Affinage

KCNB1

Potassium voltage-gated channel subfamily B member 1 · UniProt Q14721

Length
858 aa
Mass
95.9 kDa
Annotated
2026-06-10
100 papers in source corpus 55 papers cited in narrative 55 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNB1 encodes Kv2.1, a voltage-gated delayed-rectifier K+ channel whose biology is split between a canonical conducting role in membrane repolarization and a non-conducting structural role organizing ER–plasma membrane junctions (PMID:20566856, PMID:25908859). As a channel, Kv2.1 assembles as a tetramer through T1-domain determinants (a CDD motif and His105) that also govern heteromerization with silent regulatory subunits such as Kv5.1 and Kv6.1, which reshape its gating (PMID:19717558, PMID:19074135, PMID:9696692, PMID:8980147), and it is decorated by accessory subunits AMIGO, MiRP2/KCNE3, and MinK/MiRP1 that tune current density and kinetics (PMID:22056818, PMID:12954870, PMID:19219384). Its voltage dependence is graded by an unusually rich array of reversible modifications: multisite C-terminal serine phosphorylation by CDK5 and AMPK opposed by calcineurin-mediated dephosphorylation (PMID:16917065, PMID:9351973, PMID:22006306, PMID:21712386), Src-mediated tyrosine phosphorylation (PMID:12615930), SUMOylation at K470 (PMID:21518833, PMID:19223394), and PIP2 binding (PMID:29379118), so that activity-dependent signals (e.g. extrasynaptic NMDA receptor activation) reset neuronal excitability through cluster dispersal and dephosphorylation (PMID:18753382). Strikingly, only ~2% of surface channels conduct, while clustered channels are largely electrically silent and instead tether cortical ER to the plasma membrane via the VAP-family protein VAPA, an interaction directed by an autonomous, actin-gated C-terminal targeting module (PMID:8978827, PMID:20566856, PMID:25908859, PMID:16988031, PMID:32937450). These non-conducting junctions scaffold Ca2+ signaling triads coupling L-type Ca2+ channels to ryanodine receptors, support activity-dependent ER Ca2+ uptake and synaptic vesicle fusion, organize membrane-protein trafficking platforms, and drive insulin granule recruitment in beta-cells—functions that survive in clustering-competent but conduction-independent constructs (PMID:31663850, PMID:35862456, PMID:22648171, PMID:28607108, PMID:24962901). In pancreatic beta-cells Kv2.1 dominates action-potential repolarization and restrains glucose-stimulated insulin secretion, and is itself regulated by SNARE proteins, lipid rafts, and incretin/leptin signaling (PMID:12270920, PMID:12403834, PMID:15073181, PMID:26453299). Kv2.1 also executes a pro-apoptotic program in which oxidant- or injury-triggered Zn2+/CaMKII signaling drives SNARE-dependent insertion of channels and a surge of K+ efflux, gated by coordinated Src-Y124 and p38-S800 phosphorylation and Cys73-dependent oxidative oligomerization that activates integrin-FAK and c-Src/JNK signaling (PMID:12832499, PMID:23918396, PMID:23275378, PMID:28383553, PMID:23223293, PMID:26115091). Beyond neurons it organizes integrin α5β5 "integrin-K+ channel complexes" required for neocortical neuronal migration and connectivity, and contributes a sex-dependent structural role in arterial smooth muscle by clustering CaV1.2 (PMID:36207442, PMID:32015129). De novo KCNB1 missense mutations cause epileptic encephalopathy, acting through loss of ion selectivity with a gained inward cation conductance, dominant-negative suppression of endogenous Kv2 current, or disruption of the non-conducting ER–PM junction–inducing and integrin-signaling functions (PMID:25164438, PMID:26503721, PMID:26477325, PMID:33132203, PMID:36207442).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1995 High

    Established a high-affinity pharmacological probe and showed Kv2.1's toxin sensitivity maps outside the canonical scorpion-toxin pore region, defining a distinct gating-modifier interaction surface.

    Evidence Tarantula hanatoxin isolation and voltage-clamp kinetics across channel families

    PMID:7576642

    Open questions at the time
    • Structural basis of the hanatoxin binding site not resolved
    • Does not address physiological regulation
  2. 1997 High

    Localized the gating-modulatory phosphorylation to the C-terminal cytoplasmic domain, establishing that reversible C-terminal serine phosphorylation directly sets Kv2.1 voltage dependence.

    Evidence C-terminal truncation, 32P labeling, and patch-clamp with intracellular phosphatase rescue

    PMID:9351973

    Open questions at the time
    • Specific kinases and sites not yet identified
    • Number of functional phospho-sites unknown
  3. 1996 High

    Defined an autonomous C-terminal cytoplasmic domain necessary and sufficient for high-density clustering and polarized targeting, the first hint that localization is genetically separable from channel function.

    Evidence Truncation and chimeric constructs in polarized MDCK cells with detergent-solubility analysis

    PMID:8978827

    Open questions at the time
    • Molecular tether mediating clustering not identified
    • Link between detergent insolubility and cytoskeleton not directly shown
  4. 1996 High

    Showed Kv2.1 coassembles with silent Kv6 subunits to generate heteromeric channels with novel gating, expanding the functional repertoire of Kv2.1-containing channels.

    Evidence Two-electrode voltage-clamp and yeast two-hybrid of N-terminal interactions (Kv6.1; extended to Kv5.1/Kv6.1)

    PMID:8980147 PMID:9696692

    Open questions at the time
    • Stoichiometry of heteromers in vivo unknown
    • Physiological contexts of silent-subunit modulation not defined
  5. 2003 High

    Demonstrated Kv2.1 is the dominant beta-cell delayed rectifier restraining insulin secretion, defining a non-neuronal physiological role in glucose homeostasis.

    Evidence Dominant-negative knockout, selective antagonist, Ca2+ imaging, and islet perfusion

    PMID:12270920

    Open questions at the time
    • Did not yet distinguish conducting vs structural contributions to secretion
    • In vivo whole-animal phenotype not addressed
  6. 2003 High

    Identified Kv2.1 as necessary and sufficient for the apoptotic K+ efflux in neurons, linking the channel to programmed cell death.

    Evidence Dominant-negative expression and reconstitution in channel-null CHO cells with multiple apoptogens

    PMID:12832499

    Open questions at the time
    • Mechanism of the apoptotic current surge not defined
    • Signaling triggers upstream unknown
  7. 2003 High

    Mapped early protein interactions and modifications governing channel function: SNAP-25 binding to the N-terminus, Src phosphorylation of T1-domain Y124, and direct N–C terminal interaction controlling kinetics.

    Evidence Co-IP, in vitro kinase/substrate-trapping, GST pulldown, and electrophysiology

    PMID:12403834 PMID:12560340 PMID:12615930

    Open questions at the time
    • Whether these interactions cooperate was not established
    • In vivo relevance of Y124 phosphorylation not tested
  8. 2006 High

    Established graded, multisite phosphorylation as the logic of Kv2.1 regulation and showed the C-terminal domain is a transferable module conferring clustering, gating, and cholinergic/calcineurin modulation.

    Evidence MS-SILAC site mapping with additive mutagenesis; domain-swap chimeras with biochemical and electrophysiological readouts; FRET reporting N–C domain rearrangement on gating

    PMID:16407566 PMID:16690619 PMID:16917065

    Open questions at the time
    • Individual kinases for most sites not yet assigned
    • Structural model of clustering still absent
  9. 2006 High

    Revealed cortical actin as a perimeter fence retaining mobile channels within clusters and restricting somatic localization, providing the cytoskeletal basis for cluster organization.

