Affinage

KCNIP2

A-type potassium channel modulatory protein KCNIP2 · UniProt Q9NS61

Length
270 aa
Mass
30.9 kDa
Annotated
2026-06-10
52 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNIP2 (KChIP2) is a cytosolic, Ca2+-binding auxiliary subunit that is the obligate determinant of the cardiac transient outward potassium current (Ito,f): its genetic deletion abolishes Ito and prolongs action potential duration, predisposing to ventricular tachycardia through loss of the transmural Ito gradient (PMID:11747815, PMID:23713033). KChIP2 generates functional Ito by binding the pore-forming Kv4.2/Kv4.3 subunits, stabilizing Kv4 protein in the biosynthetic pathway against degradation, promoting surface trafficking, and tuning gating—slowing closed-state inactivation, promoting open-state inactivation, and markedly accelerating recovery from inactivation, with Ca2+/EF-hand-dependent control of inactivation kinetics that depends on CaMKII (PMID:12967630, PMID:14724186, PMID:16820361, PMID:28735419). Distinct splice isoforms and protein domains separate these gating functions, and a polybasic motif in certain isoforms gates whether Ca2+ can regulate the channel (PMID:12433945, PMID:11897837, PMID:15107477, PMID:30622142). Beyond Kv4, KChIP2 is a multichannel regulator: it binds the N-terminal inhibitory module of CaV1.2 to augment ICa,L independent of Ca2+ binding, associates with Nav1.5/Navβ1 to support INa, and reduces Kv1.5 surface expression by inhibiting ER-to-membrane trafficking (PMID:15878168, PMID:18565539, PMID:19461043, PMID:26764482). KChIP2 abundance—and hence Ito density—is set transcriptionally: NF-κB represses KChIP2 downstream of α1-adrenergic, TNFα, and MG53–TAK1–IκBα signaling, while angiotensin II/ROS-driven CREB degradation lowers KChIP2 during cardiac memory (PMID:12598586, PMID:21252158, PMID:20346417, PMID:30760025). Subcellular partitioning is controlled by palmitoylation: palmitoylated KChIP2 clusters at the membrane, whereas stress-induced depalmitoylation drives nuclear entry, where KChIP2 acts as a transcriptional repressor of miR-34b/c to preserve INa and Ito (PMID:28263709, PMID:31362018). In the spinal dorsal horn, Kcnip2-expressing inhibitory interneurons gate cold sensitivity by inhibiting nociceptive projection neurons (PMID:36323322).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    Whether KChIP2 was essential for native cardiac Ito was unknown; the knockout established it as the indispensable subunit whose loss creates an arrhythmogenic substrate.

    Evidence KChIP2 knockout mouse with single-cell patch-clamp and ECG

    PMID:11747815

    Open questions at the time
    • Did not resolve whether the defect was trafficking, gating, or protein stability
    • Mechanism of arrhythmia susceptibility beyond Ito gradient loss not dissected
  2. 2002 High

    It was unclear how KChIP2 shapes Kv4 current; isoform and domain studies showed it increases current density, modulates inactivation via EF-hands, and accelerates recovery via a separable non-EF-hand region.

    Evidence Heterologous co-expression with Kv4.3 in HEK cells and Xenopus oocytes, minimal-isoform cloning, EF-hand domain analysis

    PMID:11897837 PMID:12135940 PMID:12433945

    Open questions at the time
    • Structural basis of domain-specific modulation not defined
    • Relevance of each isoform to native cardiomyocyte Ito only inferred from expression patterns
  3. 2003 High

    The basis of regional Ito heterogeneity was unknown; KChIP2 protein and mRNA were shown to track Ito density across the ventricle and to be sufficient to induce Ito,f in immature myocytes via enhanced Kv4 surface trafficking.

    Evidence Regional canine ventricle qRT-PCR/Western/patch-clamp; adenoviral KChIP2 overexpression in E12 rat cardiomyocytes

    PMID:12598586 PMID:12967630

    Open questions at the time
    • Upstream transcriptional control of the regional gradient not identified
    • Whether trafficking is the sole limiting step left open
  4. 2004 High

    The kinetic mechanism of KChIP2 action was refined: it modulates distinct inactivation pathways (Ca2+-independent closed-state, Ca2+-dependent open-state), and additional isoforms expand the repertoire of current phenotypes.

