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Protein

Potassium voltage-gated channel subfamily D member 2

Gene

KCND2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Mediates the major part of the dendritic A-type current I(SA) in brain neurons (By similarity). 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 rhytm 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. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient (PubMed:10551270, PubMed:15454437, PubMed:14695263, PubMed:14623880, PubMed:14980201, PubMed:16934482, PubMed:24811166, PubMed:24501278). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:11507158). 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. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. 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:15454437, PubMed:14623880, PubMed:14980201, PubMed:19171772, PubMed:24501278, PubMed:24811166). Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity (By similarity).By similarity11 Publications

Kineticsi

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.2 Publications

      Sites

      Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
      Metal bindingi105 – 1051Zinc; via pros nitrogenBy similarity
      Metal bindingi132 – 1321ZincBy similarity
      Metal bindingi133 – 1331ZincBy similarity

      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: UniProtKB
      • cardiac conduction Source: Reactome
      • cellular response to hypoxia Source: UniProtKB
      • locomotor rhythm Source: Ensembl
      • neuronal action potential Source: Ensembl
      • potassium ion transmembrane transport Source: UniProtKB
      • protein homooligomerization Source: InterPro
      • sensory perception of pain Source: Ensembl
      • synaptic transmission Source: UniProtKB
      Complete GO annotation...

      Keywords - Molecular functioni

      Ion channel, Potassium channel, Voltage-gated channel

      Keywords - Biological processi

      Ion transport, Potassium transport, Transport

      Keywords - Ligandi

      Metal-binding, Potassium, Zinc

      Enzyme and pathway databases

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

      Protein family/group databases

      TCDBi1.A.1.2.5. the voltage-gated ion channel (vic) superfamily.

      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
      Name:KCND2
      Synonyms:KIAA1044
      OrganismiHomo sapiens (Human)
      Taxonomic identifieri9606 [NCBI]
      Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
      Proteomesi
      • UP000005640 Componenti: Chromosome 7

      Organism-specific databases

      HGNCiHGNC:6238. KCND2.

      Subcellular locationi

      Topology

      Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
      Topological domaini1 – 182182CytoplasmicBy similarityAdd
      BLAST
      Transmembranei183 – 20422Helical; Name=Segment S1By similarityAdd
      BLAST
      Topological domaini205 – 22824ExtracellularBy similarityAdd
      BLAST
      Transmembranei229 – 25022Helical; Name=Segment S2By similarityAdd
      BLAST
      Topological domaini251 – 26111CytoplasmicBy similarityAdd
      BLAST
      Transmembranei262 – 27918Helical; Name=Segment S3By similarityAdd
      BLAST
      Topological domaini280 – 2867ExtracellularBy similarity
      Transmembranei287 – 30620Helical; Voltage-sensor; Name=Segment S4By similarityAdd
      BLAST
      Topological domaini307 – 32115CytoplasmicBy similarityAdd
      BLAST
      Transmembranei322 – 34322Helical; Name=Segment S5By similarityAdd
      BLAST
      Topological domaini344 – 35714ExtracellularBy similarityAdd
      BLAST
      Intramembranei358 – 36912Helical; Name=Pore helixBy similarityAdd
      BLAST
      Intramembranei370 – 3778By similarity
      Topological domaini378 – 3847ExtracellularBy similarity
      Transmembranei385 – 41329Helical; Name=Segment S6By similarityAdd
      BLAST
      Topological domaini414 – 630217CytoplasmicBy similarityAdd
      BLAST

      GO - Cellular componenti

      • cell junction Source: UniProtKB-SubCell
      • dendritic spine Source: UniProtKB
      • integral component of plasma membrane Source: UniProtKB
      • intrinsic component of plasma membrane Source: UniProtKB
      • neuronal cell body membrane Source: UniProtKB
      • perikaryon Source: UniProtKB-SubCell
      • plasma membrane Source: Reactome
      • plasma membrane raft Source: UniProtKB
      • postsynaptic membrane Source: UniProtKB
      • voltage-gated potassium channel complex Source: UniProtKB
      Complete GO annotation...

