Affinage

KCNIP2

A-type potassium channel modulatory protein KCNIP2 · UniProt Q9NS61

Length
270 aa
Mass
30.9 kDa
Annotated
2026-04-28
52 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNIP2 (KChIP2) is a calcium-sensing auxiliary subunit essential for cardiac transient outward potassium current (Ito) and a multifunctional regulator of cardiac ion channel expression, trafficking, and gating. KChIP2 binds both the N- and C-termini of Kv4.2/4.3, stabilizing Kv4 protein post-translationally, promoting surface expression in lipid rafts, slowing inactivation, and accelerating recovery from inactivation in a Ca²⁺- and splice isoform-dependent manner, with distinct EF-hand domains mediating Ca²⁺-dependent versus Ca²⁺-independent gating effects and a polybasic N-terminal domain controlling isoform-specific Ca²⁺ regulation (PMID:11747815, PMID:23713033, PMID:16820361, PMID:30622142, PMID:28735419). Beyond Kv4 channels, KChIP2 directly binds CaV1.2 to augment L-type Ca²⁺ current independently of trafficking, suppresses Nav1.5 surface expression, inhibits Kv1.5 forward trafficking from the ER, and transcriptionally represses miR-34b/c to maintain INa and Ito, while its own expression is regulated by NF-κB (via MG53/TAK1/IκBα), CREB (via angiotensin II/ROS/proteasomal degradation), and palmitoylation-dependent shuttling between plasma membrane and nucleus (PMID:19461043, PMID:15878168, PMID:28263709, PMID:21252158, PMID:30760025, PMID:31362018). In the nervous system, Kcnip2-expressing inhibitory interneurons in the spinal dorsal horn selectively gate cold sensitivity by inhibiting nociceptive projection neurons (PMID:36323322).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    The fundamental question of whether KChIP2 is required for cardiac Ito was answered: KChIP2 knockout abolished Ito entirely and created a substrate for ventricular tachycardia, establishing it as an indispensable auxiliary subunit rather than a modulatory factor.

    Evidence KChIP2 knockout mouse with patch-clamp electrophysiology and ECG

    PMID:11747815

    Open questions at the time
    • Mechanism of KChIP2-dependent Kv4 channel assembly or trafficking not resolved
    • Whether KChIP2 regulates non-Kv4 channels unknown at this point
  2. 2002 High

    Systematic biophysical characterization of KChIP2 splice variants revealed that isoform diversity generates functionally distinct Ito phenotypes, with different variants exerting divergent effects on inactivation kinetics, recovery, and voltage dependence—and that Ca²⁺ binding selectively controls inactivation but not recovery.

    Evidence Heterologous expression of multiple cloned isoforms in oocytes and mammalian cells; voltage clamp; EF-hand mutagenesis

    PMID:11897837 PMID:12135940 PMID:12433945

    Open questions at the time
    • Structural basis for isoform-specific gating effects unknown
    • Which isoforms predominate in specific cardiac regions not fully mapped
  3. 2004 High

    Detailed kinetic analysis dissected how KChIP2 separately modulates closed-state (Ca²⁺-independent) and open-state (Ca²⁺-dependent) inactivation of Kv4.3, and identified additional novel isoforms (KChIP2e/f/g) with divergent functional signatures, establishing that both N- and C-terminal alternative splicing generates functional diversity.

    Evidence Two-electrode voltage clamp in oocytes with kinetic modeling; cloning from human heart and brain

    PMID:14724186 PMID:15107477

    Open questions at the time
    • Physiological relevance of each isoform in native tissue undetermined
    • No structural model of KChIP2-Kv4 complex available
  4. 2005 High

    The discovery that KChIP2 co-immunoprecipitates with Kv1.5 and inhibits its ER-to-surface trafficking established KChIP2 as a multi-channel regulatory subunit extending beyond the Kv4 family.

    Evidence Co-IP from mouse heart; surface biotinylation and patch-clamp in HEK-293 cells

    PMID:15878168

    Open questions at the time
    • Binding interface for Kv1.5 not mapped
    • In vivo significance for IKur regulation not tested
  5. 2006 High

    Mapping of KChIP2 binding to both the N- and C-termini of Kv4.2 resolved how KChIP2 stabilizes Kv4.2 protein (~8-fold slower degradation) and increases surface expression, with the C-terminal interaction critical for post-translational stabilization.