    Evidence FRAP, quantum-dot tracking, and latrunculin A disruption in HEK cells and neurons

    PMID:16988031

    Open questions at the time
    • Molecular link between C-terminus and actin not defined
    • How clusters nucleate not addressed
  10. 2008 High

    Connected physiological signaling to Kv2.1 regulation by showing extrasynaptic NMDA receptor activation specifically declusters and dephosphorylates the channel, and linked Kv2.1 to integrin/FAK signaling via an N-terminal LD-like motif.

    Evidence Pharmacological synaptic/extrasynaptic dissection with biochemical and electrophysiological readouts; co-IP, knockdown, and migration assays

    PMID:18615577 PMID:18753382

    Open questions at the time
    • FAK interaction confidence is Medium and single-lab
    • Physiological trigger linking glutamate to FAK not unified
  11. 2009 High

    Defined T1-domain assembly determinants (CDD motif) and demonstrated SUMOylation as a reversible inhibitory modification of beta-cell and neuronal Kv2.1 current.

    Evidence FRET/co-IP charge-reversal mutagenesis; SUMO1 infusion with SENP1 rescue in HEK and human beta-cells; NFATc3-dependent transcriptional downregulation in smooth muscle; MinK/MiRP1 cardiac complexes

    PMID:15322114 PMID:19219384 PMID:19223394 PMID:19717558

    Open questions at the time
    • Coordination between SUMO and phospho-regulation not resolved
    • Cardiac role of Kv2.1 physiologically uncertain (Medium evidence)
  12. 2010 High

    Overturned the assumption that clusters are conducting reservoirs by showing only ~2% of surface channels conduct and declustering does not unmask current, separating Kv2.1's conducting and clustering roles.

    Evidence Spatially resolved cell-attached single-channel recording with FRAP, phosphatase, and actin perturbation

    PMID:20566856

    Open questions at the time
    • Function of the non-conducting cluster pool not yet known at this point
    • Why most channels are silent unexplained
  13. 2011 High

    Assigned specific kinases to the graded regulation: CDK5 sets the constitutive high-phosphorylation state, AMPK phosphorylates S440 to hyperpolarize gating and reduce firing, and SUMOylation occurs at K470 with single-subunit graded effects.

    Evidence In vitro kinase assays, phosphospecific antibodies, MS, mutagenesis, and single-channel recordings in neurons

    PMID:21518833 PMID:21712386 PMID:22006306 PMID:22056818

    Open questions at the time
    • Integration of multiple kinase inputs in vivo not modeled
    • Upstream activation of CDK5/AMPK pools on Kv2.1 unclear
  14. 2012 High

    Demonstrated clusters function as exocytic insertion platforms for membrane proteins and that oxidative Cys73 oligomerization blocks endocytosis to drive raft disruption and c-Src/JNK pro-apoptotic signaling.

    Evidence TIRF-FRAP and quantum-dot trafficking imaging; biochemical oligomerization, dynamin/cholesterol manipulation, and kinase inhibition with C73A control

    PMID:22648171 PMID:23275378

    Open questions at the time
    • Identity of the oxidant sensor coupling to Cys73 in vivo not defined
    • How clusters template exocytosis mechanistically unresolved
  15. 2013 High

    Defined the apoptotic insertion cascade: oxidant-evoked Ca2+/CaMKII modulates the syntaxin–Kv2.1 interaction to drive SNARE-dependent surface insertion and the lethal K+ surge.

    Evidence CaMKII inhibition, Ca2+ imaging, syntaxin co-IP, electrophysiology, and viability assays

    PMID:23918396

    Open questions at the time
    • SNARE machinery components beyond syntaxin not fully mapped
    • Link to physiological injury triggers indirect
  16. 2014 High

    First identified KCNB1 as a human disease gene, with de novo missense mutations causing epileptic encephalopathy through loss of ion selectivity and a gained depolarizing cation conductance, and localized Kv2.1 clusters adjacent to RyR cisternae in striatal neurons.

    Evidence Exome sequencing with heterologous functional electrophysiology; EM-immunogold and phosphospecific labeling in MSNs

    PMID:24962901 PMID:25164438

    Open questions at the time
    • Whether conducting or non-conducting defects dominate disease not resolved
    • In vivo neuronal consequences of mutations not yet tested
  17. 2015 High

    Resolved distinct disease mechanisms (loss of selectivity, voltage-sensor disruption, dominant-negative pore mutations), defined dual Golgi-dependent/independent trafficking to soma vs AIS, and showed the clustering role—not conductance—drives beta-cell granule recruitment.

    Evidence Heterologous and endogenous-neuron electrophysiology of patient variants; FRAP with Golgi-pathway dissection; clustering-deficient ΔC318 mutant with TIRF granule imaging

    PMID:26442584 PMID:26477325 PMID:26503721 PMID:28607108 PMID:29042434 PMID:29379118

    Open questions at the time
    • AIS trafficking motif's binding partners unknown
    • Functional significance of M-phase clustering (Medium) not established
  18. 2015 High

    Established that pro-apoptotic Y124 and S800 phosphorylation are co-dependent and that beta-cell incretin/leptin and CXCR4 signaling route through Kv2.1 modification to set survival vs death outcomes.

    Evidence Phosphospecific co-IP and combinatorial mutagenesis (Y124/S800/C73); incretin PKA/MSK-1/CBP and leptin AMPK/PKA pathway dissection; CXCR4-p38-S800A causal mutant

    PMID:21818121 PMID:23223293 PMID:26115091 PMID:26453299

    Open questions at the time
    • Several pathway steps are Medium-confidence single-lab
    • Spatial coordination of Src and p38 on the channel not visualized
  19. 2019 High

    Showed clustered Kv2.1 builds ER–PM junctions that scaffold LTCC–RyR Ca2+ triads and unexpectedly enhance LTCC opening at polarized potentials, defining a non-conducting Ca2+-signaling organizer role.

    Evidence BioID proximity proteomics, co-localization, Ca2+ spark imaging, LTCC single-channel recording, and Kv2.1 KO/KD

    PMID:31663850

    Open questions at the time
    • Mechanism by which clusters enhance LTCC opening unresolved
    • Direct vs indirect Kv2.1–LTCC contacts not defined
  20. 2020 High

    Identified VAPA as the ER tether mediating Kv2.1-dependent junctions, showed a peptide disrupting Kv2.1–VAPA is neuroprotective in ischemia, and dissected a sex-dependent structural Kv2.1 role clustering CaV1.2 in arterial myocytes; a DEE variant fails to induce junctions dominant-negatively.

    Evidence TAT-peptide disruption with co-IP and in vivo ischemia-reperfusion; KO with TIRF CaV1.2 imaging and sex stratification; HEK ER-PM junction assay of G379R

    PMID:32015129 PMID:32937450 PMID:33132203

    Open questions at the time
    • G379R junction defect is Medium-confidence heterologous only
    • Whether VAPA is the sole ER tether across cell types unknown
  21. 2022 High

    Cemented the essential non-conducting roles: VAP-dependent Kv2.1 enables activity-dependent ER Ca2+ uptake and synaptic vesicle fusion, and KCNB1 forms integrin α5β5 complexes required for neocortical migration, with a DEE knock-in mouse rescued by FAK activation.