      Keywords - Cellular componenti

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

      Pathology & Biotechi

      Involvement in diseasei

      KNCD2 mutations have been found in a family with autism and epilepsy and may play a role in disease pathogenesis. Autism is a complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Epilepsy is characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system.

      A KCND2 mutation leading to the production of a C-terminally truncated protein has been identified in a patient with epilepsy. Epilepsy is characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system.

      Mutagenesis

      Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
      Mutagenesisi309 – 3091G → A: Increases peak current amplitude and causes a negative shift in the voltage-dependence of activation. 1 Publication
      Mutagenesisi311 – 3111R → A: No effect on peak current amplitude, but causes a positive shift in the voltage-dependence of activation. May increase the affinity for the closed-inactivated state of the channel. 1 Publication
      Mutagenesisi312 – 3121I → A: Increases peak current amplitude and causes a positive shift in the voltage-dependence of activation. 1 Publication
      Mutagenesisi313 – 3131L → A: Causes a positive shift in the voltage-dependence of activation. May decrease the affinity for the closed-inactivated state of the channel. 1 Publication
      Mutagenesisi314 – 3141G → A: Loss of channel activity. 1 Publication
      Mutagenesisi315 – 3151Y → A: Increases peak current amplitude but has a minor effect on the voltage-dependence of activation. 1 Publication
      Mutagenesisi316 – 3161T → A: Increases peak current amplitude and causes a positive shift in the voltage-dependence of activation. 1 Publication
      Mutagenesisi317 – 3171L → A: Increases peak current amplitude and causes a positive shift in the voltage-dependence of activation. 1 Publication
      Mutagenesisi318 – 3181K → A: Increases peak current amplitude and causes a positive shift in the voltage-dependence of activation. 1 Publication
      Mutagenesisi319 – 3191S → A: May impair protein folding. 1 Publication
      Mutagenesisi320 – 3201C → A: Increases peak current amplitude and causes a positive shift in the voltage-dependence of activation. 1 Publication
      Mutagenesisi320 – 3201C → S: Increases peak current amplitude and slows the onset of inactivation at low voltage, but has no effect on the voltage-dependence of activation. 1 Publication
      Mutagenesisi322 – 3221S → A: Increases peak current amplitude and causes a positive shift in the voltage-dependence of activation. May increase the affinity for the closed-inactivated state of the channel. 1 Publication
      Mutagenesisi323 – 3231E → A: Slightly increases peak current amplitude and causes a negative shift in the voltage-dependence of activation. May decrease the affinity for the closed-inactivated state of the channel. 1 Publication
      Mutagenesisi324 – 3241L → A: May impair protein folding. 1 Publication
      Mutagenesisi327 – 3271L → A: Loss of channel activity. 1 Publication
      Mutagenesisi328 – 3281L → A: May impair protein folding. 1 Publication
      Mutagenesisi329 – 3291F → A: Loss of channel activity. 1 Publication
      Mutagenesisi397 – 3971V → A: May impair protein folding. 1 Publication
      Mutagenesisi398 – 3981I → A: Loss of channel activity. 1 Publication
      Mutagenesisi399 – 3991A → V: May impair protein folding. 1 Publication
      Mutagenesisi401 – 4011P → A: May impair protein folding. 1 Publication
      Mutagenesisi402 – 4043VPV → IPI: Increases pak current amplitude and causes a positive shift in the voltage-dependence of activation and steady-state inactivation. May increase the affinity for the closed-inactivated state of the channel. 1 Publication
      Mutagenesisi403 – 4031P → A: Loss of channel activity. 1 Publication
      Mutagenesisi405 – 4051I → A: Loss of channel activity. 1 Publication
      Mutagenesisi406 – 4061V → A: Loss of channel activity. 1 Publication
      Mutagenesisi407 – 4071S → A: Increases peak current amplitude but has no effect on the voltage-dependence of activation. May increase the affinity for the closed-inactivated state of the channel. 1 Publication
      Mutagenesisi408 – 4081N → A: Decreases peak current amplitude and causes a positive shift in the voltage-dependence of activation. May increase the affinity for the closed-inactivated state of the channel. 1 Publication
      Mutagenesisi409 – 4091F → A: May impair protein folding. 1 Publication
      Mutagenesisi601 – 6044PTPP → ATAA: Abolishes interaction with FLNC. 1 Publication