    Evidence Co-IP, GST pull-down, pulse-chase, truncation mutagenesis, and patch-clamp in heterologous cells

    PMID:16820361

    Open questions at the time
    • Post-translational degradation pathway (proteasomal vs. lysosomal) not identified
    • Whether stabilization mechanism differs among Kv4 family members unknown
  6. 2008 High

    KChIP2 knockdown was found to suppress not only Ito but also INa by reducing Nav channel subunit expression, revealing an unexpected functional coupling between depolarizing and repolarizing currents through a shared auxiliary protein.

    Evidence siRNA in neonatal rat ventricular myocytes; Co-IP; patch-clamp; Western blot and RT-PCR

    PMID:18565539

    Open questions at the time
    • Direct vs. indirect mechanism of Nav subunit regulation not resolved
    • Whether KChIP2 binds Nav subunits directly untested
  7. 2009 High

    Direct binding of KChIP2 to the CaV1.2 N-terminal inhibitory module was demonstrated, with KChIP2 augmenting ICa,L through gating modulation rather than trafficking—revealing a Ca²⁺-independent mechanism distinct from its Kv4 stabilization role.

    Evidence KChIP2⁻/⁻ mouse myocytes; heterologous co-expression; Co-IP; biochemical binding; patch-clamp

    PMID:19461043 PMID:19713767

    Open questions at the time
    • Structural basis of KChIP2-CaV1.2 interaction not determined
    • Relative contribution of ICa,L modulation to arrhythmia phenotype in KO unclear
  8. 2010 High

    Three upstream transcriptional mechanisms converging on KChIP2 were identified: NF-κB-mediated repression (bidirectionally validated), CREB-dependent activation degraded via angiotensin II/ROS/proteasome pathway, and developmental upregulation driving Ito emergence, placing KChIP2 at a signaling hub for electrical remodeling.

    Evidence Adenoviral IκBα/IKKβ manipulation; CREB/ubiquitin/proteasome pathway dissection; developmental RT-PCR and adenoviral rescue in rat cardiomyocytes

    PMID:12967630 PMID:20346417 PMID:21252158

    Open questions at the time
    • Whether NF-κB and CREB act on overlapping or distinct KChIP2 promoter elements not resolved
    • Epigenetic regulation not explored
  9. 2013 High

    The post-translational stabilization mechanism was definitively confirmed: KChIP2 deletion eliminated Kv4.2 protein without affecting its transcript, proving that KChIP2 is required specifically for Kv4 protein stability rather than transcription.

    Evidence KChIP2⁻/⁻ mouse; Western blot vs. RT-PCR dissociation; adenoviral rescue attempt

    PMID:23713033

    Open questions at the time
    • Identity of the degradation pathway consuming Kv4.2 in absence of KChIP2 not determined
    • Whether re-expression of KChIP2 can fully rescue Kv4.2 protein in adult hearts unclear
  10. 2014 Medium

    Lipid raft localization of the Kv4.2-KChIP2 complex was established as functionally relevant: cholesterol depletion displaced both proteins from raft fractions and reduced Ito.

    Evidence Sucrose density gradient fractionation and patch-clamp with methyl-β-cyclodextrin in rat ventricular myocytes

    PMID:24793047

    Open questions at the time
    • Mechanism by which KChIP2 targets Kv4.2 to rafts unknown
    • Modest (~12%) Ito reduction with cholesterol depletion suggests additional non-raft pool contributes
  11. 2017 High

    A transcriptional role for KChIP2 was uncovered: it represses miR-34b/c through chromatin interaction, and loss of this repression allows miR-34b/c to suppress both INa and Ito channel subunits, establishing a KChIP2-miRNA axis governing cardiac electrical remodeling beyond its chaperone/gating functions.

    Evidence Chromatin interaction assays; miRNA inhibitors; gene transfer; patch-clamp in rat and human cardiomyocytes

    PMID:28263709

    Open questions at the time
    • How KChIP2 accesses chromatin and what co-factors it engages for transcriptional repression not determined
    • Genome-wide transcriptional targets of KChIP2 unknown
  12. 2017 High

    EF-hand-specific mutagenesis showed that Ca²⁺ binding to EF-hand 2 and EF-hand 3 differentially tunes inactivation and recovery kinetics, and that CaMKII activity is required for Ca²⁺-dependent recovery modulation, linking intracellular Ca²⁺ signaling to acute Ito regulation through KChIP2.