    Evidence shRNA knockdown with compartmental Ca2+ and SV-fusion imaging; KCNB1 null and R312H knock-in mice with co-IP and angiotensin-II FAK rescue

    PMID:35862456 PMID:36207442

    Open questions at the time
    • How integrin-FAK signaling drives migration mechanistically incomplete
    • Relative contribution of conducting vs structural roles to brain development not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dozens of phosphorylation, SUMOylation, oxidation, and lipid inputs are integrated in space and time to switch Kv2.1 between conducting, junction-organizing, and pro-apoptotic states remains unresolved, as does a unified structural model of the cluster and its ER tether.
  • No high-resolution structure of the clustered channel–VAPA junction
  • Quantitative model integrating multisite modifications absent
  • Causal hierarchy of conducting vs structural deficits in human disease unsettled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0005215 transporter activity 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 3 GO:0005856 cytoskeleton 3
Pathway
R-HSA-1643685 Disease 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 1
Partners
AMIGO1ITGA5KCNE3KCNG1PTK2SNAP25STX1AVAPA
Complex memberships
Kv2.1 homotetramer / Kv2.1-Kv6.1 heterotetramerKv2.1-LTCC-RyR Ca2+ signaling triadKv2.1-VAPA ER-PM junction complexintegrin α5β5-K+ channel complex (IKC)