      Keywords - Diseasei

      Autism, Autism spectrum disorder, Disease mutation, Epilepsy

      Organism-specific databases

      PharmGKBiPA30030.

      Chemistry

      ChEMBLiCHEMBL2362996.
      DrugBankiDB00321. Amitriptyline.
      DB06637. Dalfampridine.
      DB00280. Disopyramide.
      DB00458. Imipramine.

      Polymorphism and mutation databases

      BioMutaiKCND2.
      DMDMi38258257.

      PTM / Processingi

      Molecule processing

      Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
      Chaini1 – 630630Potassium voltage-gated channel subfamily D member 2PRO_0000054064Add
      BLAST

      Amino acid modifications

      Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
      Modified residuei38 – 381PhosphothreonineBy similarity
      Modified residuei438 – 4381PhosphoserineBy similarity
      Modified residuei548 – 5481PhosphoserineBy similarity
      Modified residuei552 – 5521PhosphoserineBy similarity
      Modified residuei572 – 5721PhosphoserineBy similarity
      Modified residuei575 – 5751PhosphoserineBy similarity
      Modified residuei602 – 6021PhosphothreonineBy similarity
      Modified residuei607 – 6071PhosphothreonineBy similarity
      Modified residuei616 – 6161PhosphoserineBy similarity

      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 (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 similarity

      Keywords - PTMi

      Phosphoprotein

      Proteomic databases

      PaxDbiQ9NZV8.
      PRIDEiQ9NZV8.

      PTM databases

      iPTMnetiQ9NZV8.
      PhosphoSiteiQ9NZV8.

      Expressioni

      Tissue specificityi

      Detected in ovary, in corpus luteum and in granulosa and theca cells in the follicle (at protein level) (PubMed:15991246). Highly expressed throughout the brain (PubMed:10551270, PubMed:10729221). Detected in amygdala, caudate nucleus, cerebellum, hippocampus, substantia nigra and thalamus (PubMed:10551270, PubMed:10729221). Expression is not detectable or very low in heart, kidney, liver, lung, pancreas and skeletal muscle (PubMed:10551270, PubMed:10729221). Not detectable in human heart atrium (PubMed:12395204).4 Publications

      Gene expression databases

      BgeeiQ9NZV8.
      CleanExiHS_KCND2.
      ExpressionAtlasiQ9NZV8. baseline and differential.
      GenevisibleiQ9NZV8. HS.

      Organism-specific databases

      HPAiHPA029068.

      Interactioni

      Subunit structurei

      Homotetramer or heterotetramer with KCND1 or KCND3 (PubMed:14980201, PubMed:16934482, PubMed:24811166). Associates with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4 (PubMed:10676964, PubMed:11287421, PubMed:11847232, PubMed:12451113, PubMed:15358149, PubMed:14623880, PubMed:14980201, PubMed:14980207, PubMed:24811166). In vivo, probably exists as heteromeric complex containing variable proportions of KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (PubMed:19171772). The tetrameric channel can associate with up to four regulatory subunits, such as KCNIP2 or KCNIP4 (PubMed:14623880, PubMed:14980201, PubMed:24811166). Interaction with four KCNIP4 chains does not reduce interaction with DPP10 (PubMed:24811166). Interacts with DLG4 and NCS1/FREQ (By similarity). Interacts with DLG1 (PubMed:19213956). Probably part of a complex consisting of KCNIP1, KCNIP2 isoform 3 and KCND2 (PubMed:15358149). Interacts with FLNA, FLNC, DPP6 and DPP10 (PubMed:11102480, PubMed:15454437, PubMed:24811166).By similarity1 Publication13 Publications