    Evidence EF-hand point mutagenesis; BAPTA buffering; CaMKII inhibitor KN-93; patch-clamp in HEK293

    PMID:28735419

    Open questions at the time
    • Whether CaMKII phosphorylates KChIP2 directly or acts on Kv4 subunit not resolved
    • Physiological Ca²⁺ concentrations at which each EF-hand is occupied in native myocytes undefined
  13. 2019 High

    Palmitoylation was identified as a regulatory switch: palmitoylated KChIP2 clusters at the plasma membrane, while depalmitoylation (triggered by cardiac stress) promotes nuclear translocation, providing a mechanism linking its membrane chaperone and transcriptional functions.

    Evidence FRAP imaging of palmitoylation-deficient mutants; rat cardiac arrest model; biochemical fractionation

    PMID:31362018

    Open questions at the time
    • Specific palmitoyl acyltransferase(s) and thioesterase(s) acting on KChIP2 not identified
    • Nuclear targets beyond miR-34b/c not characterized
  14. 2019 High

    The polybasic N-terminal domain present in longer KChIP2 isoforms (KChIP2a/a1) was shown to prevent Ca²⁺-dependent augmentation of Kv4.2 current, while shorter isoforms lacking this domain support Ca²⁺ regulation, revealing a molecular switch encoded by alternative splicing.

    Evidence Site-directed mutagenesis of polybasic residues; whole-cell patch-clamp in HEK293T with isoform-specific constructs

    PMID:30622142

    Open questions at the time
    • Structural mechanism by which the polybasic domain occludes Ca²⁺ signaling undetermined
    • Regional distribution of polybasic-containing versus polybasic-lacking isoforms in human heart incomplete
  15. 2019 High

    MG53 was identified as an upstream regulator acting through NF-κB: MG53 interacts with TAK1/IκBα to suppress NF-κB binding at the KChIP2 promoter, connecting membrane repair signaling to electrical remodeling.

    Evidence MG53 KO mice; ChIP; Co-IP; adenoviral overexpression/knockdown; transverse aortic constriction model

    PMID:30760025

    Open questions at the time
    • Whether MG53-mediated regulation is cardiac-specific or generalizable to other tissues unknown
    • Direct phosphorylation or ubiquitination events linking MG53 to TAK1/IκBα not fully mapped
  16. 2022 High

    PKA-mediated phosphorylation of Kv4.2 at S552 was shown to disrupt Kv4.2-KChIP2 interaction and eject Kv4.2 from lipid rafts, providing a molecular mechanism for adrenergic Ito suppression and dynamic regulation of the channel complex.

    Evidence Phosphomimetic mutagenesis; Co-IP; surface biotinylation; lipid raft fractionation; high-resolution imaging in HEK293 and NRVMs

    PMID:35508186

    Open questions at the time
    • Whether other kinases similarly regulate Kv4.2-KChIP2 association unknown
    • Fate of freed KChIP2 after dissociation (nuclear entry? degradation?) not tracked
  17. 2022 High

    Beyond the heart, Kcnip2-expressing inhibitory interneurons in the spinal dorsal horn were shown to selectively gate cold sensitivity by inhibiting nociceptive projection neurons, establishing a neural circuit function for this gene.

    Evidence Intersectional genetics; diphtheria toxin ablation; DREADD activation; circuit tracing; behavioral assays in mice

