Q9Z0V2 · KCND2_MOUSE

  • Protein
    A-type voltage-gated potassium channel KCND2
  • Gene
    Kcnd2
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

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:10601491, PubMed:11909823, PubMed:23713033, PubMed:9734479).
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:22311982, PubMed:9734479).
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).
Upon depolarization, the channel goes from a resting closed state (C state) to an activated but non-conducting state (C* state), from there, the channel may either inactivate (I state) or open (O state) (By similarity).

Miscellaneous

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.
Is specifically and reversibly inhibited by the scorpion toxin Ts8 (AC P69940).

Catalytic activity

Kinetics

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.

Features

Showing features for binding site.

TypeIDPosition(s)Description
Binding site105Zn2+ (UniProtKB | ChEBI); ligand shared between homotetrameric partners; in chain A
Binding site111Zn2+ (UniProtKB | ChEBI); ligand shared between homotetrameric partners; in chain B
Binding site132Zn2+ (UniProtKB | ChEBI); ligand shared between homotetrameric partners; in chain A
Binding site133Zn2+ (UniProtKB | ChEBI); ligand shared between homotetrameric partners; in chain A
Binding site370K+ (UniProtKB | ChEBI); ligand shared between homotetrameric partners
Binding site371K+ (UniProtKB | ChEBI); ligand shared between homotetrameric partners
Binding site372K+ (UniProtKB | ChEBI); ligand shared between homotetrameric partners
Binding site373K+ (UniProtKB | ChEBI); ligand shared between homotetrameric partners

GO annotations

AspectTerm
Cellular Componentanchoring junction
Cellular Componentcaveola
Cellular Componentdendrite
Cellular Componentdendritic spine
Cellular ComponentGABA-ergic synapse
Cellular Componentglutamatergic synapse
Cellular ComponentKv4.2-KChIP2 channel complex
Cellular Componentmembrane
Cellular Componentneuronal cell body
Cellular Componentneuronal cell body membrane
Cellular Componentperikaryon
Cellular Componentperinuclear endoplasmic reticulum
Cellular Componentplasma membrane
Cellular Componentplasma membrane raft
Cellular Componentpostsynaptic membrane
Cellular Componentpostsynaptic specialization membrane
Cellular Componentpotassium channel complex
Cellular Componentsarcolemma
Cellular ComponentT-tubule
Cellular Componentvoltage-gated potassium channel complex
Molecular FunctionA-type (transient outward) potassium channel activity
Molecular Functionmetal ion binding
Molecular Functionmonoatomic ion channel activity
Molecular Functionpotassium channel activity
Molecular Functionprotein-containing complex binding
Molecular Functionvoltage-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential
Molecular Functionvoltage-gated potassium channel activity
Biological Processaction potential
Biological Processcardiac muscle cell action potential
Biological Processcellular response to hypoxia
Biological Processlocomotor rhythm
Biological Processmembrane repolarization
Biological Processmuscle contraction
Biological Processneuronal action potential
Biological Processpotassium ion transmembrane transport
Biological Processprotein homooligomerization
Biological Processregulation of heart contraction
Biological Processsensory perception of pain

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    A-type voltage-gated potassium channel KCND2
  • Alternative names
    • Potassium voltage-gated channel subfamily D member 2
    • Voltage-gated potassium channel subunit Kv4.2

Gene names

    • Name
      Kcnd2
    • Synonyms
      Kiaa1044
    • ORF names
      MNCb-7013

Organism names

  • Taxonomic identifier
  • Strains
    • Swiss Webster
    • C57BL/6J
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    Q9Z0V2
  • Secondary accessions
    • Q8BSK3
    • Q8CHB7
    • Q9JJ60