    Evidence Detailed kinetic analysis and novel isoform characterization in Xenopus oocyte two-electrode voltage-clamp

    PMID:14724186 PMID:15107477

    Open questions at the time
    • Endogenous abundance of novel isoforms in heart not established
    • Molecular coupling of Ca2+ binding to open-state inactivation unresolved
  5. 2005 High

    Whether KChIP2 acts only on Kv4 was tested; it was found to bind Kv1.5 and suppress its surface expression, revealing KChIP2 as a negative regulator of a non-Kv4 channel via ER trafficking control.

    Evidence Reciprocal Co-IP from mouse ventricle, HEK-293 expression, surface biotinylation, patch-clamp

    PMID:15878168

    Open questions at the time
    • Trafficking step targeted not directly visualized
    • Physiological significance for native IKur in heart not quantified
  6. 2006 High

    The mechanism of Kv4 stabilization was clarified: KChIP2 binds the Kv4.2 C-terminus and slows its degradation ~8-fold, doubling protein levels and boosting current.

    Evidence Kv4.2 truncation mutagenesis, Co-IP, GST pulldown competition, pulse-chase in heterologous cells

    PMID:16820361

    Open questions at the time
    • Degradation machinery acting on free Kv4.2 not identified
    • Whether C-terminal binding contributes to gating versus stability not separated
  7. 2008 High

    Coupling between Ito and sodium current was unknown; KChIP2 knockdown was shown to suppress INa and reduce Nav alpha/beta1 subunits, with Navβ1–Kv4.x co-assembly indicating a coordinated channel macrocomplex.

    Evidence siRNA knockdown in NRVMs, Co-IP from neonatal rat myocardium, patch-clamp, mRNA/protein quantification

    PMID:18565539

    Open questions at the time
    • Whether KChIP2 binds Nav subunits directly not established
    • Mechanism by which KChIP2 controls Nav subunit levels unresolved
  8. 2009 High

    KChIP2's role in L-type Ca2+ current was defined: it binds the CaV1.2 N-terminal inhibitory module and augments ICa,L in a Ca2+-binding-independent manner without changing channel expression or trafficking.

    Evidence KChIP2-/- myocyte and heterologous patch-clamp, Co-IP/pulldown with CaV1.2 N-terminus from cardiac tissue

    PMID:19461043 PMID:19713767

    Open questions at the time
    • Structural detail of N-terminal module relief not resolved
    • Confirmatory Co-IP in 19713767 added limited new mechanism
  9. 2013 High

    Whether KChIP2 controls Kv4 transcript or protein was resolved: its deletion eliminates Kv4.2 protein without lowering Kcnd2 mRNA, and re-expression rescues ICa,L but not Ito, establishing biosynthetic protein stabilization as the critical determinant.

    Evidence KChIP2 knockout protein vs mRNA analysis, patch-clamp, adenoviral re-expression rescue

    PMID:23713033

    Open questions at the time
    • Reason Ito,f could not be rescued by re-expression not fully explained
    • Developmental window for Kv4 stabilization not defined
  10. 2010 High

    Transcriptional control of KChIP2 was established: NF-κB represses KChIP2 downstream of α1-adrenergic and TNFα signaling, while KChIP2 overexpression attenuates hypertrophy via the calcineurin/NFAT pathway.

    Evidence NF-κB pathway gain/loss-of-function in NRVMs; KChIP2 gene transfer in vitro and in aortic-banding rats with electrophysiology, Ca2+ imaging, echocardiography

    PMID:20051248 PMID:21252158

    Open questions at the time
    • Direct NF-κB binding site not yet mapped at this stage
    • Whether anti-hypertrophic effect is channel-dependent or transcriptional not separated
  11. 2010 Medium

    A pathological route to KChIP2 downregulation was identified: cardiac memory drives angiotensin II/ROS-dependent CREB ubiquitination and proteasomal degradation, lowering KChIP2.

    Evidence In vivo dog LV pacing, H2O2-treated cardiomyocytes, AT-receptor blockade, proteasome inhibition, CREB ubiquitination assay

    PMID:20346417

    Open questions at the time
    • Direct CREB occupancy at KChIP2 promoter not demonstrated
    • Single lab pharmacological mechanism
  12. 2010 High

    KChIP2's neuronal role was addressed: it co-assembles with KChIP3/KChIP4 and Kv4.2 in cortical neurons, where the three KChIPs are interdependently required for Kv4-encoded A-type current.