    PMID:36323322

    Open questions at the time
    • Whether KChIP2 ion channel modulation underlies the cold-gating function of these neurons or serves as a marker is unknown
    • Relevance to human cold pain processing untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of KChIP2 interactions with its diverse channel partners, the full scope of its nuclear transcriptional targets, the identity of the palmitoylation/depalmitoylation enzymes controlling its subcellular shuttling, and whether its cardiac and neuronal functions are mechanistically unified.
  • No high-resolution structure of KChIP2 in complex with any full-length channel partner
  • Genome-wide chromatin binding profile of nuclear KChIP2 absent
  • Palmitoyl acyltransferase and thioesterase identities unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8 GO:0008092 cytoskeletal protein binding 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3 R-HSA-9609507 Protein localization 3 R-HSA-112316 Neuronal System 2
Partners
CACNA1CKCNA5KCND2KCND3PSEN1SCN1BSCN5A
Complex memberships
Kv4.2/KChIP2 channel complexKv4.3/KChIP2 channel complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 KChIP2 knockout mice exhibit complete absence of the transient outward potassium current (Ito) in ventricular myocytes, establishing KChIP2 as an essential auxiliary subunit for Ito and demonstrating that its loss confers susceptibility to ventricular tachycardia via elimination of the transmural gradient of Ito. KChIP2 knockout mouse model; single-cell patch-clamp electrophysiology; ECG recordings Cell High 11747815
2002 KChIP2 splice variants increase Kv4.3 current density, slow current decay in a Ca2+-dependent manner, and hasten recovery from inactivation in a splice variant-specific fashion, demonstrating isoform-dependent modulation of Kv4-encoded currents. Heterologous expression in mammalian cells; whole-cell patch-clamp; kinetic RT-PCR; Western blot; immunocytochemistry Circulation High 12135940
2002 KChIP2d, a minimal isoform containing only the C-terminal 70 amino acids with a single EF-hand, accelerates recovery and slows inactivation kinetics of Kv4.3; the EF-hand modulates inactivation but not recovery, and distinct regions mediate Ca2+-independent effects on recovery versus Ca2+-dependent effects on inactivation. Cloning of minimal isoform; expression in Xenopus oocytes; two-electrode voltage clamp; EF-hand mutagenesis The Journal of physiology High 12433945
2002 KChIP2 isoforms differentially modulate Kv4.3 in Xenopus oocytes: all isoforms accelerate recovery kinetics ~4-fold, but only KChIP2a produces large depolarizing shifts in voltage-dependence of activation and inactivation resembling native rapidly recovering Ito. Cloning from ferret heart; expression in Xenopus oocytes; two-electrode voltage clamp; immunoblot; RNA analysis The Journal of physiology High 11897837
2004 KChIP2 isoforms (KChIP2b and KChIP2d) accelerate recovery, slow closed-state inactivation, and promote open-state inactivation of Kv4.3 channels; closed-state inactivation modulation is Ca2+-independent while open-state inactivation modulation is Ca2+-dependent. Two-electrode voltage clamp in Xenopus oocytes; kinetic modeling of inactivation mechanisms The Journal of physiology High 14724186
2004 Novel KChIP2 isoforms with alternatively spliced C-termini (KChIP2e, KChIP2f) or N-terminus (KChIP2g) exert distinct and divergent effects on Kv4.3 current amplitude, inactivation kinetics, recovery from inactivation, and voltage dependence of inactivation. Cloning from human heart and brain; expression in Xenopus oocytes; two-microelectrode voltage clamp The Journal of physiology High 15107477
2005 KChIP2 co-immunoprecipitates with Kv1.5 from adult mouse ventricles and reduces cell surface expression of Kv1.5-encoded K+ channels by inhibiting forward trafficking from the endoplasmic reticulum, demonstrating KChIP2 is a multifunctional Kv channel accessory subunit beyond the Kv4 subfamily. Co-immunoprecipitation from mouse heart; heterologous expression in HEK-293; cell surface biotinylation; immunohistochemistry; patch-clamp Journal of molecular and cellular cardiology High 15878168
2006 KChIP2 interacts directly with both the N-terminus and C-terminus of Kv4.2; the C-terminal domain interaction stabilizes Kv4.2 protein (~8-fold slower degradation), increases surface expression, and modulates voltage-dependent activation gating. Co-immunoprecipitation; GST pull-down competitive binding assay; pulse-chase experiments; truncation mutagenesis; patch-clamp in heterologous cells The Journal of biological chemistry High 16820361
2003 KChIP2 mRNA levels increase 731-fold during rat ventricular development (embryonic day 12 to postnatal day 10), and adenoviral overexpression of KChIP2 in embryonic myocytes induces Ito,f and enhances trafficking of Kv4.2 to the cell surface, establishing KChIP2 as a critical determinant of Ito,f generation during development. Real-time RT-PCR; adenoviral gene transfer; whole-cell patch-clamp; immunocytochemistry in rat cardiomyocytes Journal of molecular and cellular cardiology High 12967630
