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Potassium voltage-gated channel subfamily D member 2



Mus musculus (Mouse)
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli


Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in rodent heart. Mediates the major part of the dendritic A-type current I(SA) in brain neurons (PubMed:10818150, PubMed:17122039, PubMed:18045912, PubMed:18187474, PubMed:20371829, PubMed:22815518). This current is activated at membrane potentials that are below the threshold for action potentials. It regulates neuronal excitability, prolongs the latency before the first spike in a series of action potentials, regulates the frequency of repetitive action potential firing, shortens the duration of action potentials and regulates the back-propagation of action potentials from the neuronal cell body to the dendrites (PubMed:10818150, PubMed:17122039, PubMed:22815518). Contributes to the regulation of the circadian rhythm of action potential firing in suprachiasmatic nucleus neurons, which regulates the circadian rhythm of locomotor activity (PubMed:22815518). Functions downstream of the metabotropic glutamate receptor GRM5 and plays a role in neuronal excitability and in nociception mediated by activation of GRM5 (PubMed:18045912). Mediates the transient outward current I(to) in rodent heart left ventricle apex cells, but not in human heart, where this current is mediated by another family member (PubMed:9734479, PubMed:10601491, PubMed:11909823, PubMed:23713033). Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:9734479, PubMed:22311982). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCND2 and KCND3; channel properties depend on the type of pore-forming alpha subunits that are part of the channel (PubMed:11909823). In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes (PubMed:11909823). Interaction with specific isoforms of the regulatory subunits KCNIP1, KCNIP2, KCNIP3 or KCNIP4 strongly increases expression at the cell surface and thereby increases channel activity; it modulates the kinetics of channel activation and inactivation, shifts the threshold for channel activation to more negative voltage values, shifts the threshold for inactivation to less negative voltages and accelerates recovery after inactivation (By similarity). Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity (PubMed:22311982).By similarity9 Publications


The transient neuronal A-type potassium current called I(SA) is triggered at membrane potentials that are below the threshold for action potentials. It inactivates rapidly and recovers rapidly from inactivation. It regulates the firing of action potentials and plays a role in synaptic integration and plasticity. Potassium channels containing KCND2 account for about 80% of the neuronal A-type potassium current. In contrast, the potassium channel responsible for the cardiac I(to) current differs between species; it is mediated by KCND2 in rodents. In human and other non-rodents KCND3 may play an equivalent role.2 Publications4 Publications
Is specifically and reversibly inhibited by the scorpion toxin Ts8 (AC P69940).By similarity


Homotetrameric channels activate rapidly, i.e within a few msec. After that, they inactivate rapidly, i.e within about 50-100 msec. The voltage-dependence of activation and inactivation and other channel characteristics vary depending on the experimental conditions, the expression system and the presence or absence of ancillary subunits. Homotetrameric channels have a unitary conductance of about 4 pS when expressed in a heterologous system. For the activation of homotetrameric channels expressed in xenopus oocytes, the voltage at half-maximal amplitude is about -10 mV. The time constant for inactivation is about 20 msec. For inactivation, the voltage at half-maximal amplitude is -62 mV. The time constant for recovery after inactivation is about 70 msec.1 Publication


      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Metal bindingi105Zinc; via pros nitrogenBy similarity1
      Metal bindingi132ZincBy similarity1
      Metal bindingi133ZincBy similarity1

      GO - Molecular functioni

      • A-type (transient outward) potassium channel activity Source: UniProtKB
      • metal ion binding Source: UniProtKB-KW
      • voltage-gated potassium channel activity Source: UniProtKB

      GO - Biological processi

      • action potential Source: MGI
      • cardiac muscle cell action potential Source: UniProtKB
      • cellular response to hypoxia Source: UniProtKB
      • locomotor rhythm Source: UniProtKB
      • neuronal action potential Source: UniProtKB
      • potassium ion transmembrane transport Source: UniProtKB
      • protein homooligomerization Source: InterPro
      • sensory perception of pain Source: UniProtKB


      Molecular functionIon channel, Potassium channel, Voltage-gated channel
      Biological processIon transport, Potassium transport, Transport
      LigandMetal-binding, Potassium, Zinc

      Enzyme and pathway databases

      ReactomeiR-MMU-1296072. Voltage gated Potassium channels.
      R-MMU-5576894. Phase 1 - inactivation of fast Na+ channels.

