal somatosensation: in Aδ nociceptors it limits heat pain, while in dorsal horn interneurons it inhibits capsaicin-induced pain but facilitates somatostatin/SSTR2-mediated itch.

    Evidence Global and Lbx1-conditional Slick KO mice, immunostaining, behavioral assays, ERK phosphorylation, intrathecal pharmacology

    PMID:35303056

    Open questions at the time
    • Mechanism of Slick modulation by SSTR2 not defined
    • Contribution of heteromeric vs. homomeric channels in spinal circuits not determined
  20. 2023 High

    Systematic pharmacological profiling of 14 KCNT2 pathogenic variants demonstrated that GoF variants are uniformly blocked by quinidine/fluoxetine, while LoF variants show variant-specific responses to loxapine and riluzole, providing a framework for precision therapy.

    Evidence Whole-cell electrophysiology in HEK-293 and SH-SY5Y cells with pharmacological dose-response for each variant

    PMID:37062836

    Open questions at the time
    • No in vivo or clinical validation of pharmacological rescue
    • Drug binding sites on Slick not identified
  21. 2024 High

    Conditional KO of Slick in Nav1.8⁺ sensory neurons established that TRPM3-mediated Na⁺ influx activates Slick to provide negative feedback limiting heat nociception, completing a molecular circuit from heat sensor to K⁺ channel brake.

    Evidence SNS-Slick conditional KO, behavioral heat assays, patch-clamp with pregnenolone sulfate (TRPM3 agonist), NaCl-to-choline substitution confirming Na⁺ dependence

    PMID:39744124

    Open questions at the time
    • Whether Slick and TRPM3 physically associate or merely couple via diffusible Na⁺ is unknown
    • Other ion channels that may participate in this feedback loop not surveyed
  22. 2024 Medium

    CircGRIN2B was identified as an upstream activator of KCNT2 transcription by binding NF-κB, linking non-coding RNA regulation to Slick expression and neuropathic pain.

    Evidence RNA pulldown, RIP assay, siRNA knockdown, patch-clamp in DRG neurons, CCI rat pain model

    PMID:38600344

    Open questions at the time
    • CircGRIN2B-NF-κB interaction not confirmed by independent methods beyond RNA pulldown/RIP
    • Whether circGRIN2B regulates KCNT2 in non-DRG tissues unknown
    • Single study without independent replication
  23. 2026 High

    Global and conditional cardiac myofibroblast-specific Slick KO reduced post-MI fibrosis by limiting SOCE-dependent fibrogenesis, revealing a non-excitable-cell function where Slick K⁺ efflux modulates store-operated Ca²⁺ entry.

    Evidence Global and conditional CMF-specific KO mice, ischemia-reperfusion model, live-cell imaging, patch-clamp, SOCE assay

    PMID:41842949

    Open questions at the time
    • How K⁺ efflux through Slick mechanistically enhances SOCE not defined
    • Whether pharmacological Slick inhibition phenocopies KO in cardiac fibrosis not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive functional characterization, no high-resolution structure of KCNT2 exists, and the conformational pathway linking Na⁺ binding at D757 through the RCK domains to selectivity-filter gating remains structurally undefined.
  • No cryo-EM or crystal structure of Slo2.1 homomeric or heteromeric channels
  • Coupling mechanism from C-terminal Na⁺ sensor to selectivity filter gate unknown
  • PKC phosphorylation site(s) mediating Gαq-dependent inhibition not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3
Partners
DPP10KCNT1NALCNSAP102SNCBTMEM263
Complex memberships
SLO2.1/NALCN complexSlick/Slack heteromeric KNa channel