2008 KChIP2 silencing in neonatal rat ventricular myocytes suppresses both Ito and INa; KChIP2 knockdown reduces Na channel alpha and beta1 subunit mRNA and protein, suggesting KChIP2 functionally couples Ito and INa channels. Co-immunoprecipitation demonstrates a structural association between Kv4.x and Navβ1 subunits. siRNA knockdown; co-immunoprecipitation from neonatal rat ventricular myocardium; whole-cell patch-clamp; Western blot; RT-PCR Journal of molecular and cellular cardiology High 18565539
2009 KChIP2 directly interacts with the N-terminal inhibitory module of the CaV1.2 alpha1C subunit and augments L-type Ca2+ current (ICa,L) density without increasing CaV1.2 protein expression or plasma membrane trafficking; this effect is independent of Ca2+ binding to KChIP2. ICa,L density is reduced by 28% in KChIP2-/- myocytes. KChIP2-/- mouse myocytes; heterologous expression; co-immunoprecipitation; biochemical binding assay; whole-cell patch-clamp Circulation research High 19461043
2009 KChIP2 and CaV1.2 co-immunoprecipitate from cardiac tissue, further supporting a direct interaction; KChIP2-/- mice show increased transcription of the CaVβ2 subunit (CACNB2) without change in CaV1.2 expression. Co-immunoprecipitation; gene-chip and real-time PCR from KChIP2-/- mouse hearts Channels (Austin, Tex.) Medium 19713767
2010 NF-κB transcriptionally represses KChIP2 expression; inhibition of NF-κB (via IκBαSA overexpression) prevents α1-adrenergic- and TNFα-induced reductions in KChIP2 mRNA and Ito,f, while activation of NF-κB (via IKKβ overexpression) decreases KChIP2 expression and Ito,f. Adenoviral overexpression of IκBαSA and IKKβ in neonatal rat ventricular myocytes; RT-PCR; Western blot; whole-cell patch-clamp Circulation research High 21252158
2010 KChIP2, KChIP3, and KChIP4 all co-immunoprecipitate with Kv4.2 in mouse cortical pyramidal neurons; simultaneous RNAi-mediated knockdown of all three KChIP isoforms markedly reduces IA densities, demonstrating interdependent and redundant roles in forming Kv4-encoded IA channels in neurons. Co-immunoprecipitation from cortex; KChIP2-/- and KChIP3-/- mouse models; siRNA triple knockdown; patch-clamp electrophysiology The Journal of neuroscience High 20943905
2013 KChIP2 deletion results in complete loss of Kv4.2 protein (without affecting Kv4.2 transcript), demonstrating that KChIP2 stabilizes Kv4 protein post-translationally and that this protein stabilization is required for native cardiac Ito,f channel expression. KChIP2-/- mouse; Western blot; RT-PCR; adenovirus-mediated rescue; whole-cell patch-clamp The Journal of physiology High 23713033
2010 CREB transcriptionally regulates KChIP2 gene expression; left ventricular pacing induces angiotensin II production and reactive oxygen species, leading to CREB ubiquitination and proteasomal degradation, thereby reducing KChIP2 transcription and Ito. In vivo pacing model in dogs; angiotensin II receptor blocker intervention; proteasomal inhibitor (lactacystin); ubiquitination assay; siRNA knockdown of ubiquitin in neonatal rat cardiomyocytes; RT-PCR; Western blot Heart rhythm High 20346417
2017 KChIP2 functions as a transcriptional repressor of miR-34b and miR-34c through interaction with genetic regulatory elements; loss of KChIP2 de-represses miR-34b/c, which then suppress INa and Ito by targeting their respective channel subunits, establishing a KChIP2/miR-34 axis as a regulator of cardiac electrical remodeling. Rat and human derived cardiomyocytes; chromatin interaction assays; miRNA inhibitors; gene transfer; patch-clamp; arrhythmia induction assays eLife High 28263709
2019 MG53 regulates KChIP2 expression and Ito,f by modulating NF-κB activity; MG53 physically interacts with TAK1 and IκBα (key NF-κB pathway components), and chromatin immunoprecipitation shows NF-κB binding to the KChIP2 gene 5' regulatory region is decreased by MG53 overexpression and increased by MG53 knockdown. MG53 knockout mice; adenoviral overexpression/knockdown; chromatin immunoprecipitation (ChIP); co-immunoprecipitation; Western blot; patch-clamp; transverse aortic constriction model Circulation High 30760025
2019 Palmitoylation of KChIP2 regulates its subcellular trafficking: palmitoylatable KChIP2 clusters at the plasma membrane while unpalmitoylatable KChIP2 has higher cytoplasmic mobility and faster nuclear entry. Acute cardiac stress (arrest/resuscitation) promotes KChIP2 depalmitoylation and nuclear entry in native cardiomyocytes. Imaging and FRAP of palmitoylatable vs. unpalmitoylatable KChIP2 variants in COS-7 cells and cardiomyocytes; rat cardiac arrest/resuscitation model; biochemical fractionation Journal of molecular and cellular cardiology High 31362018