      Names & Taxonomyi

      Protein namesi
      Recommended name:
      Potassium voltage-gated channel subfamily D member 2
      Alternative name(s):
      Voltage-gated potassium channel subunit Kv4.2
      Gene namesi
      ORF Names:MNCb-7013
      OrganismiMus musculus (Mouse)
      Taxonomic identifieri10090 [NCBI]
      Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
      • UP000000589 Componenti: Chromosome 6

      Organism-specific databases

      MGIiMGI:102663. Kcnd2.

      Subcellular locationi


      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Topological domaini1 – 182CytoplasmicBy similarityAdd BLAST182
      Transmembranei183 – 204Helical; Name=Segment S1By similarityAdd BLAST22
      Topological domaini205 – 228ExtracellularBy similarityAdd BLAST24
      Transmembranei229 – 250Helical; Name=Segment S2By similarityAdd BLAST22
      Topological domaini251 – 261CytoplasmicBy similarityAdd BLAST11
      Transmembranei262 – 279Helical; Name=Segment S3By similarityAdd BLAST18
      Topological domaini280 – 286ExtracellularBy similarity7
      Transmembranei287 – 306Helical; Voltage-sensor; Name=Segment S4By similarityAdd BLAST20
      Topological domaini307 – 321CytoplasmicBy similarityAdd BLAST15
      Transmembranei322 – 343Helical; Name=Segment S5By similarityAdd BLAST22
      Topological domaini344 – 357ExtracellularBy similarityAdd BLAST14
      Intramembranei358 – 369Helical; Name=Pore helixBy similarityAdd BLAST12
      Intramembranei370 – 377By similarity8
      Topological domaini378 – 384ExtracellularBy similarity7
      Transmembranei385 – 413Helical; Name=Segment S6By similarityAdd BLAST29
      Topological domaini414 – 630CytoplasmicBy similarityAdd BLAST217

      GO - Cellular componenti

      • caveola Source: UniProtKB
      • cell junction Source: UniProtKB-SubCell
      • dendrite Source: UniProtKB
      • dendritic spine Source: MGI
      • integral component of plasma membrane Source: UniProtKB
      • integral component of postsynaptic membrane Source: SynGO
      • intrinsic component of plasma membrane Source: MGI
      • membrane Source: MGI
      • neuronal cell body Source: UniProtKB
      • neuronal cell body membrane Source: UniProtKB
      • perikaryon Source: UniProtKB-SubCell
      • plasma membrane raft Source: UniProtKB
      • postsynaptic membrane Source: SynGO
      • sarcolemma Source: UniProtKB
      • T-tubule Source: UniProtKB
      • voltage-gated potassium channel complex Source: UniProtKB

      Keywords - Cellular componenti

      Cell junction, Cell membrane, Cell projection, Membrane, Postsynaptic cell membrane, Synapse

