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Potassium voltage-gated channel subfamily D member 2



Rattus norvegicus (Rat)
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 (PubMed:1840649, PubMed:1722463, PubMed:9093524, PubMed:9058605, PubMed:10676964, PubMed:12592409, PubMed:12754210, PubMed:16207878, PubMed:16123112, PubMed:19279261, PubMed:25352783, PubMed:14980206). Mediates the major part of the dendritic A-type current I(SA) in brain neurons (PubMed:16207878, PubMed:17026528). 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. Contributes to the regulation of the circadian rhythm of action potential firing in suprachiasmatic nucleus neurons, which regulates the circadian rhythm of locomotor activity (By similarity). Functions downstream of the metabotropic glutamate receptor GRM5 and plays a role in neuronal excitability and in nociception mediated by activation of GRM5 (By similarity). 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:9093524, PubMed:9058605). 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:1840649, PubMed:1722463, PubMed:9093524, PubMed:10676964, PubMed:12451113, PubMed:12592409, PubMed:12754210, PubMed:15452711, PubMed:16207878, PubMed:16820361, PubMed:25352783, PubMed:14980206). 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:25352783). In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes (PubMed:12451113, PubMed:16123112). 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 (PubMed:12451113, PubMed:15452711, PubMed:16123112, PubMed:16820361, PubMed:20045463, PubMed:14980206). Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity (PubMed:15671030, PubMed:16123112, PubMed:19441798, PubMed:19901547, PubMed:19279261).By similarityCurated22 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 Publications1 Publication
Is specifically and reversibly inhibited by the scorpion toxin Ts8 (AC P69940).1 Publication

Enzyme regulationi

Inhibited by 5 mM 4-aminopyridine (4-AP) (PubMed:1840649, PubMed:1722463, PubMed:9093524). Not inhibited by dendrotoxins and by tetraethylammonium (TEA) (PubMed:1722463). Inhibited by 10 mM flecainide and 20 mM quinidine (PubMed:9093524). Inhibited by the heteropodatoxins HpTx1, HpTx2, and HpTx3 (PubMed:9058605).4 Publications


Homotetrameric channels activate rapidly, i.e within a few msec (PubMed:1722463, PubMed:9093524). After that, they inactivate rapidly, i.e within about 50-100 msec (PubMed:1722463, PubMed:9093524). 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 (PubMed:19901547, PubMed:19279261). Homotetrameric channels have a unitary conductance of about 4 pS when expressed in a heterologous system (PubMed:19279261). For the activation of homotetrameric channels expressed in xenopus oocytes, the voltage at half-maximal amplitude is about -10 mV (PubMed:12451113). The time constant for inactivation is about 20 msec (PubMed:12451113). For inactivation, the voltage at half-maximal amplitude is -62 mV (PubMed:12451113). The time constant for recovery after inactivation is about 70 msec (PubMed:12451113).1 Publication5 Publications


      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Metal bindingi105Zinc; via pros nitrogenCombined sources1
      Metal bindingi132ZincCombined sources1
      Metal bindingi133ZincCombined sources1

      GO - Molecular functioni

      • A-type (transient outward) potassium channel activity Source: UniProtKB
      • ion channel activity Source: RGD
      • metal ion binding Source: UniProtKB-KW
      • potassium channel activity Source: RGD
      • protein heterodimerization activity Source: RGD
      • voltage-gated ion channel activity involved in regulation of postsynaptic membrane potential Source: SynGO
      • voltage-gated potassium channel activity Source: UniProtKB

      GO - Biological processi

      • action potential Source: RGD
      • cardiac muscle cell action potential Source: UniProtKB
      • cellular response to drug Source: RGD
      • cellular response to hypoxia Source: UniProtKB
      • cellular response to mechanical stimulus Source: RGD
      • potassium ion transmembrane transport Source: UniProtKB
      • potassium ion transport Source: RGD
      • protein heterooligomerization Source: RGD
      • protein homooligomerization Source: InterPro


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

      Names & Taxonomyi

      Protein namesi
      Recommended name:
      Potassium voltage-gated channel subfamily D member 2
      Alternative name(s):
      RK52 Publications
      Shal11 Publication
      Voltage-gated potassium channel subunit Kv4.21 Publication
      Gene namesi
      OrganismiRattus norvegicus (Rat)
      Taxonomic identifieri10116 [NCBI]
      Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
      • UP000002494 Componenti: Unplaced

      Organism-specific databases

      RGDi68393. 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: RGD
      • dendritic spine Source: UniProtKB
      • integral component of plasma membrane Source: RGD
      • neuronal cell body Source: RGD
      • neuronal cell body membrane Source: UniProtKB
      • neuron projection Source: RGD
      • perikaryon Source: UniProtKB-SubCell
      • perinuclear endoplasmic reticulum Source: RGD
      • plasma membrane Source: RGD
      • plasma membrane raft Source: UniProtKB
      • postsynaptic density Source: RGD
      • postsynaptic membrane Source: UniProtKB
      • potassium channel complex Source: RGD
      • 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