2017 In guinea pig myocytes lacking Kv4 expression, KChIP2 knockdown prolongs the cardiac action potential by enhancing ICa,L through increased CaV1.2 protein and reduces INa through decreased Nav1.5 protein, revealing KChIP2 regulation of cardiac repolarization and depolarization independent of Ito. siRNA knockdown in isolated adult guinea pig myocytes; whole-cell patch-clamp; Western blot PloS one Medium 26764482
2017 KChIP2 loss in guinea pig myocytes reduces Ca2+ spark frequency and prolongs Ca2+ decay through delocalization of presenilin away from sarcomeric banding, impairing ryanodine receptor (RyR) open probability and reducing contractility. siRNA knockdown in isolated guinea pig myocytes; Ca2+ spark imaging; sarcomeric shortening measurements; immunofluorescence of presenilin localization; Western blot PloS one Medium 28384221
2022 PKA-mediated phosphorylation of Kv4.2 disrupts Kv4.2-KChIP2 interaction, causing Kv4.2 to exit lipid rafts and undergo internalization; KChIP2 assists Kv4.2 localization in lipid rafts, and adrenergic stimulation with phenylephrine recapitulates this dissociation in native neonatal rat ventricular myocytes. High-resolution fluorescence microscopy; co-immunoprecipitation; phosphomimetic mutagenesis (S552D); surface biotinylation; lipid raft fractionation in HEK293 and NRVMs American journal of physiology. Cell physiology High 35508186
2019 Alternatively spliced KChIP2 isoforms lacking a polybasic N-terminal domain (KChIP2b and KChIP2c) support Ca2+-mediated increases in Kv4.2 current density (~1.5-fold), whereas longer isoforms with the polybasic motif (KChIP2a, KChIP2a1) do not; acidification of the basic residues in KChIP2a1 rescues Ca2+ regulation, demonstrating that the polybasic domain prevents Ca2+ regulation of Kv4 channels. Whole-cell patch-clamp in HEK293T cells; isoform-specific expression; site-directed mutagenesis of polybasic domain The Journal of biological chemistry High 30622142
2017 Ca2+ binding to KChIP2 EF-hand 2 and EF-hand 3 differentially modulates Kv4.3/KChIP2 channel inactivation and recovery kinetics; Ca2+-mediated modulation of recovery kinetics requires CaMKII activity (blocked by KN-93), establishing a CaMKII-dependent mechanism by which intracellular Ca2+ acutely modulates Ito kinetics. Whole-cell patch-clamp in HEK293 cells; EF-hand mutagenesis (ΔEF2, ΔEF3, ΔEF4); intracellular Ca2+ buffering with BAPTA; CaMKII inhibitor KN-93 Pflugers Archiv : European journal of physiology High 28735419
2014 Kv4.2 and KChIP2 are partially localized in lipid rafts of rat left ventricular myocytes; cholesterol depletion by methyl-beta-cyclodextrin shifts Kv4.2 and KChIP2 from low-density (raft) to high-density fractions and reduces Ito by ~12%, linking raft localization to functional channel expression. Sucrose density gradient fractionation; Western blot; whole-cell patch-clamp; cholesterol depletion with methyl-beta-cyclodextrin Pflugers Archiv : European journal of physiology Medium 24793047
2010 The compound NS5806 increases Kv4.3/KChIP2 peak current and slows current decay in a KChIP2-dependent manner; other accessory subunits (DPP6, DPP10, KCNE2, KCNE3) modulate the NS5806 response but current decay slowing requires the presence of KChIP2, demonstrating that NS5806 acts through the Kv4.3/KChIP2 complex. Heterologous expression in Xenopus oocytes and CHO-K1 cells; two-electrode and whole-cell voltage clamp; pharmacological dissection British journal of pharmacology Medium 20649599
2022 Kcnip2-expressing inhibitory interneurons in the mouse spinal dorsal horn selectively control cold sensitivity; diphtheria toxin-mediated ablation of these neurons increases cold sensitivity without affecting other somatosensory modalities, and chemogenetic activation reduces cold and heat sensitivity. These neurons inhibit spinal nociceptive output neurons projecting to the lateral parabrachial nucleus. Intersectional genetics; diphtheria toxin-mediated neuronal ablation; chemogenetic (DREADD) activation; circuit tracing; behavioral assays in mice Neuron High 36323322
2007 Chemically synthesized minimal KChIP2d protein is primarily alpha-helical, becomes more structured upon Ca2+ binding (assessed by NMR and CD spectroscopy), exists in a monomer-dimer equilibrium, and shows evidence for two monomer binding sites on the Kv4.2 N-terminal peptide. Total chemical synthesis using Boc chemistry and native chemical ligation; CD spectroscopy; 1H-NMR; analytical ultracentrifugation Protein science Medium 17660260
2010 KChIP2 overexpression in neonatal cardiomyocytes increases Kv4.2 and Kv4.3 protein levels; in vivo gene transfer in hypertrophic rats increases Ito density, shortens action potential duration, alters Ca2+ transients, increases SERCA2a and NCX expression, and reduces calcineurin/NFAT pathway activation, demonstrating KChIP2 attenuates hypertrophy partly through modulation of intracellular calcium. Adenoviral gene transfer in neonatal cardiomyocytes and in vivo in rats; patch-clamp; Ca2+ imaging; Western blot; 4-aminopyridine pharmacology; echocardiography Journal of molecular and cellular cardiology High 20051248