    Evidence Co-IP from mouse cortex, single KO electrophysiology, triple RNAi in cortical neurons

    PMID:20943905

    Open questions at the time
    • KChIP2-specific (versus redundant) neuronal function not isolated
    • Behavioral or circuit consequence not tested here
  13. 2017 High

    A nuclear, non-channel function was discovered: KChIP2 acts as a transcriptional repressor of miR-34b/c that target INa and Ito, and maintaining KChIP2 or inhibiting miR-34 prevents reentrant arrhythmia.

    Evidence Rat and human cardiomyocytes, knockdown/overexpression, chromatin interaction assays, patch-clamp, arrhythmia induction

    PMID:28263709

    Open questions at the time
    • Direct DNA-binding mode of KChIP2 not structurally defined
    • Cofactors mediating repression not identified
  14. 2019 High

    The switch between membrane and nuclear roles was mechanistically linked to palmitoylation: palmitoylated KChIP2 clusters at the membrane while stress-induced depalmitoylation drives nuclear entry, and MG53–TAK1–IκBα signaling tunes NF-κB occupancy at the KChIP2 promoter.

    Evidence Palmitoylation-mutant live imaging/FRAP/fractionation plus in vivo cardiac arrest model; MG53 KO, ChIP of NF-κB at KChIP2 5' region, Co-IP, rescue

    PMID:30760025 PMID:31362018

    Open questions at the time
    • Enzymes mediating KChIP2 palmitoylation/depalmitoylation not identified
    • Quantitative link between nuclear pool size and transcriptional output not established
  15. 2017 Medium

    The Ca2+ transduction mechanism was dissected: individual EF-hands differentially set the direction of Ca2+-dependent recovery modulation, with CaMKII activity required for the Ca2+-mediated effect.

    Evidence EF-hand point mutants with controlled intracellular Ca2+, BAPTA, and CaMKII inhibitor KN-93 in HEK293 patch-clamp

    PMID:28735419

    Open questions at the time
    • Direct demonstration of KChIP2 phosphorylation by CaMKII lacking
    • Single expression system
  16. 2017 Medium

    Ito-independent cardiac roles were confirmed in a Kv4-lacking species: KChIP2 knockdown prolonged the action potential via increased CaV1.2/ICa,L and decreased Nav1.5/INa, and impaired Ca2+ handling through presenilin/RyR control.

    Evidence siRNA knockdown in guinea pig myocytes, patch-clamp, Ca2+ spark imaging, confocal immunofluorescence, Western blot

    PMID:26764482 PMID:28384221

    Open questions at the time
    • Whether presenilin/RyR effect is direct not established
    • Species-specific findings need cross-validation
  17. 2019 Medium

    Isoform-specific Ca2+ sensitivity was explained: a polybasic domain present in some KChIP2 isoforms blocks Ca2+-mediated regulation of Kv4.2, and neutralizing its basic residues restores sensitivity.

    Evidence HEK293T patch-clamp with site-directed acidification of the polybasic motif

    PMID:30622142

    Open questions at the time
    • Structural mechanism by which the polybasic motif occludes Ca2+ regulation not defined
    • Single lab, limited methods
  18. 2022 High

    Adrenergic regulation of channel surface stability was mechanistically resolved: PKA phosphorylation of Kv4.2 dissociates the Kv4.2–KChIP2 complex, ejecting Kv4.2 from lipid rafts and triggering internalization.

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

    PMID:35508186

    Open questions at the time
    • In vivo relevance during sustained adrenergic states not quantified
    • Whether KChIP2 itself is modified during this dissociation not addressed
  19. 2022 High

    A distinct neuronal function emerged: Kcnip2-expressing inhibitory interneurons in the spinal dorsal horn gate cold sensitivity by inhibiting nociceptive projection neurons.