Proteomes

Organism-specific databases

Subcellular Location

Cell membrane
; Multi-pass membrane protein
Synapse
Perikaryon
Cell junction
Membrane, caveola
Note: In neurons, primarily detected on dendrites, dendritic spines and on the neuron cell body, but not on axons (PubMed:17122053, PubMed:22098631).
Localized preferentially at the dendrites of pyramidal cells in the hippocampus CA1 layer. Detected at GABAergic synapses (PubMed:16009497).
Detected at cell junctions that are distinct from synaptic cell contacts (By similarity).
Detected in lipid rafts (By similarity).
Detected primarily at the endoplasmic reticulum or Golgi when expressed by itself (By similarity).
Interaction with KCNIP1, KCNIP2, KCNIP3 or KCNIP4 promotes expression at the cell membrane (PubMed:22311982).
Interaction with DPP6 or DPP10 promotes expression at the cell membrane (By similarity).
Internalized from the cell membrane by clathrin-dependent endocytosis in response to activation of AMPA-selective glutamate receptors and PKA-mediated phosphorylation at Ser-552. Redistributed from dendritic spines to the main dendritic shaft in response to activation of AMPA-selective glutamate receptors and activation of PKA (By similarity).

Features

Showing features for topological domain, transmembrane, intramembrane.

TypeIDPosition(s)Description
Topological domain1-184Cytoplasmic
Transmembrane185-206Helical; Name=Segment S1
Topological domain207-226Extracellular
Transmembrane227-249Helical; Name=Segment S2
Topological domain250-256Cytoplasmic
Transmembrane257-281Helical; Name=Segment S3
Topological domain282-287Extracellular
Transmembrane288-307Helical; Voltage-sensor; Name=Segment S4
Topological domain308-321Cytoplasmic
Transmembrane322-345Helical; Name=Segment S5
Topological domain346-357Extracellular
Intramembrane358-369Helical; Name=Pore helix
Intramembrane370-377
Topological domain378-380Extracellular
Transmembrane381-403Helical; Name=Segment S6
Topological domain404-630Cytoplasmic

Keywords

Phenotypes & Variants

Disruption phenotype

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).

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis362Abolishes channel activity. Alters potassium channel kinetics in heart myocytes. Abolishes the fast component of I(to) in heart ventricle.
Mutagenesis602No effect on the regulation of neuronal A-type current in response to activation of metabotropic glutamate receptors.
Mutagenesis607No effect on the regulation of neuronal A-type current in response to activation of metabotropic glutamate receptors.
Mutagenesis616Abolishes regulation of neuronal A-type current in response to activation of metabotropic glutamate receptors.

Variants

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The viewer provides 20 variants from UniProt as well as other sources including ClinVar and dbSNP.

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Chemistry

PTM/Processing

Features

Showing features for chain, modified residue.

TypeIDPosition(s)Description
ChainPRO_00000540651-630A-type voltage-gated potassium channel KCND2
Modified residue38Phosphothreonine
Modified residue438Phosphoserine
Modified residue548Phosphoserine
Modified residue552Phosphoserine
Modified residue572Phosphoserine
Modified residue575Phosphoserine
Modified residue602Phosphothreonine
Modified residue607Phosphothreonine
Modified residue616Phosphoserine

Post-translational modification

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).

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

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:11909823, PubMed:16293790, PubMed:23713033, PubMed:9734479).
Detected in brain and heart (PubMed:16293790).

Gene expression databases

Interaction

Subunit

Homotetramer or heterotetramer with KCND3 or KCND1 (PubMed:11909823, PubMed:19713751, PubMed:20943905, PubMed:9734479).
Associates with the regulatory subunits KCNIP2, KCNIP3 and KCNIP4 (PubMed:11909823, PubMed:19713751, PubMed:20943905).
Interacts with the regulatory subunit KCNIP1; this interaction mediates the capture of both the N- and C-terminus of KCND2, preventing N-type inactivation and stabilizing the S6 conformation, thereby accelerating closed state inactivation and recovery (By similarity).
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 DPP10 (PubMed:22311982).
Identified in a complex with cAMP-dependent protein kinase (PKA), CAV3, AKAP6 and KCND3 in cardiac myocytes (By similarity).
Interacts (via S1 and S2 helices) with DPP6; this interaction stabilizes the conformation of the S1-S2 helices and facilitates S4 conformational change, including S4 sliding up and down, thereby accelerating activation, inactivation, and recovery (PubMed:22311982).