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell 346 11747815
2002 Regulation of Kv4.3 current by KChIP2 splice variants: a component of native cardiac I(to)? Circulation 101 12135940
2003 Concordant expression of KChIP2 mRNA, protein and transient outward current throughout the canine ventricle. The Journal of physiology 79 12598586
2008 Post-transcriptional gene silencing of KChIP2 and Navbeta1 in neonatal rat cardiac myocytes reveals a functional association between Na and Ito currents. Journal of molecular and cellular cardiology 73 18565539
2009 Accessory subunit KChIP2 modulates the cardiac L-type calcium current. Circulation research 71 19461043
2002 Elucidating KChIP effects on Kv4.3 inactivation and recovery kinetics with a minimal KChIP2 isoform. The Journal of physiology 65 12433945
2002 Heterogeneous expression of KChIP2 isoforms in the ferret heart. The Journal of physiology 61 11897837
2004 Regulation of Kv4.3 voltage-dependent gating kinetics by KChIP2 isoforms. The Journal of physiology 59 14724186
2011 Nuclear factor kappaB downregulates the transient outward potassium current I(to,f) through control of KChIP2 expression. Circulation research 56 21252158
2010 Interdependent roles for accessory KChIP2, KChIP3, and KChIP4 subunits in the generation of Kv4-encoded IA channels in cortical pyramidal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 20943905
2005 KChIP2 modulates the cell surface expression of Kv 1.5-encoded K(+) channels. Journal of molecular and cellular cardiology 45 15878168
2019 MG53, A Novel Regulator of KChIP2 and Ito,f, Plays a Critical Role in Electrophysiological Remodeling in Cardiac Hypertrophy. Circulation 42 30760025
2010 Effect of the I(to) activator NS5806 on cloned K(V)4 channels depends on the accessory protein KChIP2. British journal of pharmacology 39 20649599
2004 Novel KChIP2 isoforms increase functional diversity of transient outward potassium currents. The Journal of physiology 39 15107477
2010 KChIP2 attenuates cardiac hypertrophy through regulation of Ito and intracellular calcium signaling. Journal of molecular and cellular cardiology 33 20051248
2013 Stabilization of Kv4 protein by the accessory K(+) channel interacting protein 2 (KChIP2) subunit is required for the generation of native myocardial fast transient outward K(+) currents. The Journal of physiology 32 23713033
2006 Spatial distributions of Kv4 channels and KChip2 isoforms in the murine heart based on laser capture microdissection. Cardiovascular research 29 17289005
2008 Deleting the accessory subunit KChIP2 results in loss of I(to,f) and increased I(K,slow) that maintains normal action potential configuration. Heart rhythm 28 19251214
2017 KChIP2 is a core transcriptional regulator of cardiac excitability. eLife 27 28263709
2014 Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2. American journal of physiology. Heart and circulatory physiology 26 24486512
2008 Effects of MiRP1 and DPP6 beta-subunits on the blockade induced by flecainide of Kv4.3/KChIP2 channels. British journal of pharmacology 23 18536731
2007 Diminished Kv4.2/3 but not KChIP2 levels reduce the cardiac transient outward K+ current in spontaneously hypertensive rats. Cardiovascular research 23 17289007
2012 Impact of KChIP2 on Cardiac Electrophysiology and the Progression of Heart Failure. Frontiers in physiology 21 22586403
2003 Contribution of KChIP2 to the developmental increase in transient outward current of rat cardiomyocytes. Journal of molecular and cellular cardiology 21 12967630
2006 C-terminal domain of Kv4.2 and associated KChIP2 interactions regulate functional expression and gating of Kv4.2. The Journal of biological chemistry 19 16820361
2010 Determinants of CREB degradation and KChIP2 gene transcription in cardiac memory. Heart rhythm 17 20346417