Evidence

Reading pass · 55 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Kv2.1 is graded-regulated by variable phosphorylation: mass spectrometry-SILAC identified 16 phosphorylation sites, of which 7 are dephosphorylated by calcineurin. Mutation of individual calcineurin-regulated sites to alanine produced incremental hyperpolarizing shifts in voltage-dependent activation, while aspartate mutations conferred resistance to calcineurin. Multiple site mutations were additive, demonstrating that variable phosphorylation at many sites allows graded, activity-dependent regulation of Kv2.1 gating and neuronal firing. Mass spectrometry-SILAC, site-directed mutagenesis, whole-cell patch-clamp Science High 16917065
1995 Hanatoxin (HaTx1/2) from Chilean tarantula venom inhibits Kv2.1 channels with Kd ~42 nM via a bimolecular reaction. The toxin binding site is distinct from the scorpion toxin site (S5-S6 linker), as regions outside this linker determine HaTx sensitivity. Shaker-, Shaw-, and eag-family channels are relatively insensitive, while Shal-related channels are sensitive. Peptide isolation, bacterial expression, voltage-clamp electrophysiology, kinetic analysis Neuron High 7576642
2003 Kv2.1-encoded K+ channels are necessary and sufficient for the apoptotic K+ efflux in cortical neurons. Dominant-negative Kv2.1 expression eliminated the enhancement of K+ currents accompanying apoptosis and protected neurons from oxidant- and staurosporine-induced death. CHO cells (lacking endogenous voltage-gated K+ channels) became more susceptible to apoptosis after Kv2.1 transfection. Dominant-negative expression, whole-cell patch-clamp, cell viability assays The Journal of Neuroscience High 12832499
2002 Kv2.1 is the dominant voltage-dependent K+ channel in pancreatic beta-cells, responsible for action potential repolarization. Dominant-negative knockout of Kv2.1 enhanced glucose-stimulated insulin secretion. A selective Kv2.1 antagonist (C-1) blocked Kv2.1-mediated currents, enhanced membrane depolarization and Ca2+ responses to glucose, and augmented first- and second-phase insulin secretion from perfused pancreas. Dominant-negative expression, whole-cell patch-clamp, intracellular Ca2+ imaging, isolated islet perfusion The Journal of Biological Chemistry High 12270920
1997 Phosphorylation of the Kv2.1 C-terminal cytoplasmic domain (residues 667–853) shifts voltage-dependent activation to more depolarized potentials. Intracellular alkaline phosphatase eliminated differences in voltage dependence between wild-type and C-terminal truncation mutants, demonstrating that C-terminal phosphorylation directly modulates Kv2.1 gating. Phosphorylation was restricted to serine residues. Truncation mutagenesis, 32P in vivo labeling, phosphoamino acid analysis, whole-cell patch-clamp with intracellular alkaline phosphatase Molecular Pharmacology High 9351973
1996 A cytoplasmic domain of Kv2.1 (amino acids 536–666 in the C-terminus) is necessary and sufficient for polarized lateral membrane targeting and high-density cluster formation. This domain also correlates with detergent insolubility, suggesting interaction with the detergent-insoluble cytoskeleton underlies proper localization. C-terminal truncation mutants expressed in MDCK cells, chimeric HA-Kv2.1 constructs, immunofluorescence, detergent solubility assay The Journal of Cell Biology High 8978827
2010 Clustered Kv2.1 channels do not efficiently conduct K+; nonclustered channels carry the high-threshold delayed-rectifier current. Only ~2% of surface channels conduct. Dephosphorylation (alkaline phosphatase) caused a 25 mV hyperpolarizing shift without increasing whole-cell current, while actin depolymerization-induced declustering did not alter activation midpoint. Thus clusters do not contain a reservoir of non-conducting channels released upon declustering. Cell-attached patch clamp at defined surface locations (clustered vs. non-clustered), FRAP, alkaline phosphatase treatment, actin depolymerization Proceedings of the National Academy of Sciences High 20566856
2015 Kv2.1 clustering directly induces stable endoplasmic reticulum–plasma membrane junctions (EPJs). Using TIRF and electron microscopy, clustered Kv2.1 was shown to tether cortical ER to the plasma membrane in HEK 293 cells and hippocampal neurons. These non-conducting clusters serve as membrane-trafficking hubs for delivery and retrieval of multiple membrane proteins. Glutamate exposure causes loss of Kv2.1 clusters and retraction of cortical ER from the plasma membrane. TIRF microscopy, electron microscopy, live imaging, glutamate treatment Journal of Cell Science High 25908859
2011 AMPK directly phosphorylates Kv2.1 at S440 and S537. Phosphorylation at S440 (but not S537) mediates hyperpolarizing shifts in voltage-dependent activation and inactivation. In cultured rat hippocampal neurons, AMPK activation reduced neuronal firing frequency. Effects were abolished by S440A substitution, confirmed by phosphospecific antibodies and quantitative mass spectrometry. In vitro kinase assay, phosphospecific antibodies, quantitative mass spectrometry, site-directed mutagenesis, whole-cell patch-clamp, intracellular dialysis with thiophosphorylated AMPK Proceedings of the National Academy of Sciences High 22006306
2011 SUMO1 is conjugated to Kv2.1 at lysine K470 on the neuronal cell surface, shifting the half-maximal activation voltage (V1/2) by up to 35 mV. Only K470 is sumoylated; no more than two non-adjacent subunits in the tetramer carry SUMO concurrently. One SUMO shifts V1/2 by 15 mV; two SUMOs produce the full response, demonstrating graded regulation of neuronal excitability. SUMO conjugation assays, K470 mutagenesis, single-channel recordings, immunostaining of native SUMO and Kv2.1 in hippocampal neurons The Journal of General Physiology High 21518833
2011 CDK5 directly phosphorylates Kv2.1 and determines the constitutive high phosphorylation state of the channel in neurons. CDK5 also controls the rapid increase in Kv2.1 phosphorylation upon activity blockade and the recovery of phosphorylation after stimulus-induced dephosphorylation. CDK5 regulation of Kv2.1 is independent of CDK5's previously described regulation of PP1. In vitro kinase assay, CDK5 inhibition (pharmacological and genetic), phosphospecific antibody immunoblotting in hippocampal neurons The Journal of Biological Chemistry High 21712386
2006 The Kv2.1 cytoplasmic C-terminal domain is an autonomous transferable module sufficient to confer Kv2.1-like phosphorylation-dependent clustering, voltage-dependent activation, and muscarinic (cholinergic) modulation to heterologous Kv channels. Cholinergic stimulation triggers Ca2+/calcineurin-dependent dephosphorylation of Kv2.1, dispersal of clusters, and hyperpolarizing shifts in gating. Chimeric Kv channel constructs, immunocytochemistry, biochemical phosphorylation assays, patch-clamp in HEK293 cells and hippocampal neurons The Journal of Neuroscience High 16407566
1998 Kv5.1 and Kv6.1 are regulatory (silent) alpha-subunits that coassemble with Kv2.1 into heterotetrameric channels with altered gating. Kv2.1/Kv5.1 selectively accelerated inactivation at intermediate potentials and cumulative inactivation, and slowed deactivation. Kv2.1/Kv6.1 shifted activation to negative potentials and markedly slowed deactivation. Heteromeric assembly was confirmed by co-immunoprecipitation and single-channel conductance heterogeneity. Two-electrode voltage-clamp in Xenopus oocytes, co-immunoprecipitation, single-channel recordings The American Journal of Physiology High 9696692