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 KCNT2 (Slick/Slo2.1) was cloned and characterized as a K+ channel activated by intracellular Na+ and Cl-, and inhibited by intracellular ATP. A consensus ATP binding site near the C terminus is required for ATP and its nonhydrolyzable analogs to reduce open probability. Cloning, heterologous expression, electrophysiology (patch-clamp), mutagenesis of ATP binding site The Journal of neuroscience High 14684870
2005 Slick (KCNT2) protein is widely distributed in the rat CNS, with strong expression in brainstem auditory neurons, olfactory bulb, hippocampal CA1-CA3, dentate gyrus, hypothalamus, and cortical layers; its distribution partially overlaps with but also differs from Slack. Computer simulations indicate Slick currents cause spike-frequency adaptation, allowing neurons to respond to high-frequency stimulation with temporally locked lower-frequency firing. In situ hybridization, immunohistochemistry, computational simulation The Journal of comparative neurology High 15717307
2006 Slick (Slo2.1/KCNT2) activity is inhibited by Gαq-protein coupled receptor (GqPCR) stimulation (M1 muscarinic and mGluR1), opposite to Slack which is activated. PKC activator PMA inhibits Slo2.1 whole-cell currents. The distal carboxyl region of Slo2.1 controls sensitivity to PMA. Xenopus oocyte coexpression, whole-cell electrophysiology, PKC activator (PMA) pharmacology, chimeric channel analysis, immunocytochemistry The Journal of neuroscience High 16687497
2007 Slo2.1 (KCNT2) is expressed in striatal cholinergic interneurons and functions as a Cl--activated K+ channel that is inhibited by mGluR1/5 activation and volatile anesthetics; this modulation was reconstituted in HEK293 cells transfected with Slo2.1 and mGluR. Electrophysiological recordings in brain slices, immunohistochemistry, in situ hybridization, HEK293 reconstitution, gramicidin perforated-patch The Journal of neuroscience High 17699666
2009 Slick (KCNT2) and Slack subunits coassemble to form heteromeric KNa channels. Heteromer formation requires the N-terminal domain of Slack-B. The Slack-B N-terminal domain also facilitates localization of heteromeric channels to the plasma membrane. Heteromers differ from homomers in unitary conductance, kinetics, subcellular localization, and PKC response. Co-immunoprecipitation, single-channel and whole-cell electrophysiology, immunocytochemistry, N-terminal domain deletion/fusion experiments The Journal of neuroscience High 19403831
2008 Slick (KCNT2) and Slack KNa channels are required for the depolarizing afterpotential (DAP) in medium diameter rat DRG neurons. Native KNa channels in these neurons have 201 pS conductance, are activated by cytoplasmic Na+ (EC50 ~35 mM) and Cl-, and Slick/Slack gene expression was confirmed by RT-PCR. Inside-out and whole-cell patch-clamp, RT-PCR, TTX pharmacology Acta pharmacologica Sinica Medium 18664322
2010 Slo2.1 (KCNT2) channel gating can be activated by fenamates (niflumic acid, flufenamic acid) independently of intracellular Na+. The weak voltage dependence of Slo2.1 is independent of charged residues in S1-S4 but depends on R190 in the S4-S5 linker. External K+ and Na+ modulate channel conductance. Xenopus oocyte expression, voltage-clamp electrophysiology, site-directed mutagenesis of S1-S4 and S4-S5 linker The Journal of general physiology High 20176855
2012 PIP2 activates both Slick (KCNT2) and Slack channels expressed in Xenopus oocytes. This activation appears to occur via direct interaction with lysine 306 in Slick (and K339 in Slack) at the proximal C-terminus. PIP2 sensitivity is distinct from Slick's cell volume sensitivity. Xenopus oocyte expression, two-electrode voltage clamp, exogenous PIP2 application, site-directed mutagenesis (K306) Biochemical and biophysical research communications Medium 22728883
2012 Fenamates activate Slo2.1 (KCNT2) with biphasic effects: rapid activation followed by slow inhibition. The minimal pharmacophore is N-phenylanthranilic acid. A278R mutation in the pore-lining S6 segment increases sensitivity to activation and reduces inhibition by NFA, suggesting two binding sites: an extracellular site for activation and a cytoplasmic pore site for inhibition. Xenopus oocyte expression, structure-activity relationship analysis, site-directed mutagenesis (A278R in S6) Molecular pharmacology High 22851714
2013 The selectivity filter (not the S6 bundle crossing) gates ion permeation in Slo2.1 (KCNT2). Verapamil blocks Slo2.1 in an activation-independent manner, indicating the S6 bundle crossing does not gate access. Pro271 and Glu275 in S6 maintain the inner pore in an open configuration by preventing tight S6 bundle crossing. Phe240 in the pore helix is critical: substitution with polar residues causes constitutive activation. Dynamic coupling between the pore helix and S5/S6 mediates channel activation. Xenopus oocyte expression, Ala-scanning mutagenesis of S5, S6, pore helix; intragenic rescue by second-site mutations; pharmacological probing with verapamil; homology modeling The Journal of general physiology High 24166878