2014 Loss of K+ currents in heart failure is accentuated in KChIP2 deficient mice. Journal of cardiovascular electrophysiology 16 24678923
2009 Transcriptional and electrophysiological consequences of KChIP2-mediated regulation of CaV1.2. Channels (Austin, Tex.) 16 19713767
2007 Molecular and functional characterization of Kv4.2 and KChIP2 expressed in the porcine left ventricle. Pflugers Archiv : European journal of physiology 15 17242957
2014 Localization of Kv4.2 and KChIP2 in lipid rafts and modulation of outward K+ currents by membrane cholesterol content in rat left ventricular myocytes. Pflugers Archiv : European journal of physiology 12 24793047
2019 Dynamic palmitoylation regulates trafficking of K channel interacting protein 2 (KChIP2) across multiple subcellular compartments in cardiac myocytes. Journal of molecular and cellular cardiology 11 31362018
2015 Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2. American journal of physiology. Heart and circulatory physiology 11 26055791
2005 Inhibition of Kv4.3/KChIP2.2 channels by bupivacaine and its modulation by the pore mutation Kv4.3V401I. Anesthesiology 11 16192772
2022 Inhibitory Kcnip2 neurons of the spinal dorsal horn control behavioral sensitivity to environmental cold. Neuron 10 36323322
2017 KChIP2 regulates the cardiac Ca2+ transient and myocyte contractility by targeting ryanodine receptor activity. PloS one 10 28384221
2016 Myocardial KChIP2 Expression in Guinea Pig Resolves an Expanded Electrophysiologic Role. PloS one 10 26764482
2007 Total chemical synthesis and biophysical characterization of the minimal isoform of the KChIP2 potassium channel regulatory subunit. Protein science : a publication of the Protein Society 10 17660260
2017 Modulation of human Kv4.3/KChIP2 channel inactivation kinetics by cytoplasmic Ca2. Pflugers Archiv : European journal of physiology 9 28735419
2018 Regulation of Kv4.3 and hERG potassium channels by KChIP2 isoforms and DPP6 and response to the dual K+ channel activator NS3623. Biochemical pharmacology 8 29378180
2004 Interaction of ropivacaine with cloned cardiac Kv4.3/KChIP2.2 complexes. Anesthesiology 8 15564942
2005 Kv4.2 and KChIP2 transcription in individual cardiomyocytes from the rat left ventricular free wall. Journal of molecular and cellular cardiology 7 15946675
2022 Kv4.2 phosphorylation by PKA drives Kv4.2-KChIP2 dissociation, leading to Kv4.2 out of lipid rafts and internalization. American journal of physiology. Cell physiology 6 35508186
2019 A polybasic motif in alternatively spliced KChIP2 isoforms prevents Ca2+ regulation of Kv4 channels. The Journal of biological chemistry 5 30622142
2021 Inducing Ito,f and phase 1 repolarization of the cardiac action potential with a Kv4.3/KChIP2.1 bicistronic transgene. Journal of molecular and cellular cardiology 4 34823101
2013 NHE isoform switching and KChIP2 upregulation in aging porcine atria. PloS one 4 24376615
2016 Potassium Channel Interacting Protein 2 (KChIP2) is not a transcriptional regulator of cardiac electrical remodeling. Scientific reports 3 27349185
2024 Inhibition of Cardiac Kv4.3/KChIP2 Channels by Sulfonylurea Drug Gliquidone. Molecular pharmacology 2 38164605
2022 Modulation of KV4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2. International journal of molecular sciences 2 36012438
2020 A Soluble Epoxide Hydrolase Inhibitor Upregulated KCNJ12 and KCNIP2 by Downregulating MicroRNA-29 in a Mouse Model of Myocardial Infarction. The heart surgery forum 2 32990585
2009 [Atrial myocytes KChIP2 mRNA expression in rheumatic heart disease patients with atrial fibrillation]. Zhonghua xin xue guan bing za zhi 2 19927631
2017 KChIP2 genotype dependence of transient outward current (Ito) properties in cardiomyocytes isolated from male and female mice. PloS one 1 28141821
2025 KCNIP2: A key regulator in cardiac electrophysiology and tumorigenesis. Gene 0 40490090