      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Mutagenesisi7 – 11Missing : Greatly reduces interaction with KCNIP1. 1 Publication5
      Mutagenesisi8W → A: Abolishes interaction with KCNP1; when associated with A-11. 1 Publication1
      Mutagenesisi11F → A: Abolishes interaction with KCNP1; when associated with A-8. 1 Publication1
      Mutagenesisi66L → R: Abolishes expression. 1 Publication1
      Mutagenesisi71E → K: Abolishes interaction with KCNIP1. 1 Publication1
      Mutagenesisi73D → M: Abolishes interaction with KCNIP1. 1 Publication1
      Mutagenesisi74F → R: Abolishes interaction with KCNIP1. 1 Publication1
      Mutagenesisi79E → L or R: Abolishes interaction with KCNIP1. 1 Publication1
      Mutagenesisi93R → A: Greatly reduces expression and changes multimerization. 1 Publication1
      Mutagenesisi105H → A: Abolishes tetramerization and assembly of a functional channel. 1 Publication1
      Mutagenesisi111C → A: Abolishes tetramerization and assembly of a functional channel; when associated with A-105; A-132 and A-133. 1 Publication1
      Mutagenesisi132C → A: Abolishes tetramerization and assembly of a functional channel; when associated with A-105; A-111 and A-133. 1 Publication1
      Mutagenesisi133C → A: Abolishes tetramerization and assembly of a functional channel; when associated with A-105; A-111 and A-132. 1 Publication1
      Mutagenesisi481 – 482Missing : Loss of dendritic targeted expression. 1 Publication2
      Mutagenesisi552S → A: Abolishes PKA-mediated modulation of cell surface expression and channel activity. 2 Publications1
      Mutagenesisi627 – 630Missing : Abolishes interaction with DLG4. 2 Publications4

      Chemistry databases


      PTM / Processingi

      Molecule processing

      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      ChainiPRO_00000540671 – 630Potassium voltage-gated channel subfamily D member 2Add BLAST630

      Amino acid modifications

      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Modified residuei38Phosphothreonine1 Publication1
      Modified residuei438Phosphoserine1 Publication1
      Modified residuei548PhosphoserineCombined sources1 Publication1
      Modified residuei552PhosphoserineCombined sources5 Publications1
      Modified residuei572PhosphoserineCombined sources1 Publication1
      Modified residuei575PhosphoserineCombined sources1 Publication1
      Modified residuei602Phosphothreonine1 Publication1
      Modified residuei607Phosphothreonine1 Publication1
      Modified residuei616Phosphoserine1 Publication1

      Post-translational modificationi

      Phosphorylation at Ser-438 in response to MAPK activation is increased in stimulated dendrites (PubMed:24404150). Interaction with KCNIP2 and DPP6 propomtes phosphorylation by PKA at Ser-552 (PubMed:19441798). Phosphorylation at Ser-552 has no effect on interaction with KCNIP3, but is required for the regulation of channel activity by KCNIP3 (PubMed:12451113). Phosphorylation at Ser-552 leads to KCND2 internalization (PubMed:17582333). Phosphorylated by MAPK in response to signaling via the metabotropic glutamate receptor GRM5 (By similarity). Phosphorylation at Ser-616 is required for the down-regulation of neuronal A-type currents in response to signaling via GRM5 (By similarity).By similarity4 Publications

      Keywords - PTMi


      Proteomic databases


      PTM databases



      Tissue specificityi

      Detected in brain cortex, hippocampus, dentate gyrus, thalamus and cerebellum (PubMed:16123112). Detected in neurons from the primary visual cortex (PubMed:16207878). Detected in the supraoptic nucleus in hypothalamus, in hippocampus and the habenular nucleus of the thalamus (PubMed:9070739). Detected in the bed nucleus of the stria terminalis (PubMed:24037673). Detected in dendritic fields in the hippocampus CA1 layer, in stratum radiatum, stratum oriens, stratum lacunosum-moleculare and stratum pyramidale (PubMed:10676964, PubMed:22098631). Detected in dendritic fields in the hippocampus CA3 layer and in dentate gyrus (PubMed:10676964). Detected in the cerebellum granule cell layer, where it localizes at synapses (PubMed:11102480, PubMed:10676964, PubMed:15736227). Detected in the main olfactory bulb, especially in the granule cell layer and the external plexiform layer, but also the mitral layer (PubMed:18371079). Detected in heart atrium and ventricle (PubMed:10860776). Detected in heart left ventricle (at protein level) (PubMed:24793047). Highly expressed in heart and throughout the brain, with similar levels in cortex and hypothalamus, and much higher levels in hippocampus, dentate gyrus and the habenular nucleus of the thalamus. Detected in brain, and at lower levels in heart atrium and ventricle (PubMed:1705709). Detected in neurons from the bed nucleus of the stria terminalis (PubMed:24037673). Detected in aorta, cardiac and smooth muscle.11 Publications