2014 Cell volume changes selectively regulate Slick (KCNT2) but not Slack channels: swelling stimulates Slick current (~196% of control) and shrinkage inhibits it (~57%). This volume sensitivity does not depend on an intact actin cytoskeleton, ATP release, or vesicle fusion. Xenopus oocyte coexpression with aquaporin-1, two-electrode voltage clamp, hypo/hypertonic challenge, pharmacological dissection PloS one Medium 25347289
2014 Intracellular ATP does not inhibit Slo2.1 (KCNT2) channels. Direct application of 5 mM ATP to excised inside-out patches did not inhibit Slo2.1; metabolic depletion of ATP did not activate Slo2.1; and mutation of the conserved ATP binding site residue did not enhance channel activity. This contradicts the original characterization. Excised inside-out macropatch recording in Xenopus oocytes, metabolic inhibition (NaN3), ATP binding site mutagenesis, whole-cell voltage clamp in HEK293 Physiological reports High 25214519
2015 A single Asp residue (D757) in the C-terminus of Slo2.1 (KCNT2) is the intracellular Na+ sensor. D757R mutation abolishes Na+-activated currents but the channel can still be activated by niflumic acid, confirming functional expression. Fenamates are ~14-fold more potent activators of Slo2.1 than intracellular Na+. Site-directed mutagenesis, Xenopus oocyte expression with NaCl microelectrode voltage-clamp, whole-cell voltage clamp in HEK293, excised inside-out macropatches The Journal of biological chemistry High 25903137
2015 KCNT2 (Slick) gene expression is transcriptionally regulated by NF-κB. Two NF-κB binding sites were identified in the KCNT2/Kcnt2 promoter. ChIP confirmed NF-κB binding in vivo. Under hypoxic conditions in PC-12 cells, only NF-κB-intact promoter constructs showed activity. NF-κB inhibition decreased Slick transcript in primary neurons. ChIP assay, luciferase reporter assay, promoter mutagenesis, RT-qPCR in primary neurons, hypoxia cell culture The Journal of biological chemistry High 26100633
2015 Hydrophobic interactions between S5 residues and the pore helix (Phe240) stabilize Slo2.1 (KCNT2) in its closed state. Ala substitution of five residues on one face of S5 induced constitutive channel activity. Leu-209 in S5, predicted to face Phe-240 in the pore helix, when mutated to Glu or Gln causes maximal channel activation. Xenopus oocyte expression, Ala-scanning mutagenesis of S5, combined S5 triple-mutation, whole-cell voltage clamp Biochimica et biophysica acta High 26724206
2015 Slick (KCNT2) and Slack channels co-localize and co-assemble into identical cellular complexes in native mouse brain. Beta-synuclein, TMEM263, DPP10 (inactive dipeptidyl-peptidase), and SAP102 (synapse associated protein 102) were identified as interaction partners of native Slick and Slack channel complexes. Co-immunoprecipitation, Western blot, double immunofluorescence, mass spectrometric sequencing Biochemistry and biophysics reports Medium 29124216
2015 Slick (Slo2.1/KCNT2) and Slack channels show distinct distribution patterns in mouse brain; Slick shows intense immunoreactivity in processes, varicosities, and cell bodies in olfactory bulb, hippocampus, amygdala, and brainstem, while Slack shows primarily diffuse immunostaining. These patterns differ from rat brain distribution. In situ hybridization, immunohistochemistry in mouse brain sections The Journal of comparative neurology Medium 26587966
2016 Slo2.1 (KCNT2/Slick) is required for volatile anesthetic (VA)-stimulated K+ transport in cardiomyocytes and mitochondria, and for anesthetic preconditioning (APC)-induced cardioprotection against ischemia-reperfusion injury. Slo2.1 knockout hearts fail to show APC protection, while Slo2.2 knockout hearts respond like wild-type. Perfused heart ischemia-reperfusion model, fluorescent K+ flux assay, Slo2.1 global knockout mice, Slo2.2 knockout mice, double knockout mice Anesthesiology High 26845140
2017 A de novo KCNT2 variant (Phe240Leu) causes early infantile epileptic encephalopathy by altering ion selectivity: Cl- sensitivity is reversed, channels favor Na+ over K+ (loss of K+ selectivity), and inward conductance is increased. Rslick channels also induced membrane hyperexcitability in primary neurons. Exome sequencing, Sanger confirmation, whole-cell patch-clamp in heterologous cells, primary neuron expression and electrophysiology Cell reports High 29069600
2017 Slick (Kcnt2) channels are exclusively expressed in small- and medium-sized CGRP-containing DRG neurons, with a pool localized to large dense-core vesicles (LDCV) containing CGRP. Upon stimulation for CGRP release, Slick channels translocate from LDCVs to the neuronal membrane. Slick KO mice show increased basal heat detection and exacerbated thermal hyperalgesia. Immunocytochemistry, live-cell imaging (LDCV translocation), Slick knockout mouse behavioral studies, patch-clamp electrophysiology of DRG neurons Journal of experimental neuroscience High 28943756