    Evidence Intersectional genetics, diphtheria toxin ablation, chemogenetic activation, circuit tracing, behavior in mice

    PMID:36323322

    Open questions at the time
    • Whether KChIP2's channel/transcriptional functions underlie this circuit role not tested
    • Molecular identity of the cold-gating current in these neurons not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The enzymes and signals that toggle KChIP2 between its membrane channel-modulatory role and its nuclear transcriptional role, and the structural basis of its multichannel and DNA interactions, remain unresolved.
  • Palmitoyl-transferase/thioesterase for KChIP2 unidentified
  • No structural model of KChIP2 bound to DNA or to CaV1.2/Nav complexes
  • CaMKII phosphorylation of KChIP2 not directly demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 2 GO:0003677 DNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-112316 Neuronal System 2 R-HSA-397014 Muscle contraction 2
Partners
CACNA1CKCNA5KCND2KCND3KCNIP3MG53SCN1BSCN5A
Complex memberships
Kv4.2/KChIP2 channel complexKv4.3/KChIP2 channel complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 KChIP2 knockout mice exhibit complete loss of cardiac transient outward potassium current (Ito) and prolonged action potential duration, establishing KChIP2 as an essential auxiliary subunit required for Ito and demonstrating that its deficiency confers susceptibility to ventricular tachycardia via loss of the transmural gradient of Ito. KChIP2 knockout mouse model, single-cell patch-clamp electrophysiology, ECG analysis Cell High 11747815
2002 KChIP2 splice variants differentially modulate Kv4.3-encoded current by increasing current density, slowing current decay in a Ca2+-dependent manner, and hastening recovery from inactivation in a splice variant-specific fashion. KChIP2 is localized to t-tubules and the nucleus in cardiomyocytes. Heterologous expression in HEK cells, whole-cell patch-clamp, kinetic RT-PCR, Western blot, immunocytochemistry Circulation High 12135940
2002 A minimal KChIP2 isoform (KChIP2d) comprising the C-terminal 70 amino acids with only one EF-hand is sufficient to accelerate Kv4.3 recovery from inactivation and slow inactivation kinetics. Distinct KChIP2 domains mediate modulation of inactivation (via EF-hand) versus recovery (via a short non-EF-hand stretch). Ca2+-dependent effects on inactivation are mediated through the slow time constant of inactivation. Cloning of minimal KChIP2d isoform from ferret heart, co-expression with Kv4.3 in Xenopus oocytes, two-electrode voltage-clamp, EF-hand domain analysis The Journal of physiology High 12433945
2002 Three KChIP2 isoforms from ferret heart all accelerate Kv4.3 recovery kinetics ~4-fold, but only KChIP2a produces large depolarizing shifts in steady-state activation and inactivation resembling native Ito. KChIP2b is the most abundant isoform expressed in a transmural gradient paralleling Ito distribution. Cloning of KChIP2 isoforms from ferret heart, co-expression in Xenopus oocytes, two-electrode voltage-clamp, immunoblot, RNA expression analysis The Journal of physiology High 11897837
2003 KChIP2 protein levels closely parallel mRNA expression across nine different regions of the canine ventricle and match the regional density of Ito, establishing that transcriptional regulation of KChIP2 is a primary determinant of Ito expression in the heart. Regional dissection of canine ventricle, quantitative RT-PCR, Western blot, patch-clamp electrophysiology, microarray The Journal of physiology High 12598586
2003 KChIP2 overexpression via adenoviral gene transfer in embryonic (E12) rat cardiomyocytes, which normally lack Ito,f, induced a large Ito,f and enhanced trafficking of Kv4.2 channels to the cell surface, demonstrating that KChIP2 plays a critical role in generating functional Ito,f channels during cardiac development. Adenoviral gene transfer of KChIP2 into E12 rat cardiomyocytes, patch-clamp electrophysiology, immunocytochemistry, real-time RT-PCR Journal of molecular and cellular cardiology High 12967630
2004 KChIP2 isoforms accelerate Kv4.3 recovery from inactivation, slow closed-state inactivation, and promote open-state inactivation. Closed-state inactivation transitions are Ca2+-independent with KChIPs, while open-state inactivation is Ca2+-dependent. A detailed gating model places KChIP2 as modulating distinct inactivation mechanisms. Xenopus oocyte expression, two-electrode voltage-clamp, detailed kinetic analysis of macroscopic inactivation and recovery The Journal of physiology High 14724186