1996 Kv6.1 and Kv2.1 form heterotetrameric channels with a novel current distinct from homomeric Kv2.1, including decreased deactivation rates, decreased TEA sensitivity, and a hyperpolarizing shift of half-maximal activation. Protein-protein interaction between Kv2.1 and Kv6.1 N-termini was confirmed by yeast two-hybrid; Kv6.1 amino termini could not form homomultimers but specifically interacted with Kv2.1 N-termini. Two-electrode voltage-clamp in Xenopus oocytes, yeast two-hybrid assay FEBS Letters High 8980147
2006 Kv2.1 surface clusters are bounded by a cortical actin-based perimeter fence. Channels within clusters are mobile (FRAP tau ~14 s) but are retained within the cluster boundary. Latrunculin A treatment caused cluster enlargement and loss of soma restriction, demonstrating that cortical actin maintains both cluster size and somatic localization. Channels lacking the C-terminus do not form clusters and diffuse freely. FRAP, quantum dot single-channel tracking, latrunculin A treatment, GFP-Kv2.1 live imaging in HEK cells and hippocampal neurons The Journal of Neuroscience High 16988031
2012 Kv2.1 surface clusters serve as specialized insertion platforms for membrane protein trafficking. TIRF-FRAP and quantum dot imaging showed >85% of cytoplasmic and recycling Kv2.1, and >85% of recycling Kv1.4, are delivered to the cell surface at Kv2.1 cluster perimeters. Actin depolymerization redirected Kv2.1 exocytosis to cluster-free membrane areas. TIRF-FRAP, quantum dot single-channel imaging, actin depolymerization, live-cell imaging in HEK cells and hippocampal neurons Molecular Biology of the Cell High 22648171
2019 Kv2.1 clustering at ER-plasma membrane junctions promotes spatial and functional coupling of L-type Ca2+ channels (LTCCs) to ryanodine receptor (RyR) ER Ca2+ release channels. Kv2.1 clustering unexpectedly enhanced LTCC opening at polarized membrane potentials. This enabled Kv2.1-LTCC-RyR triads to generate localized Ca2+ sparks independently of action potentials. Proximity proteomics (BioID), immunofluorescence co-localization, Ca2+ spark imaging, LTCC single-channel recordings, Kv2.1 knockout/knockdown eLife High 31663850
2003 SNAP-25 associates with Kv2.1 via the channel's N-terminus and reduces Kv2.1-mediated currents by ~70% in heterologous cells and ~40% in rat beta-cells. Co-dialysis of a Kv2.1 N-terminal peptide partially relieved inhibition. SNAP-25 had no effect on beta-cell K+ currents after dominant-negative Kv2.1 knockout, confirming specificity. Co-immunoprecipitation, in vitro peptide binding, whole-cell patch-clamp, dominant-negative KO in beta-cells Molecular Endocrinology High 12403834
2004 Kv2.1 and CaV1.2 (but not Kv1.4, SUR1, or Kir6.2) localize to cholesterol-rich lipid raft domains in pancreatic beta-cell plasma membranes, along with SNARE proteins syntaxin 1A, SNAP-25, and VAMP-2. Disruption of lipid rafts by methyl-β-cyclodextrin shunts Kv2.1 out of rafts and inhibits Kv2.1 (but not CaV1.2) channel activity, enhancing insulin exocytosis. Detergent-resistant membrane fractionation, methyl-β-cyclodextrin treatment, whole-cell patch-clamp, single-cell exocytosis imaging The Journal of Biological Chemistry High 15073181
2004 Syntaxin 1A (Syx) physically interacts with the Kv2.1 C-terminus at the cell surface, causing hyperpolarizing shifts in steady-state activation and inactivation. Peptides competing for Syx binding to the C-terminus reversed these effects when injected into oocytes already co-expressing both proteins. The t-SNARE complex (Syx/SNAP-25) also binds the Kv2.1 C-terminus and modulates inactivation; partial C-terminal deletions dissipated both interactions. Competitive peptide injection in Xenopus oocytes, C-terminal deletion mutagenesis, two-electrode voltage-clamp Molecular Pharmacology High 15525758
2003 Tyrosine 124 in the T1 cytosolic domain of Kv2.1 is phosphorylated by Src kinase in vitro and in cells. Y124 phosphorylation is critical for Src-mediated upregulation (~3-fold) of Kv2.1 K+ current; Y124F mutation greatly reduced current upregulation by Src. The phosphatase cyt-PTPepsilon dephosphorylates Y124, counteracting Src. Expression, localization, and voltage dependence were unchanged in Y124F channels. In vitro kinase assay, substrate-trapping mutant co-IP, site-directed mutagenesis (Y124F), whole-cell patch-clamp The Journal of Biological Chemistry High 12615930
2008 Extrasynaptic (but not synaptic) NMDA receptor activation potently unclusters and dephosphorylates Kv2.1, producing a hyperpolarizing shift in voltage-dependent activation of hippocampal I_K. Inhibition of glutamate transporters (EAAT2) activated extrasynaptic NMDA receptors and dephosphorylated Kv2.1. Moderate seizure activity in vivo did not dephosphorylate Kv2.1, demonstrating specificity for extrasynaptic receptor pools. Bath NMDA application, selective extrasynaptic NMDA receptor activation, EAAT inhibition, immunoblot for Kv2.1 phosphorylation, immunofluorescence cluster analysis, whole-cell patch-clamp The Journal of Neuroscience High 18753382
2013 CaMKII activation (triggered by oxidant-induced intracellular Ca2+ release) is required for the pro-apoptotic insertion of Kv2.1 channels into the plasma membrane. CaMKII modulates the interaction of syntaxin with Kv2.1, enabling the SNARE-dependent membrane insertion responsible for the K+ current surge that drives apoptotic K+ loss. CaMKII inhibition prevented K+ current enhancement and increased neuronal viability. Pharmacological and molecular CaMKII inhibition, intracellular Ca2+ imaging, whole-cell patch-clamp, syntaxin-Kv2.1 co-IP, cell viability assay Proceedings of the National Academy of Sciences High 23918396
2011 AMIGO (an adhesion protein with LRR and Ig domains) is an auxiliary subunit of the Kv2.1 channel complex, showing extensive co-localization and co-immunoprecipitation with Kv2.1 in mouse brain. AMIGO increases Kv2.1 conductance in a voltage-dependent manner in HEK cells. Inhibition of endogenous AMIGO suppresses neuronal I_K at negative membrane voltages. Co-immunoprecipitation from mouse brain, immunohistochemistry, whole-cell patch-clamp in HEK cells and hippocampal neurons, endogenous AMIGO RNAi knockdown EMBO Reports High 22056818
2003 The N- and C-terminal intracellular regions of Kv2.1 interact directly (demonstrated by GST pulldown of the N-terminus binding the C-terminus) and together determine channel activation kinetics. Specific residues in the N-terminal T1 domain (Q67, D75) and the C-terminal CTA domain (aa 740–853) modulate activation rate, and N-C terminal interactions are required for normal kinetics. GST fusion protein pulldown, chimeric channels between human and rat Kv2.1, two-electrode voltage-clamp in Xenopus oocytes The Journal of Biological Chemistry High 12560340
2006 Voltage-gating of Kv2.1 induces relative rearrangements between N- and C-terminal domains: FRET between N- and C-terminal fluorescent tags on the same or different subunits decreased upon depolarization (+60 mV). N-terminal tags did not rearrange relative to each other. These movements occur in a plane parallel to the plasma membrane within 1–10 nm, and are distinct from movements relative to the membrane. FRET microscopy with N- and C-terminal CFP/YFP fusions, combined with patch-clamp (COS1 cells) The Journal of Biological Chemistry High 16690619
2008 Kv2.1 forms a complex with focal adhesion kinase (FAK) through an LD-like motif in its N-terminus, promoting FAK phosphorylation at Y397 and Y576/577. FAK expression promotes polarized membrane distribution of Kv2.1. shRNA knockdown of Kv2.1 or N-terminal point mutations minimized FAK phosphorylation and impaired cell migration. Co-immunoprecipitation, shRNA knockdown, N-terminal point mutations, phosphospecific immunoblotting, migration assays Journal of Cellular Physiology Medium 18615577