2017 TNF-α inhibits SLICK (KCNT2) KNa channel activity in rat dorsal horn neurons via the p38 MAPK pathway. The p38 inhibitor SB202190 blocked TNF-α-induced reduction of KNa current. Modulation occurs through posttranslational modification rather than changes in channel gating. Cultured DH neuron patch-clamp, TNF-α application, p38 MAPK inhibitor pharmacology Journal of pain research Medium 28579824
2017 Heteromeric Slick/Slack channels show graded volume sensitivity depending on the number of Slick α-subunits in the tetrameric channel; the more Slick subunits present, the greater the volume sensitivity. Xenopus oocyte coexpression of homomeric and heteromeric channels with aquaporin-1, two-electrode voltage clamp, hypo/hypertonic challenge PloS one Medium 28222129
2018 SLO2.1 (KCNT2) is expressed and active at the resting membrane potential in myometrial smooth muscle cells (MSMCs). Oxytocin, via oxytocin receptor and Gαq/PKC signaling, inhibits SLO2.1, leading to membrane depolarization, voltage-dependent Ca2+ channel activation, and calcium influx that contributes to uterine contraction. Patch-clamp electrophysiology in MSMCs, pharmacological inhibition of PKC, oxytocin receptor activation, calcium imaging The Journal of physiology High 30334255
2020 Two truncating KCNT2 mutations (frameshift p.L48Qfs43 in N-terminal domain; nonsense p.K564* in C-terminal region) significantly decrease the global current density of heteromeric KNa1.1/KNa1.2 channels by ~55% and ~25% respectively, demonstrating loss-of-function effects on heteromeric channels in EIMFS patients. Whole-cell patch-clamp in CHO cells expressing homomeric KNa1.2 or heteromeric KNa1.1/KNa1.2 channels Frontiers in cellular neuroscience High 32038177
2021 SLO2.1 (KCNT2) and NALCN form a functional complex in myometrial smooth muscle cells: Na+ entering through NALCN activates SLO2.1, causing K+ efflux and membrane hyperpolarization. Decreased SLO2.1/NALCN activity leads to membrane depolarization, Ca2+ entry, and uterine contraction. NALCN and SLO2.1 are in close proximity in human MSMCs. Patch-clamp electrophysiology, proximity ligation/colocalization assays, pharmacological channel blockade, intracellular Ca2+ measurements iScience High 34746693
2022 Slick (KCNT2) expressed in nociceptive Aδ-fibers modulates heat-induced pain, while Slick expressed in spinal cord interneurons inhibits capsaicin-induced pain but facilitates somatostatin-induced itch via SSTR2 co-localization. Slick KO and conditional dorsal horn KO mice showed differential pain and itch phenotypes. Immunostaining, in situ hybridization, Western blot, RT-qPCR, global Slick KO and conditional Lbx1-Slick KO mouse behavioral studies, ERK phosphorylation assay, intrathecal pharmacology Anesthesiology High 35303056
2023 KCNT2 pathogenic variants cause either gain-of-function (GoF) or loss-of-function (LoF) in vitro. Quinidine and fluoxetine block all GoF variants; loxapine and riluzole activate some LoF variants while blocking others, demonstrating variant-specific pharmacological profiles. Whole-cell electrophysiology in HEK-293 and SH-SY5Y cells, pharmacological profiling of 14 novel/untested variants Annals of neurology High 37062836
2024 Slick (KCNT2) in Nav1.8-expressing sensory neurons limits TRPM3-mediated heat nociception. Slick is highly co-expressed with TRPM3 in sensory neurons. TRPM3 activation increases Na+-dependent outward K+ current (IK) in sensory neurons; replacing NaCl with choline chloride abolished this current, confirming Na+-activation of Slick downstream of TRPM3. Conditional knockout (SNS-Slick-/-), in situ hybridization, behavioral heat assays, patch-clamp recording in sensory neurons, TRPM3 agonist (pregnenolone sulfate) pharmacology, ion substitution experiments Frontiers in pharmacology High 39744124
2024 CircGRIN2B promotes SLICK (KCNT2) gene transcription by binding to NF-κB. CircGRIN2B knockdown reduced SLICK channel protein and mRNA expression, reduced Na+-dependent K+ current in DRG neurons, and exacerbated neuropathic pain behaviors in CCI rat models. siRNA knockdown, overexpression, FISH, whole-cell patch-clamp, RNA pulldown, RIP assay, mass spectrometry, CCI pain model behavioral assessment Neuromolecular medicine Medium 38600344
2026 Slick (Slo2.1/KCNT2) channels at the plasma membrane of cardiac fibroblasts and myofibroblasts regulate K+ efflux and modulate store-operated calcium entry (SOCE). Global and conditional cardiac myofibroblast-specific Slick KO reduced post-MI fibrosis and preserved left ventricular function, associated with diminished CMF activation and reduced SOCE-dependent fibrogenesis. Live-cell imaging, whole-cell patch-clamp, global KO and conditional CMF-specific KO mice, ischemia/reperfusion model, fibrosis quantification, SOCE assay JCI insight High 41842949