2004 Three novel KChIP2 isoforms (KChIP2e, KChIP2f, KChIP2g) differentially modulate Kv4.3 currents: KChIP2e reduces amplitude and accelerates inactivation; KChIP2f increases amplitude and slows inactivation; KChIP2g increases amplitude, slows inactivation, and shifts half-maximal inactivation to more negative potentials. Cloning of novel KChIP2 isoforms, co-expression with Kv4.3 in Xenopus oocytes, two-microelectrode voltage-clamp The Journal of physiology High 15107477
2005 KChIP2 co-immunoprecipitates with Kv1.5 (as well as Kv4.2/Kv4.3) from adult mouse ventricles. Co-expression of KChIP2 reduces Kv1.5-encoded K+ currents and decreases cell surface expression of Kv1.5, likely by inhibiting forward trafficking from the ER, without affecting time- or voltage-dependent properties. Co-immunoprecipitation from adult mouse ventricles, heterologous expression in HEK-293 cells, patch-clamp, immunohistochemistry, cell surface biotinylation Journal of molecular and cellular cardiology High 15878168
2006 KChIP2 directly interacts with the C-terminus of Kv4.2 (comparable binding affinity to N-terminus), slows Kv4.2 degradation ~8-fold (pulse-chase experiments), doubles Kv4.2 protein expression and increases current amplitude up to 8-fold. The Kv4.2 C-terminal domain plays a critical role in voltage-dependent activation and surface expression modulated through its direct interaction with KChIP2. C-terminal truncation mutagenesis of Kv4.2, co-expression with KChIP2, patch-clamp, co-immunoprecipitation, GST pulldown competitive binding assay, pulse-chase degradation experiments The Journal of biological chemistry High 16820361
2008 siRNA-mediated silencing of KChIP2 in neonatal rat ventricular myocytes suppressed both Ito and INa, and reduced Nav channel alpha and beta1 subunit mRNA/protein while leaving Kv4.x mRNAs unaltered. Co-immunoprecipitation demonstrated a structural association between Navβ1 and Kv4.x subunits, indicating a functional coupling of Ito and INa channels. siRNA knockdown in NRVMs, co-immunoprecipitation from neonatal rat ventricular myocardium, whole-cell patch-clamp, Western blot, mRNA quantification Journal of molecular and cellular cardiology High 18565539
2009 KChIP2 directly modulates the cardiac L-type Ca2+ current (ICa,L): ICa,L density is reduced 28% in KChIP2-/- myocytes. KChIP2 binds to the N-terminal inhibitory module of CaV1.2 alpha1C subunit and augments ICa,L current density without increasing CaV1.2 protein expression or plasma membrane trafficking. This regulation is Ca2+-binding independent. KChIP2 knockout mouse myocytes patch-clamp, transfected cell line electrophysiology, biochemical interaction analysis (Co-IP/pulldown with CaV1.2 N-terminus), Western blot Circulation research High 19461043
2009 KChIP2 and CaV1.2 co-immunoprecipitate from cardiac tissue, providing biochemical support for their direct interaction. KChIP2-/- mice show increased CACNB2 transcriptional activity while CaV1.2 expression is preserved. Co-immunoprecipitation from cardiac tissue, gene-chip microarray, real-time PCR, patch-clamp Channels Medium 19713767
2010 NF-κB downregulates KChIP2 mRNA expression and thereby reduces Ito,f following α1-adrenergic receptor stimulation or TNFα application. Overexpression of IκBαSA (phosphorylation-deficient IκBα) prevented PE/Pro-induced reductions in Ito,f and KChIP2 mRNA without affecting Kv4.2 or Kv4.3. IκB kinase-β overexpression decreased KChIP2 and Ito,f. Neonatal rat ventricular myocytes, adenoviral overexpression of IκBαSA and IKKβ, patch-clamp, real-time RT-PCR, Western blot Circulation research High 21252158
2010 KChIP2, KChIP3, and KChIP4 all co-immunoprecipitate with Kv4.2 in cortical neurons. Triple RNA interference targeting KChIP2, KChIP3, and KChIP4 markedly reduces IA densities and induces Kv current remodeling, establishing interdependent roles for all three KChIP subunits in generating Kv4-encoded IA channels in cortical pyramidal neurons. Co-immunoprecipitation from adult mouse cortex, KChIP2/KChIP3 single knockout mice electrophysiology, triple RNAi in cortical neurons, whole-cell patch-clamp The Journal of neuroscience High 20943905