      Pathology & Biotechi

      Disruption phenotypei

      Mice are viable, fertile and appear to be in good health (PubMed:16293790, PubMed:22738428). The loss of KCND2 has only minor functional consequences, probably due to an increase of the activity of other potassium channels, even though there is no visible change of their expression levels (PubMed:20371829). Mutant mice show no sign of heart dysfunction, but the fast component of the rapidly inactivating and rapidly recovering potassium current I(to) is lost in their ventricular myocytes (PubMed:16293790). Instead, a slowly inactivating current is expressed that is not observed in wild-type (PubMed:16293790). Electrocardiograms of mutant hearts display no significant differences relative to wild-type regarding their QT, PR, QRS and RR intervals (PubMed:16293790). The neuronal A-type current is reduced by about 80% in brain cortex and hippocampus CA1 pyramidal neurons, by about 50% in suprachiasmatic nucleus neurons and by about 60% in dorsal horn neurons (PubMed:17122039, PubMed:18045912, PubMed:18187474, PubMed:20371829, PubMed:22815518). The dendritic A-type current is abolished in pyramidal neurons from the hippocampus CA1 layer (PubMed:17122039). Concomitantly, the back-propagation of action potential in dendrites is increased (PubMed:17122039). This may lower the treshold for neuronal long-term potentiation (LTP) (PubMed:17122039). Loss of KCND2 does not influence the levels of KCND3 or KCNA4, but leads to reduced KCNIP1, KCNIP2 and KCNIP3 protein levels (PubMed:17122039, PubMed:18187474, PubMed:22612819). Mutant mice show only minor differences in their behavior when compared to wild-type; they display hyperactivity to some, but not all, novel stimuli (PubMed:22738428). Mutant mice show subtle spatial learning deficits (PubMed:20857488). Mutant mice display shorter periods of locomotor activity that wild-type littermates, due to a corresponding change in the circadian rhythm of repetitive firing in suprachiasmatic nucleus neurons (PubMed:22815518). Mutant mice display loss of spontaneous nociceptive behavior that is caused by the activation of GRM5 (PubMed:18045912).9 Publications


      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Mutagenesisi362W → F: Abolishes channel activity. Alters potassium channel kinetics in heart myocytes. Abolishes the fast component of I(to) in heart ventricle. 2 Publications1
      Mutagenesisi602T → A: No effect on the regulation of neuronal A-type current in response to activation of metabotropic glutamate receptors. 1 Publication1
      Mutagenesisi607T → A: No effect on the regulation of neuronal A-type current in response to activation of metabotropic glutamate receptors. 1 Publication1
      Mutagenesisi616S → A: Abolishes regulation of neuronal A-type current in response to activation of metabotropic glutamate receptors. 1 Publication1

      Chemistry databases


      PTM / Processingi

      Molecule processing

      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      ChainiPRO_00000540651 – 630Potassium voltage-gated channel subfamily D member 2Add BLAST630

      Amino acid modifications

      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Modified residuei38PhosphothreonineBy similarity1
      Modified residuei438PhosphoserineBy similarity1
      Modified residuei548PhosphoserineBy similarity1
      Modified residuei552PhosphoserineCombined sources1
      Modified residuei572PhosphoserineCombined sources1
      Modified residuei575PhosphoserineCombined sources1
      Modified residuei602PhosphothreonineBy similarity1
      Modified residuei607PhosphothreonineBy similarity1
      Modified residuei616Phosphoserine1 Publication1

      Post-translational modificationi

      Phosphorylation at Ser-438 in response to MAPK activation is increased in stimulated dendrites. Interaction with KCNIP2 and DPP6 propomtes phosphorylation by PKA at Ser-552. Phosphorylation at Ser-552 has no effect on interaction with KCNIP3, but is required for the regulation of channel activity by KCNIP3. Phosphorylation at Ser-552 leads to KCND2 internalization (By similarity). Phosphorylated by MAPK in response to signaling via the metabotropic glutamate receptor GRM5 (PubMed:18045912). Phosphorylation at Ser-616 is required for the down-regulation of neuronal A-type currents in response to signaling via GRM5 (PubMed:18045912).By similarity1 Publication