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Slick (Slo2.1), a rapidly-gating sodium-activated potassium channel inhibited by ATP. The Journal of neuroscience : the official journal of the Society for Neuroscience 172 14684870
2008 Differences in thermoregulatory ability between slick-haired and wild-type lactating Holstein cows in response to acute heat stress. Journal of dairy science 113 18765598
2014 Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle. Nature communications 112 25519203
2014 The SLICK hair locus derived from Senepol cattle confers thermotolerance to intensively managed lactating Holstein cows. Journal of dairy science 100 24996281
2005 Localization of the Na+-activated K+ channel Slick in the rat central nervous system. The Journal of comparative neurology 86 15717307
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
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
2007 TrpC3/C7 and Slo2.1 are molecular targets for metabotropic glutamate receptor signaling in rat striatal cholinergic interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 64 17699666
2018 Convergent Evolution of Slick Coat in Cattle through Truncation Mutations in the Prolactin Receptor. Frontiers in genetics 55 29527221
2016 Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway. Microbiology and molecular biology reviews : MMBR 54 27307580
2015 Differential distribution of the sodium-activated potassium channels slick and slack in mouse brain. The Journal of comparative neurology 52 26587966
2014 Genome-wide association study and ancestral origins of the slick-hair coat in tropically adapted cattle. Frontiers in genetics 45 24808908
2008 BALLDock/SLICK: a new method for protein-carbohydrate docking. Journal of chemical information and modeling 45 18646839
2014 Not just an oil slick: how the energetics of protein-membrane interactions impacts the function and organization of transmembrane proteins. Biophysical journal 43 24896109
2012 A quasi-exclusive European ancestry in the Senepol tropical cattle breed highlights the importance of the slick locus in tropical adaptation. PloS one 43 22675421
2011 Efficient inducible Pan-neuronal cre-mediated recombination in SLICK-H transgenic mice. Genesis (New York, N.Y. : 2000) 39 21671347
2017 A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy. Cell reports 37 29069600
2007 The slick hair coat locus maps to chromosome 20 in Senepol-derived cattle. Animal genetics 35 17257189
2006 SLICK--scoring and energy functions for protein-carbohydrate interactions. Journal of chemical information and modeling 32 16859295
2018 Oxytocin can regulate myometrial smooth muscle excitability by inhibiting the Na+ -activated K+ channel, Slo2.1. The Journal of physiology 30 30334255
2020 The Epilepsy of Infancy With Migrating Focal Seizures: Identification of de novo Mutations of the KCNT2 Gene That Exert Inhibitory Effects on the Corresponding Heteromeric KNa1.1/KNa1.2 Potassium Channel. Frontiers in cellular neuroscience 28 32038177
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
2017 BREEDING AND GENETICS SYMPOSIUM:Breeding heat tolerant dairy cattle: the case for introgression of the "slick" prolactin receptor variant into dairy breeds. Journal of animal science 23 28464106
2010 Activation of Slo2.1 channels by niflumic acid. The Journal of general physiology 23 20176855
2017 Slick (Kcnt2) Sodium-Activated Potassium Channels Limit Peptidergic Nociceptor Excitability and Hyperalgesia. Journal of experimental neuroscience 19 28943756
2012 Structure-activity relationship of fenamates as Slo2.1 channel activators. Molecular pharmacology 19 22851714
2013 Structural basis of ion permeation gating in Slo2.1 K+ channels. The Journal of general physiology 18 24166878
2016 Cardiac Slo2.1 Is Required for Volatile Anesthetic Stimulation of K+ Transport and Anesthetic Preconditioning. Anesthesiology 17 26845140
2015 Identification of the Intracellular Na+ Sensor in Slo2.1 Potassium Channels. The Journal of biological chemistry 17 25903137
2014 Cell volume changes regulate slick (Slo2.1), but not slack (Slo2.2) K+ channels. PloS one 17 25347289