2010 KChIP2 overexpression via gene transfer attenuated cardiac hypertrophy, increased Ito,f density, shortened action potential duration, altered Ca2+ transients, and increased SERCA2a and NCX expression. In neonatal myocytes, KChIP2 overexpression reversed Ang II-induced hypertrophic changes and decreased calcineurin expression, NFATc1 expression/nuclear translocation, and MCiP1.4, suggesting KChIP2 attenuates hypertrophy via modulation of calcineurin/NFAT pathway. Adenoviral gene transfer of KChIP2 in neonatal cardiomyocytes and in vivo adult rats (aortic banding model), patch-clamp, Ca2+ imaging, echocardiography, Western blot Journal of molecular and cellular cardiology High 20051248
2010 Cardiac memory induced by left ventricular pacing reduces KChIP2 mRNA and protein through a mechanism involving angiotensin II-mediated reactive oxygen species synthesis leading to CREB ubiquitination and proteasomal degradation; blocking proteasomal degradation (lactacystin) prevented the CREB decrease and thus the KChIP2 reduction. In vivo dog left ventricular pacing model, in vitro H2O2-treated neonatal rat cardiomyocytes, angiotensin II receptor blocker treatment, proteasomal inhibitor treatment, CREB ubiquitination assay Heart rhythm Medium 20346417
2013 Targeted deletion of KChIP2 results in complete loss of Kv4.2 protein (but not Kcnd2 transcript) and elimination of Ito,f in ventricular myocytes, demonstrating that KChIP2-mediated stabilization of Kv4 protein in the biosynthetic pathway is a critical determinant of native cardiac Ito,f channel expression. Adenovirus-mediated re-expression of KChIP2 in KChIP2-/- myocytes did not rescue Ito,f but did increase ICa,L. KChIP2 knockout mice, protein/mRNA analysis, patch-clamp, adenoviral KChIP2 re-expression The Journal of physiology High 23713033
2017 KChIP2 functions as a transcriptional repressor of miR-34b and miR-34c through interaction with genetic elements. These miRNAs target key depolarizing (INa) and repolarizing (Ito) currents. Genetically maintaining KChIP2 expression or inhibiting miR-34 under pathologic conditions restored channel function and prevented reentrant arrhythmias. Palmitoylation-dependent nuclear entry was identified as controlling this transcriptional function. Rat and human derived cardiomyocytes, miRNA expression analysis, KChIP2 knockdown/overexpression, chromatin interaction assays, patch-clamp, arrhythmia induction eLife High 28263709
2017 In guinea pig myocytes (which lack Kv4), KChIP2 knockdown significantly prolonged the cardiac action potential due to enhanced ICa,L from increased CaV1.2 protein and reduced INa from decreased Nav1.5 protein, without affecting IKr or IKs, revealing roles for KChIP2 in regulating L-type Ca2+ and Na+ currents independent of Ito. siRNA knockdown in isolated adult guinea pig myocytes, whole-cell patch-clamp, Western blot PloS one Medium 26764482
2017 KChIP2 knockdown in isolated guinea pig myocytes reduced Ca2+ transient amplitude and sarcomeric shortening, decreased Ca2+ spark frequency, and caused delocalization of presenilin away from sarcomeric banding, suggesting KChIP2 regulates RyR activity through control of presenilin localization. siRNA knockdown in guinea pig myocytes, Ca2+ spark imaging, sarcomeric shortening measurement, confocal immunofluorescence, Western blot PloS one Medium 28384221
2019 MG53 physically interacts with TAK1 and IκBα (NF-κB pathway components) and regulates NF-κB activity, which in turn controls KChIP2 transcription. ChIP assay confirmed NF-κB protein interaction with the KChIP2 gene 5' regulatory region. MG53 overexpression decreases, and MG53 knockdown increases, NF-κB enrichment at the KChIP2 gene. Normalizing NF-κB activity reverses KChIP2 alterations in MG53-manipulated cells. MG53 knockout mice, adenoviral overexpression/siRNA knockdown in NRVMs, chromatin immunoprecipitation, Co-immunoprecipitation/Western blot, patch-clamp Circulation High 30760025
2019 Palmitoylation of KChIP2 drives its clustering at the plasma membrane, while unpalmitoylatable KChIP2 exhibits higher cytoplasmic mobility and faster nuclear entry. Acute cardiac stress (arrest/resuscitation) promotes endogenous KChIP2 depalmitoylation and nuclear entry, diverting it from ion channel modulation to nuclear functions. Imaging (live cell) and biochemical experiments on palmitoylatable vs unpalmitoylatable KChIP2 variants in COS-7 cells and cardiomyocytes, FRAP, in vivo rat cardiac arrest/resuscitation model, subcellular fractionation Journal of molecular and cellular cardiology High 31362018