2014 De novo KCNB1 missense mutations causing epileptic encephalopathy result in loss of Kv2.1 ion selectivity and gain of a depolarizing inward cation conductance, as established by heterologous expression and functional electrophysiology in three patients. Whole exome sequencing, heterologous expression in mammalian cells, whole-cell patch-clamp Annals of Neurology High 25164438
2015 The KCNB1-V378A epileptic encephalopathy variant produces voltage-activated but non-selective Kv2.1 currents (loss of ion selectivity while retaining voltage sensitivity). Cell-type-dependent differences in expression and subcellular localization of V378A were observed, and co-expression of V378A and wild-type Kv2.1 reciprocally affected their trafficking. Heterologous expression, whole-cell patch-clamp, guangxitoxin-1E pharmacology, immunofluorescence The Journal of General Physiology High 26503721
2015 KCNB1-R306C (voltage sensor) disrupted voltage sensor sensitivity and cooperativity, while KCNB1-G401R (pore domain) selectively abolished endogenous Kv2 currents in transfected pyramidal neurons via dominant-negative action. Both mutants inhibited repetitive neuronal firing by preventing production of deep interspike voltages. Heterologous expression, whole-cell patch-clamp, endogenous Kv2 current measurement in pyramidal neurons, dominant-negative functional testing Scientific Reports High 26477325
2009 SUMO1 conjugation to Kv2.1 inhibits K+ current by ~80% (direct recombinant SUMO1 infusion) or ~48% (SUMO1-YFP co-expression) in HEK cells, and by ~49% in human beta-cells. The inhibitory effect results from acceleration of inactivation and inhibition of recovery from inactivation, widening beta-cell action potentials and decreasing firing frequency. Effects are augmented by Ubc9 and rescued by SENP1. Co-immunoprecipitation, direct intracellular SUMO1 peptide infusion, whole-cell patch-clamp in HEK and beta-cells, SUMO protease rescue Journal of Cell Science High 19223394
2011 Incretin hormones GIP and GLP-1 promote phosphorylation and acetylation of Kv2.1 via PKA/MSK-1 and HAT/HDAC pathways in pancreatic beta-cells. Acetylation of Kv2.1 is mediated by nuclear/cytoplasmic shuttling of CREB binding protein (CBP) and its direct interaction with Kv2.1. These post-translational modifications of Kv2.1 underlie the prosurvival effects of incretins. Overexpression and pharmacological inhibition, phosphorylation/acetylation immunoblotting, CBP-Kv2.1 co-immunoprecipitation, nuclear shuttling assays Cell Death and Differentiation Medium 21818121
2017 Kv2.1 uses two distinct trafficking pathways to reach different subcellular compartments: the conventional Golgi-dependent secretory pathway for somatodendritic targeting, and a non-conventional Golgi-independent pathway for axon initial segment (AIS) targeting. A distinct AIS trafficking motif in the Kv2.1 C-terminus with putative phosphorylation sites is required for clustered AIS localization. FRAP, Golgi disruption pharmacology, mutagenesis of C-terminal AIS motif and phosphorylation sites, photoactivatable-GFP imaging in hippocampal neurons The Journal of Neuroscience High 29042434
2009 Conserved negatively charged aspartates (CDD motif) in the A/B linker of the T1 tetramerization domain are required for efficient assembly of both homotetrameric Kv2.1 and heterotetrameric Kv2.1/Kv6.4 channels. Charge-reversal arginine substitutions in Kv2.1 or Kv6.4 blocked tetramer assembly (FRET) without impairing trafficking to the membrane. FRET confocal microscopy, co-immunoprecipitation, immunocytochemistry, charge-reversal mutagenesis The Journal of Biological Chemistry High 19717558
2008 Histidine 105 in the T1 domain of Kv2.1 is required for heteromerization with Kv6.3 and Kv6.4 but not for Kv2.1 homoassembly. H105V or H105R mutations disrupted T1-T1 interaction with Kv6.3/Kv6.4 (yeast two-hybrid), reduced FRET between Kv2.1 and Kv6.3/6.4, prevented co-immunoprecipitation, and abolished Kv6.3/6.4-mediated shifts in voltage dependence of Kv2.1 activation. Yeast two-hybrid, FRET confocal microscopy, co-immunoprecipitation, site-directed mutagenesis, whole-cell patch-clamp The Journal of Biological Chemistry High 19074135
2012 Oxidized KCNB1 channels form oligomers held by Cys-73 disulfide bridges and accumulate in the plasma membrane due to defective dynamin 2-dependent endocytosis. KCNB1 oligomers in lipid rafts disrupt raft integrity and activate c-Src/JNK signaling to promote apoptosis. C73A-mutant channels do not oligomerize and are normally internalized. Biochemical oligomerization assays, dynamin inhibition, cholesterol manipulation, c-Src/JNK inhibition (pharmacological and molecular), co-immunoprecipitation The Journal of Biological Chemistry High 23275378
2017 Oxidized KCNB1 channels form macromolecular complexes with integrin alpha-5 (integrin-α5). Upon KCNB1 oxidation, the integrin-FAK-Src/Fyn apoptotic signaling cascade is activated. C73A non-oxidizable mutant channels retained integrin-α5 interaction but did not activate FAK/Src/Fyn, demonstrating that the oxidized state specifically triggers integrin signaling. Co-immunoprecipitation from mouse brain, pharmacological integrin/FAK inhibition, C73A KCNB1 mutant, FAK/Src kinase activity assays Cell Death & Disease High 28383553
2020 Kv2.1 mediates neuroprotection by maintaining ER-plasma membrane junctions through its interaction with VAPA. TAT-DP-2, a membrane-permeable peptide derived from Kv2.2 C-terminus, disrupts the Kv2.1-VAPA association, induces Kv2.1 declustering, prevents pro-apoptotic K+ current enhancement after injury, and reduces infarct size in murine ischemia-reperfusion, demonstrating that Kv2.1-VAPA interaction is required for post-injury channel clustering and cell death. TAT-peptide declustering, Kv2.1-VAPA co-immunoprecipitation, whole-cell patch-clamp, in vivo ischemia-reperfusion mouse model, infarct size measurement Science Advances High 32937450
2022 Kv2.1 (via its non-conducting structural role binding ER protein VAP/VAMP-associated protein) enables activity-dependent ER Ca2+ uptake in both soma and axons. Kv2.1 knockdown rendered the ER unable to accumulate Ca2+ during electrical activity and impaired synaptic vesicle fusion during stimulation, revealing an essential non-conducting role for Kv2.1 in maintaining ER Ca2+ homeostasis and synaptic transmission. Kv2.1 shRNA knockdown, live Ca2+ imaging in soma and axons, synaptic vesicle fusion assays, electrical stimulation protocols Proceedings of the National Academy of Sciences High 35862456
2015 In pancreatic beta-cells, Kv2.1 (but not Kv2.2) forms clusters of 6–12 tetrameric channels at the plasma membrane and facilitates insulin exocytosis by promoting secretory granule targeting. A truncated Kv2.1 (ΔC318) that retains electrical function and syntaxin 1A binding but cannot form clusters does not enhance granule recruitment or exocytosis, demonstrating that the structural clustering role—not K+ conductance—is required for exocytosis facilitation. Kv2.1 knockdown, Kv2.1-ΔC318 expression, TIRF microscopy of granule dynamics, whole-cell patch-clamp, T2D islet experiments Diabetes High 28607108
2003 MiRP2 (KCNE3) forms native complexes with Kv2.1 in rat brain (co-immunoprecipitation). MiRP2 reduces Kv2.1 current density and slows both activation and deactivation. Altering MiRP2 expression by RNAi or cDNA transfection toggles endogenous delayed-rectifier current magnitude and kinetics in PC12 cells and hippocampal neurons. Co-immunoprecipitation from rat brain, RNAi knockdown, cDNA overexpression, whole-cell patch-clamp in PC12 cells and hippocampal neurons The Journal of Neuroscience High 12954870