      Down-regulated in response to hypoxia lasting about 15 min, a treatment that leads to spontaneous convulsive seizures in these pups.1 Publication


      Subunit structurei

      Homotetramer or heterotetramer with KCND1 or KCND3 (PubMed:12754210, PubMed:15485870, PubMed:20224290, PubMed:25352783). Associates with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4 (PubMed:10676964, PubMed:12451113, PubMed:11847232, PubMed:11805342, PubMed:15485870, PubMed:15356203, PubMed:15452711, PubMed:16820361, PubMed:20045463, PubMed:24811166, PubMed:14980206). Interacts with DPP6, DPP10, DLG4 and DLG1 (PubMed:11923279, PubMed:12575952, PubMed:14559911, PubMed:15671030, PubMed:19213956). In vivo, probably exists as heteromeric complex containing variable proportions of KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (PubMed:16123112, PubMed:19901547). The tetrameric channel can associate with up to four regulatory subunits, such as KCNIP2 or KCNIP4 (By similarity). Interaction with KCNIP3 promotes tetramerization and formation of a functional potassium channel (PubMed:15485870). Interaction with four KCNIP4 chains does not reduce interaction with DPP10 (By similarity). Probably part of a complex consisting of KCNIP1, KCNIP2 isoform 3 and KCND2 (By similarity). Interacts with FLNA and FLNC (PubMed:11102480). Interacts with NCS1/FREQ (By similarity). Identified in a complex with cAMP-dependent protein kinase (PKA), CAV3, AKAP6 and KCND3 in cardiac myocytes (PubMed:20224290).By similarity2 Publications22 Publications

      GO - Molecular functioni

      • protein heterodimerization activity Source: RGD

      Protein-protein interaction databases

      BioGridi249292. 2 interactors.
      IntActiQ63881. 3 interactors.

      Chemistry databases



      Secondary structure

      Legend: HelixTurnBeta strandPDB Structure known for this area
      Show more details
      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Helixi1 – 6Combined sources6
      Helixi9 – 17Combined sources9
      Beta strandi43 – 47Combined sources5
      Beta strandi50 – 54Combined sources5
      Helixi56 – 60Combined sources5
      Beta strandi64 – 66Combined sources3
      Helixi70 – 75Combined sources6
      Helixi78 – 80Combined sources3
      Beta strandi81 – 85Combined sources5
      Turni89 – 91Combined sources3
      Helixi92 – 101Combined sources10
      Helixi112 – 122Combined sources11
      Helixi131 – 145Combined sources15

      3D structure databases

      Select the link destinations:
      RCSB PDBi
      Links Updated
      PDB entryMethodResolution (Å)ChainPositionsPDBsum

      Miscellaneous databases


      Family & Domainsi


      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Regioni2 – 20Interaction with KCNIP1, KCNIP2, and other family members2 PublicationsAdd BLAST19
      Regioni71 – 90Interaction with KCNIP11 PublicationAdd 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 well1 PublicationAdd BLAST157
      Regioni474 – 489Required for dendritic targeting1 PublicationAdd BLAST16


      Feature keyPosition(s)DescriptionActionsGraphical viewLength
      Motifi370 – 375Selectivity filterBy similarity6
      Motifi627 – 630PDZ-binding2 Publications4


      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 (PubMed:15452711). This probably does not happen in vivo, where the N-terminal region mediates interaction with regulatory subunits, such as KCNIP1 and KCNIP2 (PubMed:16820361, PubMed:18357523, PubMed:14980206). The zinc binding sites in the N-terminal domain are important for tetramerization and assembly of a functional channel complex (PubMed:12754210). Most likely, the channel undergoes closed-state inactivation, where a subtle conformation change would render the protein less sensitive to activation.By similarity3 Publications2 Publications
      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.1 Publication

      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.

      Q63881-1 [UniParc]FASTAAdd to basket

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      Mass (Da):70,549
      Last modified:November 1, 1996 - v1

      Sequence cautioni

      The sequence AAA40929 differs from that shown. Reason: Frameshift at position 477.Curated

      Sequence databases

      Select the link destinations:
      Links Updated
      S64320 mRNA. Translation: AAB19939.1.
      M59980 mRNA. Translation: AAA40929.1. Frameshift.
      RefSeqiNP_113918.2. NM_031730.2.

      Genome annotation databases

      UCSCiRGD:68393. rat.

      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_RAT
      AccessioniPrimary (citable) accession number: Q63881
      Secondary accession number(s): Q00090, Q99249
      Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 7, 2003
      Last sequence update: November 1, 1996
      Last modified: May 10, 2017
      This is version 149 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

      3D-structure, Complete proteome, Reference proteome


      1. PDB cross-references
        Index of Protein Data Bank (PDB) cross-references
      2. SIMILARITY comments
        Index of protein domains and families