      Keywords - PTMi


      Proteomic databases


      PTM databases



      Tissue specificityi

      Detected in hippocampus, thalamus, medial habenular nucleus, striatum, amygdala, brain cortex and cerebellum (PubMed:11040264, PubMed:17122039, PubMed:18187474, PubMed:20371829, PubMed:22612819). Detected in hippocampus CA1 and CA3 layer, in stratum oriens, stratum radiatum and stratum lacunosum-moleculare and in dentate gyrus (PubMed:16009497, PubMed:22098631). Detected in dorsal horn neurons; colocalizes with GRM5 (PubMed:18045912). C-terminally phosphorylated forms are detected in the stratum radiatum and in basilar dendrites in stratum oriens in hippocampus CA1 and on cell bodies in hippocampus CA3 layers, with lower levels in stratum lacunosum-moleculare (PubMed:11040264). In contrast, N-terminally phosphorylated forms are detected in stratum lacunosum moleculare in the hippocampus CA1 layer (PubMed:11040264). Both C-terminally and N-terminally phosphorylated forms are observed on cell bodies and neuronal processes in the amygdala (PubMed:11040264). C-terminally phosphorylated forms are detected in the dentate gyrus molecular layer, while N-terminally phosphorylated forms are detected in the hilus of the dentate gyrus (PubMed:11040264). Both N-terminally and C-terminally phosphorylated forms are detected in the somatosensory cortex (PubMed:11040264). C-terminally phosphorylated forms are detected in the cerebellum granular layers (PubMed:11040264). Detected in heart ventricle myocytes (at protein level) (PubMed:9734479, PubMed:11909823, PubMed:16293790, PubMed:23713033). Detected in brain and heart (PubMed:16293790).12 Publications

      Gene expression databases

      GenevisibleiQ9Z0V2. MM.


      Subunit structurei

      Homotetramer or heterotetramer with KCND3 or KCND1 (PubMed:9734479, PubMed:11909823, PubMed:19713751, PubMed:20943905). Associates with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4 (PubMed:11909823, PubMed:19713751, PubMed:20943905). In vivo, probably exists as heteromeric complex containing variable proportions of KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (PubMed:19713751). The tetrameric channel can associate with up to four regulatory subunits, such as KCNIP2 or KCNIP4 (By similarity). Interaction with four KCNIP4 chains does not reduce interaction with DPP10 (By similarity). Interacts with DLG1 (By similarity). Interacts with DLG4 (By similarity). Interacts with NCS1/FREQ (PubMed:11606724). Probably part of a complex consisting of KCNIP1, KCNIP2 isoform 3 and KCND2 (By similarity). Interacts with FLNA and FLNC (By similarity). Interacts with DPP6 and DPP10 (PubMed:19713751, PubMed:22311982). Identified in a complex with cAMP-dependent protein kinase (PKA), CAV3, AKAP6 and KCND3 in cardiac myocytes (By similarity).By similarity5 Publications

      Binary interactionsi


      Protein-protein interaction databases

      BioGridi200890. 4 interactors.
      IntActiQ9Z0V2. 4 interactors.


      3D structure databases


      Family & Domainsi


      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Regioni2 – 20Interaction with KCNIP1, KCNIP2, and other family membersBy similarityAdd BLAST19
      Regioni71 – 90Interaction with KCNIP1By similarityAdd BLAST20
      Regioni308 – 321S4-S5 linkerBy similarityAdd BLAST14
      Regioni474 – 630Important for normal channel activation and inactivation, for interaction with KCNIP2, and probably other family members as wellBy similarityAdd BLAST157
      Regioni474 – 489Required for dendritic targetingBy similarityAdd BLAST16


      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Motifi370 – 375Selectivity filterBy similarity6
      Motifi627 – 630PDZ-bindingBy similarity4