2009 MinK (KCNE1) and MiRP1 (KCNE2) form native cardiac complexes with Kv2.1 (co-immunoprecipitation from rat heart). Both reduce Kv2.1 current density and slow activation/deactivation. Disease-associated LQTS mutations in MinK and MiRP1 further alter Kv2.1 gating (D76N-MinK reduces current density 3-fold; I57T-MiRP1 slows activation 5-fold). Co-immunoprecipitation from rat heart, whole-cell patch-clamp in CHO cells with mutant subunit co-expression The Journal of Membrane Biology Medium 19219384
2011 Src kinase phosphorylates Kv2.1 at two novel tyrosine sites: Y686 (regulates channel activity, similar to Y124) and Y810 (regulates intracellular trafficking of Kv2.1 channels). Src also increases Kv2.1 protein expression levels. Mass spectrometry identification of phosphotyrosine sites, site-directed mutagenesis, whole-cell patch-clamp, Kv2.1 trafficking assays Journal of Proteome Research Medium 22106938
2015 During M-phase of the cell cycle, Kv2.1 undergoes increased phosphorylation at C-terminal sites and redistributes from diffuse to robust clusters at plasma membrane–ER membrane contact sites (PM:ER MCS) in COS-1 cells, inducing more extensive PM:ER MCS during mitosis. The same C-terminal targeting motif required for neuronal clustering is required for M-phase clustering. Phosphospecific immunoblotting, immunofluorescence, cell cycle synchronization, confocal microscopy in COS-1/CHO cells The Journal of Biological Chemistry Medium 26442584
2018 BACE2 cleaves Kv2.1 at three sites (Thr376, Ala717, Ser769), disrupts Kv2.1 clustering, reduces delayed rectifier I_K, and causes a hyperpolarizing shift in activation in primary neurons. BACE2-cleaved Kv2.1 fragments (Kv2.1-1-375, -1-716, -1-768) each reduce apoptosis, suggesting BACE2-mediated cleavage is neuroprotective. In vitro cleavage assay identifying cleavage sites, immunofluorescence clustering analysis, whole-cell patch-clamp, apoptosis assays Molecular Psychiatry Medium 29703946
2012 Acute SDF-1α/CXCR4 signaling causes calcineurin-dependent dephosphorylation and altered localization of Kv2.1, enhancing voltage-dependent activation (neuroprotective). Prolonged SDF-1α/CXCR4 signaling activates p38 MAPK, which phosphorylates Kv2.1 at S800 and enhances surface trafficking, predisposing neurons to excessive K+ efflux and apoptosis. Kv2.1-S800A mutant prevented CXCR4-dependent apoptosis. Immunoblotting for Kv2.1 phosphorylation, S800A mutagenesis, whole-cell patch-clamp, immunofluorescence cluster analysis, CXCR4 pharmacological/genetic manipulation The Journal of Neuroscience High 23223293
2015 PIP2 regulates Kv2.1 by modulating its inactivation mechanism: PIP2 prevents rundown and shifts voltage-dependence of inactivation in inside-out patches. PIP2 depletion accelerates closed-state inactivation and delays recovery from inactivation without affecting activation. Modeled by allosteric interaction of PIP2 with the inactivation gate. Excised inside-out patch clamp with exogenous PIP2, rapamycin-induced 5-phosphatase translocation (FKBP-Inp54p), M1 receptor activation Scientific Reports Medium 29379118
2015 The pro-apoptotic dual phosphorylation of Kv2.1 at Y124 (by Src) and S800 (by p38) is co-regulated: intact Y124 is required for p38 phosphorylation of S800, and Src phosphorylation of Y124 facilitates p38 action at S800. Conversely, S800A mutation reduces Src action on Y124. Cys73 (but not Cys710) at the N-terminus is required for p38-dependent S800 phosphorylation and apoptotic K+ current enhancement. Immunoprecipitation with phosphospecific antibodies, site-directed mutagenesis of Y124, S800, C73, C710, whole-cell patch-clamp in CHO cells PloS One Medium 26115091
2022 KCNB1 forms complexes with integrins α5β5 (integrin-K+ channel complexes, IKCs) in the neocortex. KCNB1 null mice show impaired neocortical neuronal migration, disrupted morphology and synaptic connectivity. Knock-in R312H mice (DEE variant) show the same developmental defects with impaired IKC biochemical signaling. Angiotensin II (FAK agonist) rescued R312H neuronal abnormalities in vitro, implicating non-conducting IKC signaling in cortical development. KCNB1 null and knock-in (R312H) mice, neuronal migration assays, co-immunoprecipitation (KCNB1-integrin), pharmacological FAK activation rescue Cell Death and Differentiation High 36207442
2020 In arterial smooth muscle cells, Kv2.1 has a dual role: a canonical conductive role (less than 1% of channels are conductive and hyperpolarize the membrane) and a structural role in enhancing clustering and cooperative opening of CaV1.2 L-type Ca2+ channels. In female myocytes where Kv2.1 expression is higher, the structural role dominates, increasing CaV1.2 cluster size, Ca2+ influx, and myogenic tone. In male myocytes, Kv2.1 primarily controls membrane potential. Kv2.1 KO, electrophysiology, TIRF microscopy (CaV1.2 cluster imaging), sex-stratified analysis of Kv2.1 expression and function in myocytes Proceedings of the National Academy of Sciences High 32015129
2015 Leptin increases Kv2.1 surface expression in beta-cells via AMPK activation (requiring CaMKKβ) and PKA. The increased Kv2.1 surface expression depends on actin depolymerization. This trafficking regulation mirrors leptin's concurrent trafficking regulation of KATP channels, coordinately inhibiting insulin secretion by hyperpolarizing membrane potential (via KATP) and accelerating repolarization (via Kv2.1). Surface biotinylation, AMPK/PKA pharmacological and genetic manipulation, actin disruption, whole-cell patch-clamp in rodent and human beta-cells The Journal of Biological Chemistry Medium 26453299
2020 Kv2.1-G379R (DEE variant) does not induce ER-plasma membrane junction formation in HEK293T cells, and co-expression of G379R with wild-type Kv2.1 reduces EPJ induction relative to WT alone, consistent with dominant-negative disruption of the structural (non-conducting) function of Kv2.1. HEK293T cell expression, immunofluorescence of ER-PM junctions, co-expression dominant-negative assessment Neurobiology of Disease Medium 33132203
2004 NFATc3 is an obligatory component of the signaling cascade mediating Ang II-induced reduction of Kv2.1 expression in arterial smooth muscle. Sustained Ang II increases smooth muscle Ca2+ via L-type channels, activates calcineurin and NFATc3, and decreases Kv2.1 K+ channel subunit expression and Kv current. Dominant-negative NFATc3, calcineurin inhibition, pharmacological L-type Ca2+ channel block, immunoblotting, patch-clamp in arterial smooth muscle The Journal of Biological Chemistry Medium 15322114
2006 N-terminal SNAP-25 domains (residues 1–197 and 1–180), acting on the Kv2.1 cytoplasmic N-terminus, increased Kv2.1 activation rate, slowed inactivation, and potentiated external TEA block by restructuring the outer pore architecture. Full-length SNAP-25 and C-terminal domains had no such effect, demonstrating domain-specific regulation. Intracellular dialysis of SNAP-25 domain peptides, whole-cell patch-clamp, external TEA block analysis, ionic substitution experiments The Biochemical Journal Medium 16478442
2014 Somatic Kv2.1 clusters in striatal medium spiny neurons (MSNs) are juxtaposed to ryanodine receptor (RyR) Ca2+-release channel clusters at subsurface cisternae. Acute RyR stimulation in heterologous cells caused a rapid hyperpolarizing shift in Kv2.1 voltage-dependent activation consistent with Ca2+/calcineurin-dependent dephosphorylation. MSNs in direct and indirect pathways differ in Kv2.1 phosphorylation state at multiple sites. Electron microscopy-immunogold labeling, immunofluorescence in transgenic GFP-MSN mice, phosphospecific antibody immunolabeling, RyR agonist treatment in heterologous cells, patch-clamp The Journal of Comparative Neurology High 24962901