2023 KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties. Annals of neurology 16 37062836
2018 Chemogenetic Enhancement of Axon Regeneration Following Peripheral Nerve Injury in the SLICK-A Mouse. Brain sciences 16 29786639
2012 PIP₂ modulation of Slick and Slack K⁺ channels. Biochemical and biophysical research communications 15 22728883
2017 Tumor necrosis factor α modulates sodium-activated potassium channel SLICK in rat dorsal horn neurons via p38 MAPK activation pathway. Journal of pain research 14 28579824
2019 Impact of slick hair trait on physiological and reproductive performance in beef heifers consuming ergot alkaloids from endophyte-infected tall fescue1. Journal of animal science 13 30772895
2015 Transcriptional Regulation of the Sodium-activated Potassium Channel SLICK (KCNT2) Promoter by Nuclear Factor-κB. The Journal of biological chemistry 13 26100633
2021 Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy. Frontiers in genetics 12 34276763
2022 Slick Potassium Channels Control Pain and Itch in Distinct Populations of Sensory and Spinal Neurons in Mice. Anesthesiology 10 35303056
2020 Additional observation of a de novo pathogenic variant in KCNT2 leading to epileptic encephalopathy with clinical features of frontal lobe epilepsy. Brain & development 10 32773162
2021 SLO2.1/NALCN a sodium signaling complex that regulates uterine activity. iScience 9 34746693
2020 Long Non-Coding RNA HAND2-AS1 Inhibits Growth and Migration of Gastric Cancer Cells Through Regulating the miR-590-3p/KCNT2 Axis. OncoTargets and therapy 9 32368078
2015 Hydrophobic interactions between the S5 segment and the pore helix stabilizes the closed state of Slo2.1 potassium channels. Biochimica et biophysica acta 8 26724206
2015 Identification of potential novel interaction partners of the sodium-activated potassium channels Slick and Slack in mouse brain. Biochemistry and biophysics reports 8 29124216
2014 Intracellular ATP does not inhibit Slo2.1 K+ channels. Physiological reports 8 25214519
2024 Thermotolerance capabilities, blood metabolomics, and mammary gland hemodynamics and transcriptomic profiles of slick-haired Holstein cattle during mid lactation in Puerto Rico. Journal of dairy science 7 38246540
2020 New mutations in KCNT2 gene causing early infantile epileptic encephalopathy type 57: Case study and literature review. Acta biochimica Polonica 7 32931186
2017 Heteromeric Slick/Slack K+ channels show graded sensitivity to cell volume changes. PloS one 6 28222129
2021 Exposure and Recovery of the Gulf Toadfish (Opsanus beta) to Weathered Deepwater Horizon Slick Oil: Impacts on Liver and Blood Endpoints. Environmental toxicology and chemistry 5 33326153
2024 Circular RNA-GRIN2B Suppresses Neuropathic Pain by Targeting the NF-κB/SLICK Pathway. Neuromolecular medicine 3 38600344
2024 Slick potassium channels limit TRPM3-mediated activation of sensory neurons. Frontiers in pharmacology 2 39744124
2023 Lhermitte-Duclos disease with concomitant KCNT2 gene mutation: report of an extremely rare combination. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2 37368068
2025 SLICK: A Sandwich-LIke Culturing Kit for in situ Cryo-ET Sample Preparation. bioRxiv : the preprint server for biology 1 39990359
2024 Identification of a novel KCNT2 variant in a family with developmental and epileptic encephalopathies: a case report and literature review. Frontiers in genetics 1 38510274
2026 Slick K+ channels contribute to cardiac remodeling, fibrosis and dysfunction in post-infarction hearts. JCI insight 0 41842949
2025 Quantitative analysis of yearling traits in Senepol cattle carrying the slick hair gene. Tropical animal health and production 0 40624397
2025 KCNT1 (Slack/Slo2.2) and KCNT2 (Slick/Slo2.1) Dysregulation in Intellectual Disability and Behavioral Phenotypes: A Systematic Review. Cureus 0 41189825
2021 Long Non-Coding RNA HAND2-AS1 Inhibits Growth and Migration of Gastric Cancer Cells Through Regulating the miR-590-3p/KCNT2 Axis [Retraction]. OncoTargets and therapy 0 34675541