      The transmembrane segment S4 functions as voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Channel opening and closing is effected by a conformation change that affects the position and orientation of the voltage-sensor paddle formed by S3 and S4 within the membrane. A transmembrane electric field that is positive inside would push the positively charged S4 segment outwards, thereby opening the pore, while a field that is negative inside would pull the S4 segment inwards and close the pore. Changes in the position and orientation of S4 are then transmitted to the activation gate formed by the inner helix bundle via the S4-S5 linker region.By similarity
      The N-terminal cytoplasmic region can mediate N-type inactivation by physically blocking the channel (By similarity). This probably does not happen in vivo, where the N-terminal region mediates interaction with regulatory subunits, such as KCNIP1 and KCNIP2 (By similarity). The zinc binding sites in the N-terminal domain are important for tetramerization and assembly of a functional channel complex (By similarity). Most likely, the channel undergoes closed-state inactivation, where a subtle conformation change would render the protein less sensitive to activation.By similarity1 Publication
      The C-terminal cytoplasmic region is important for normal expression at the cell membrane and modulates the voltage-dependence of channel activation and inactivation. It is required for interaction with KCNIP2, and probably other family members as well.By similarity

      Sequence similaritiesi

      Keywords - Domaini

      Transmembrane, Transmembrane helix

      Phylogenomic databases

      eggNOGiKOG4390. Eukaryota.
      COG1226. LUCA.

      Family and domain databases

      InterProiView protein in InterPro
      IPR000210. BTB/POZ_dom.
      IPR005821. Ion_trans_dom.
      IPR003968. K_chnl_volt-dep_Kv.
      IPR003975. K_chnl_volt-dep_Kv4.
      IPR004055. K_chnl_volt-dep_Kv4.2.
      IPR024587. K_chnl_volt-dep_Kv4_C.
      IPR021645. Shal-type_N.
      IPR011333. SKP1/BTB/POZ.
      IPR003131. T1-type_BTB.
      IPR028325. VG_K_chnl.
      PANTHERiPTHR11537. PTHR11537. 1 hit.
      PfamiView protein in Pfam
      PF02214. BTB_2. 1 hit.
      PF11879. DUF3399. 1 hit.
      PF00520. Ion_trans. 1 hit.
      PF11601. Shal-type. 1 hit.
      PR01517. KV42CHANNEL.
      PR01491. KVCHANNEL.
      PR01497. SHALCHANNEL.
      SMARTiView protein in SMART
      SM00225. BTB. 1 hit.
      SUPFAMiSSF54695. SSF54695. 1 hit.


      Sequence statusi: Complete.

      Q9Z0V2-1 [UniParc]FASTAAdd to basket

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      Mass (Da):70,577
      Last modified:May 1, 1999 - v1

      Sequence cautioni

      The sequence BAA97986 differs from that shown. Reason: Frameshift at position 520.Curated
      The sequence BAC41464 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

      Experimental Info

      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Sequence conflicti22V → A in BAA97986 (Ref. 2) Curated1
      Sequence conflicti516S → R in BAC41464 (PubMed:12465718).Curated1

      Sequence databases

      Select the link destinations:
      Links Updated
      AF107780 mRNA. Translation: AAD16972.1.
      AB045326 mRNA. Translation: BAA97986.1. Frameshift.
      AB093280 mRNA. Translation: BAC41464.1. Different initiation.
      AK032268 mRNA. Translation: BAC27787.1.
      AK032772 mRNA. Translation: BAC28015.1.
      BC079667 mRNA. Translation: AAH79667.1.
      RefSeqiNP_062671.1. NM_019697.3.

      Genome annotation databases

      EnsembliENSMUST00000081542; ENSMUSP00000080257; ENSMUSG00000060882.
      UCSCiuc009baq.1. mouse.

      Similar proteinsi

      Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
      100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
      90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
      50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

      Entry informationi

      Entry nameiKCND2_MOUSE
      AccessioniPrimary (citable) accession number: Q9Z0V2
      Secondary accession number(s): Q8BSK3, Q8CHB7, Q9JJ60
      Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 7, 2003
      Last sequence update: May 1, 1999
      Last modified: June 7, 2017
      This is version 160 of the entry and version 1 of the sequence. See complete history.
      Entry statusiReviewed (UniProtKB/Swiss-Prot)
      Annotation programChordata Protein Annotation Program


      Keywords - Technical termi

      Complete proteome, Reference proteome


      1. MGD cross-references
        Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
      2. SIMILARITY comments
        Index of protein domains and families