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Graded regulation of the Kv2.1 potassium channel by variable phosphorylation. Science (New York, N.Y.) 232 16917065
1995 An inhibitor of the Kv2.1 potassium channel isolated from the venom of a Chilean tarantula. Neuron 219 7576642
2003 Mediation of neuronal apoptosis by Kv2.1-encoded potassium channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 202 12832499
2002 Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic beta-cells enhances glucose-dependent insulin secretion. The Journal of biological chemistry 154 12270920
2007 Kv2.1 ablation alters glucose-induced islet electrical activity, enhancing insulin secretion. Cell metabolism 151 17767909
2004 Disruption of pancreatic beta-cell lipid rafts modifies Kv2.1 channel gating and insulin exocytosis. The Journal of biological chemistry 145 15073181
1997 Phosphorylation of the Kv2.1 K+ channel alters voltage-dependent activation. Molecular pharmacology 132 9351973
2014 De novo KCNB1 mutations in epileptic encephalopathy. Annals of neurology 122 25164438
1996 Identification of a cytoplasmic domain important in the polarized expression and clustering of the Kv2.1 K+ channel. The Journal of cell biology 111 8978827
2010 Localization-dependent activity of the Kv2.1 delayed-rectifier K+ channel. Proceedings of the National Academy of Sciences of the United States of America 108 20566856
2014 Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability. Genes, brain, and behavior 107 24494598
2001 Dynamic localization and clustering of dendritic Kv2.1 voltage-dependent potassium channels in developing hippocampal neurons. Neuroscience 104 11738132
1994 Properties of Kv2.1 K+ channels expressed in transfected mammalian cells. The Journal of biological chemistry 103 8083226
2006 Kv2.1 potassium channels are retained within dynamic cell surface microdomains that are defined by a perimeter fence. The Journal of neuroscience : the official journal of the Society for Neuroscience 100 16988031
2011 SUMO modification of cell surface Kv2.1 potassium channels regulates the activity of rat hippocampal neurons. The Journal of general physiology 99 21518833
2015 Induction of stable ER-plasma-membrane junctions by Kv2.1 potassium channels. Journal of cell science 98 25908859
2011 Hypoxic preconditioning enhances bone marrow mesenchymal stem cell migration via Kv2.1 channel and FAK activation. American journal of physiology. Cell physiology 98 21562308
2011 Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability. Proceedings of the National Academy of Sciences of the United States of America 98 22006306
1998 Modulation of potassium channel gating by coexpression of Kv2.1 with regulatory Kv5.1 or Kv6.1 alpha-subunits. The American journal of physiology 94 9696692
2004 NFATc3 regulates Kv2.1 expression in arterial smooth muscle. The Journal of biological chemistry 93 15322114
2006 The Kv2.1 C terminus can autonomously transfer Kv2.1-like phosphorylation-dependent localization, voltage-dependent gating, and muscarinic modulation to diverse Kv channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 91 16407566
1996 Kv2.1 and electrically silent Kv6.1 potassium channel subunits combine and express a novel current. FEBS letters 90 8980147
2012 Kv2.1 cell surface clusters are insertion platforms for ion channel delivery to the plasma membrane. Molecular biology of the cell 85 22648171
2017 Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes. JAMA neurology 82 28806457
2019 Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in mammalian neurons. eLife 81 31663850
2007 A cytoskeletal-based perimeter fence selectively corrals a sub-population of cell surface Kv2.1 channels. Journal of cell science 81 17606996
2008 The Kv2.1 K+ channel targets to the axon initial segment of hippocampal and cortical neurons in culture and in situ. BMC neuroscience 79 19014551
2015 A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization. The Journal of general physiology 78 26503721
2009 SUMOylation regulates Kv2.1 and modulates pancreatic beta-cell excitability. Journal of cell science 78 19223394
2016 Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model. Cell death & disease 77 26890139
2003 MinK-related peptide 2 modulates Kv2.1 and Kv3.1 potassium channels in mammalian brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 75 12954870
2015 De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. Scientific reports 74 26477325
2013 Regulation of Kv2.1 K(+) conductance by cell surface channel density. The Journal of neuroscience : the official journal of the Society for Neuroscience 71 23325261
2002 Synaptosome-associated protein of 25 kilodaltons modulates Kv2.1 voltage-dependent K(+) channels in neuroendocrine islet beta-cells through an interaction with the channel N terminus. Molecular endocrinology (Baltimore, Md.) 71 12403834
2008 Glutamate transporters regulate extrasynaptic NMDA receptor modulation of Kv2.1 potassium channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 63 18753382
2013 Convergent Ca2+ and Zn2+ signaling regulates apoptotic Kv2.1 K+ currents. Proceedings of the National Academy of Sciences of the United States of America 61 23918396
2012 The role of voltage-gated potassium channels Kv2.1 and Kv2.2 in the regulation of insulin and somatostatin release from pancreatic islets. The Journal of pharmacology and experimental therapeutics 61 23161216
2011 Activity-dependent phosphorylation of neuronal Kv2.1 potassium channels by CDK5. The Journal of biological chemistry 60 21712386
2009 Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG neurons. American journal of physiology. Cell physiology 57 19357235
2010 Stromatoxin-sensitive, heteromultimeric Kv2.1/Kv9.3 channels contribute to myogenic control of cerebral arterial diameter. The Journal of physiology 56 20876197
2003 The Roles of N- and C-terminal determinants in the activation of the Kv2.1 potassium channel. The Journal of biological chemistry 56 12560340
1993 Expression of Kv2.1 delayed rectifier K+ channel isoforms in the developing rat brain. FEBS letters 55 8508921
2014 Cell type-specific spatial and functional coupling between mammalian brain Kv2.1 K+ channels and ryanodine receptors. The Journal of comparative neurology 54 24962901
2019 Spectrum of KV 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders. Annals of neurology 53 31600826
2017 Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations. Neurology. Genetics 53 29264397
2017 Trafficking of Kv2.1 Channels to the Axon Initial Segment by a Novel Nonconventional Secretory Pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 51 29042434
2007 Dynamic regulation of the voltage-gated Kv2.1 potassium channel by multisite phosphorylation. Biochemical Society transactions 51 17956280
2009 Regulation of the Kv2.1 potassium channel by MinK and MiRP1. The Journal of membrane biology 50 19219384
2003 Phosphorylation-dependent regulation of Kv2.1 Channel activity at tyrosine 124 by Src and by protein-tyrosine phosphatase epsilon. The Journal of biological chemistry 49 12615930
2019 Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature. Human mutation 47 31513310
2008 Formation of Kv2.1-FAK complex as a mechanism of FAK activation, cell polarization and enhanced motility. Journal of cellular physiology 46 18615577
2011 AMIGO is an auxiliary subunit of the Kv2.1 potassium channel. EMBO reports 42 22056818
2005 Delayed-rectifier (KV2.1) regulation of pancreatic beta-cell calcium responses to glucose: inhibitor specificity and modeling. American journal of physiology. Endocrinology and metabolism 41 16014354
2020 Kv2.1 channels play opposing roles in regulating membrane potential, Ca2+ channel function, and myogenic tone in arterial smooth muscle. Proceedings of the National Academy of Sciences of the United States of America 40 32015129
2017 Kv2.1 Clustering Contributes to Insulin Exocytosis and Rescues Human β-Cell Dysfunction. Diabetes 39 28607108
2020 Targeted disruption of Kv2.1-VAPA association provides neuroprotection against ischemic stroke in mice by declustering Kv2.1 channels. Science advances 37 32937450
2006 cAMP/protein kinase A signalling pathway protects against neuronal apoptosis and is associated with modulation of Kv2.1 in cerebellar granule cells. Journal of neurochemistry 37 17156132
2003 Temperature and redox state dependence of native Kv2.1 currents in rat pancreatic beta-cells. The Journal of physiology 37 12562993
2015 Selective down-regulation of KV2.1 function contributes to enhanced arterial tone during diabetes. The Journal of biological chemistry 35 25670860
2012 Molecular mechanisms underlying the apoptotic effect of KCNB1 K+ channel oxidation. The Journal of biological chemistry 33 23275378
2007 Localization and mobility of the delayed-rectifer K+ channel Kv2.1 in adult cardiomyocytes. American journal of physiology. Heart and circulatory physiology 33 17965280
1992 Heterologous expression of the human potassium channel Kv2.1 in clonal mammalian cells by direct cytoplasmic microinjection of cRNA. Pflugers Archiv : European journal of physiology 33 1283219
2016 SP6616 as a new Kv2.1 channel inhibitor efficiently promotes β-cell survival involving both PKC/Erk1/2 and CaM/PI3K/Akt signaling pathways. Cell death & disease 32 27148689
2016 Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 27798188
2011 Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1 delayed rectifier channels. Cell death and differentiation 32 21818121
2008 The Kv2.1 channels mediate neuronal apoptosis induced by excitotoxicity. Journal of neurochemistry 32 19077057
2020 SP6616 as a Kv2.1 inhibitor efficiently ameliorates peripheral neuropathy in diabetic mice. EBioMedicine 31 33096484
2020 Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant. Neurobiology of disease 31 33132203
2017 Characterization of a KCNB1 variant associated with autism, intellectual disability, and epilepsy. Neurology. Genetics 31 29264390
2015 AMIGO-Kv2.1 Potassium Channel Complex Is Associated With Schizophrenia-Related Phenotypes. Schizophrenia bulletin 30 26240432
2015 Concerted Trafficking Regulation of Kv2.1 and KATP Channels by Leptin in Pancreatic β-Cells. The Journal of biological chemistry 30 26453299
2012 Distinct modifications in Kv2.1 channel via chemokine receptor CXCR4 regulate neuronal survival-death dynamics. The Journal of neuroscience : the official journal of the Society for Neuroscience 30 23223293
2004 Kv2.1 channel activation and inactivation is influenced by physical interactions of both syntaxin 1A and the syntaxin 1A/soluble N-ethylmaleimide-sensitive factor-25 (t-SNARE) complex with the C terminus of the channel. Molecular pharmacology 30 15525758
2016 Novel KCNB1 mutation associated with non-syndromic intellectual disability. Journal of human genetics 28 27928161
2009 Zn2+ regulates Kv2.1 voltage-dependent gating and localization following ischemia. The European journal of neuroscience 28 20092568
2019 A molecular rheostat: Kv2.1 currents maintain or suppress repetitive firing in motoneurons. The Journal of physiology 27 31145471
2011 KV2.1 and electrically silent KV channel subunits control excitability and contractility of guinea pig detrusor smooth muscle. American journal of physiology. Cell physiology 27 21998137
2001 Heterogeneity of Kv2.1 mRNA expression and delayed rectifier current in single isolated myocytes from rat left ventricle. Circulation research 27 11249871
2022 Activity-dependent endoplasmic reticulum Ca2+ uptake depends on Kv2.1-mediated endoplasmic reticulum/plasma membrane junctions to promote synaptic transmission. Proceedings of the National Academy of Sciences of the United States of America 26 35862456
2018 Oxidation of KCNB1 channels in the human brain and in mouse model of Alzheimer's disease. Cell death & disease 26 30050035
2015 Auxiliary KCNE subunits modulate both homotetrameric Kv2.1 and heterotetrameric Kv2.1/Kv6.4 channels. Scientific reports 26 26242757
2013 Chemokine co-receptor CCR5/CXCR4-dependent modulation of Kv2.1 channel confers acute neuroprotection to HIV-1 glycoprotein gp120 exposure. PloS one 26 24086760
2006 Molecular rearrangements of the Kv2.1 potassium channel termini associated with voltage gating. The Journal of biological chemistry 26 16690619
2015 Cell Cycle-dependent Changes in Localization and Phosphorylation of the Plasma Membrane Kv2.1 K+ Channel Impact Endoplasmic Reticulum Membrane Contact Sites in COS-1 Cells. The Journal of biological chemistry 25 26442584
2013 Redistribution of Kv2.1 ion channels on spinal motoneurons following peripheral nerve injury. Brain research 25 24355600
2018 Cleavage of potassium channel Kv2.1 by BACE2 reduces neuronal apoptosis. Molecular psychiatry 24 29703946
2022 Integrin-KCNB1 potassium channel complexes regulate neocortical neuronal development and are implicated in epilepsy. Cell death and differentiation 23 36207442
2009 Conserved negative charges in the N-terminal tetramerization domain mediate efficient assembly of Kv2.1 and Kv2.1/Kv6.4 channels. The Journal of biological chemistry 23 19717558
2011 Dynamic modulation of the kv2.1 channel by SRC-dependent tyrosine phosphorylation. Journal of proteome research 22 22106938
2015 Modulation of Closed-State Inactivation in Kv2.1/Kv6.4 Heterotetramers as Mechanism for 4-AP Induced Potentiation. PloS one 21 26505474
2014 GDF15 regulates Kv2.1-mediated outward K+ current through the Akt/mTOR signalling pathway in rat cerebellar granule cells. The Biochemical journal 21 24597762
2017 Oxidation of KCNB1 potassium channels triggers apoptotic integrin signaling in the brain. Cell death & disease 20 28383553
2009 Ethanol disrupts NMDA receptor and astroglial EAAT2 modulation of Kv2.1 potassium channels in hippocampus. Alcohol (Fayetteville, N.Y.) 20 19185209
2006 Modulation of Kv2.1 channel gating and TEA sensitivity by distinct domains of SNAP-25. The Biochemical journal 20 16478442
2004 Modification of Kv2.1 K+ currents by the silent Kv10 subunits. Brain research. Molecular brain research 19 15046870
2002 KV2.1 K+ channels underlie major voltage-gated K+ outward current in H9c2 myoblasts. The Japanese journal of physiology 19 12617756
2008 Mutation of histidine 105 in the T1 domain of the potassium channel Kv2.1 disrupts heteromerization with Kv6.3 and Kv6.4. The Journal of biological chemistry 18 19074135
2018 Defective trafficking of Kv2.1 channels in MPTP-induced nigrostriatal degeneration. Journal of neurochemistry 17 29265365
2018 Regulation of Kv2.1 channel inactivation by phosphatidylinositol 4,5-bisphosphate. Scientific reports 17 29379118
2015 Regulation of Pro-Apoptotic Phosphorylation of Kv2.1 K+ Channels. PloS one 17 26115091

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