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntact
BINARY Q9Z0V2Kif17 Q99PW83EBI-959779, EBI-959754

Protein-protein interaction databases

Miscellaneous

Structure

Family & Domains

Features

Showing features for region, motif.

TypeIDPosition(s)Description
Region2-20Interaction with KCNIP1, KCNIP2, and other family members
Region71-90Interaction with KCNIP1
Region308-321S4-S5 linker
Motif370-375Selectivity filter
Region474-489Required for dendritic targeting
Region474-630Important for normal channel activation and inactivation, for interaction with KCNIP2, and probably other family members as well
Region600-623Disordered
Motif627-630PDZ-binding

Domain

The transmembrane segment S4 functions as a 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.
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).
The channel undergoes closed-state inactivation, where conformation changes lead to inactivation through an intermediate state involving breakdown of its 4-fold symmetry. that governs the distinct transient, fast-inactivating currents (By similarity).
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.

Sequence similarities

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    630
  • Mass (Da)
    70,577
  • Last updated
    1999-05-01 v1
  • Checksum
    7FB94277429E7683
MAAGVAAWLPFARAAAIGWMPVASGPMPAPPRQERKRTQDALIVLNVSGTRFQTWQDTLERYPDTLLGSSERDFFYHPETQQYFFDRDPDIFRHILNFYRTGKLHYPRHECISAYDEELAFFGLIPEIIGDCCYEEYKDRRRENAERLQDDADTDNTGESALPTMTARQRVWRAFENPHTSTMALVFYYVTGFFIAVSVIANVVETVPCGSSPGHIKELPCGERYAVAFFCLDTACVMIFTVEYLLRLAAAPSRYRFVRSVMSIIDVVAILPYYIGLVMTDNEDVSGAFVTLRVFRVFRIFKFSRHSQGLRILGYTLKSCASELGFLLFSLTMAIIIFATVMFYAEKGSSASKFTSIPAAFWYTIVTMTTLGYGDMVPKTIAGKIFGSICSLSGVLVIALPVPVIVSNFSRIYHQNQRADKRRAQKKARLARIRAAKSGSANAYMQSKRNGLLSNQLQSSEDEPAFISKSGSSFETQHHHLLHCLEKTTNHEFVDEQVFEESCMEVATVNRPSSHSPSLSSQQGVTSTCCSRRHKKTFRIPNANVSGSHRGSVQELSTIQIRCVERTPLSNSRSSLNAKMEECVKLNCEQPYVTTAIISIPTPPVTTPEGDDRPESPEYSGGNIVRVSAL

Sequence caution

The sequence BAA97986.1 differs from that shown. Reason: Frameshift
The sequence BAC41464.1 differs from that shown. Reason: Erroneous initiation Extended N-terminus.

Features

Showing features for sequence conflict.

TypeIDPosition(s)Description
Sequence conflict22in Ref. 2; BAA97986
Sequence conflict516in Ref. 3; BAC41464

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AF107780
EMBL· GenBank· DDBJ
AAD16972.1
EMBL· GenBank· DDBJ
mRNA
AB045326
EMBL· GenBank· DDBJ
BAA97986.1
EMBL· GenBank· DDBJ
mRNA Frameshift
AB093280
EMBL· GenBank· DDBJ
BAC41464.1
EMBL· GenBank· DDBJ
mRNA Different initiation
AK032268
EMBL· GenBank· DDBJ
BAC27787.1
EMBL· GenBank· DDBJ
mRNA
AK032772
EMBL· GenBank· DDBJ
BAC28015.1
EMBL· GenBank· DDBJ
mRNA
BC079667
EMBL· GenBank· DDBJ
AAH79667.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

Disclaimer

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