2019 KChIP2b and KChIP2c splice isoforms (lacking a polybasic domain present in KChIP2a1 and KChIP2a) support Ca2+-mediated regulation of Kv4.2 current density (~1.5-fold increase with elevated intracellular Ca2+). Site-directed acidification of basic residues within the polybasic motif of KChIP2a1 rescued Ca2+-mediated regulation, demonstrating that the polybasic domain prevents Ca2+ regulation of Kv4 channels. HEK293T expression, whole-cell patch-clamp, site-directed mutagenesis of polybasic domain The Journal of biological chemistry Medium 30622142
2022 KChIP2 assists Kv4.2 localization in lipid rafts. PKA-mediated phosphorylation of Kv4.2 (downstream of acute adrenergic stimulation) induces dissociation between Kv4.2 and KChIP2, resulting in Kv4.2 shifting out of lipid rafts and subsequent internalization. A phosphomimetic mutation (Kv4.2-S552D) similarly disrupted Kv4.2-KChIP2 interaction and decreased Kv4.2 surface stability. High-resolution fluorescence microscopy in HEK293 and NRVMs, PKA phosphorylation assay, Co-immunoprecipitation, lipid raft fractionation, surface biotinylation, phenylephrine stimulation American journal of physiology. Cell physiology High 35508186
2017 Ca2+ binding to specific KChIP2 EF-hands acutely modulates Kv4.3/KChIP2 channel inactivation gating. EF-hand 2 mutation abolished Ca2+-mediated slowing of recovery kinetics; EF-hand 3 mutation converted Ca2+-mediated slowing to acceleration; EF-hand 4 mutation preserved slowing. In the presence of CaMKII inhibitor KN-93, Ca2+ accelerated (rather than slowed) recovery kinetics, implicating CaMKII action in the Ca2+-dependent modulation. HEK293 expression of Kv4.3/KChIP2 with EF-hand point mutants, whole-cell patch-clamp with defined intracellular Ca2+ concentrations, BAPTA chelation, CaMKII inhibitor KN-93 Pflugers Archiv Medium 28735419
2022 Kcnip2-expressing inhibitory (GlyT2+) interneurons in the mouse spinal dorsal horn gate cold sensitivity: diphtheria toxin ablation of these neurons increased cold sensitivity selectively, and their chemogenetic activation reduced both cold and heat sensitivity. These neurons become activated upon cold exposure and inhibit spinal nociceptive output neurons projecting to the lateral parabrachial nucleus. Intersectional genetic mouse model, diphtheria toxin ablation, chemogenetic activation (DREADD), circuit tracing, behavioral assessment Neuron High 36323322

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 348 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 72 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 57 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 49 20943905
2005 KChIP2 modulates the cell surface expression of Kv 1.5-encoded K(+) channels. Journal of molecular and cellular cardiology 46 15878168
2019 MG53, A Novel Regulator of KChIP2 and Ito,f, Plays a Critical Role in Electrophysiological Remodeling in Cardiac Hypertrophy. Circulation 44 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 42 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
2017 KChIP2 is a core transcriptional regulator of cardiac excitability. eLife 28 28263709
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
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
2022 Inhibitory Kcnip2 neurons of the spinal dorsal horn control behavioral sensitivity to environmental cold. Neuron 12 36323322
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
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
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 9 29378180
2017 Modulation of human Kv4.3/KChIP2 channel inactivation kinetics by cytoplasmic Ca2. Pflugers Archiv : European journal of physiology 9 28735419
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
2022 Modulation of KV4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2. International journal of molecular sciences 4 36012438
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
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

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