      Binary interactionsi

      WithEntry#Exp.IntActNotes
      KCNIP1Q9NZI24EBI-1646745,EBI-2120635
      KCNIP2Q9NS613EBI-1646745,EBI-1052975
      KCNIP2Q9NS61-33EBI-1646745,EBI-1053010

      Protein-protein interaction databases

      BioGridi109953. 18 interactions.
      IntActiQ9NZV8. 2 interactions.
      STRINGi9606.ENSP00000333496.

      Structurei

      3D structure databases

      ProteinModelPortaliQ9NZV8.
      SMRiQ9NZV8. Positions 6-415.
      ModBaseiSearch...
      MobiDBiSearch...

      Family & Domainsi

      Region

      Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
      Regioni2 – 2019Interaction with KCNIP1, KCNIP2, and other family membersBy similarityAdd
      BLAST
      Regioni71 – 9020Interaction with KCNIP1By similarityAdd
      BLAST
      Regioni308 – 32114S4-S5 linkerBy similarityAdd
      BLAST
      Regioni474 – 630157Important for normal channel activation and inactivation, for interaction with KCNIP2, and probably other family members as wellBy similarity1 PublicationAdd
      BLAST
      Regioni474 – 48916Required for dendritic targetingBy similarityAdd
      BLAST

      Motif

      Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
      Motifi370 – 3756Selectivity filterBy similarity
      Motifi627 – 6304PDZ-bindingBy similarity

      Domaini

      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:14695263). This probably does not happen in vivo, where the N-terminal region mediates interaction with regulatory subunits, such as KCNIP1 and KCNIP2 (PubMed:15358149). 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 similarity4 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 (PubMed:16934482). It is required for interaction with KCNIP2, and probably other family members as well (By similarity).By similarity1 Publication

      Sequence similaritiesi

      Keywords - Domaini

      Transmembrane, Transmembrane helix

      Phylogenomic databases

      eggNOGiKOG4390. Eukaryota.
      COG1226. LUCA.
      GeneTreeiENSGT00760000118846.
      HOVERGENiHBG106687.
      InParanoidiQ9NZV8.
      KOiK04892.
      OMAiIPYNGQP.
      OrthoDBiEOG7SR4MG.
      PhylomeDBiQ9NZV8.
      TreeFamiTF313103.

      Family and domain databases

      Gene3Di1.20.120.350. 1 hit.
      InterProiIPR000210. BTB/POZ_dom.
      IPR027359. Channel_four-helix_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.
      [Graphical view]
      PANTHERiPTHR11537. PTHR11537. 1 hit.
      PfamiPF02214. BTB_2. 1 hit.
      PF11879. DUF3399. 1 hit.
      PF00520. Ion_trans. 1 hit.
      PF11601. Shal-type. 1 hit.
      [Graphical view]
      PRINTSiPR00169. KCHANNEL.
      PR01517. KV42CHANNEL.
      PR01491. KVCHANNEL.
      PR01497. SHALCHANNEL.
      SMARTiSM00225. BTB. 1 hit.
      [Graphical view]
      SUPFAMiSSF54695. SSF54695. 1 hit.

      Sequencei

      Sequence statusi: Complete.

      Q9NZV8-1 [UniParc]FASTAAdd to basket

      « Hide

              10         20         30         40         50
      MAAGVAAWLP FARAAAIGWM PVASGPMPAP PRQERKRTQD ALIVLNVSGT
      60 70 80 90 100
      RFQTWQDTLE RYPDTLLGSS ERDFFYHPET QQYFFDRDPD IFRHILNFYR
      110 120 130 140 150
      TGKLHYPRHE CISAYDEELA FFGLIPEIIG DCCYEEYKDR RRENAERLQD
      160 170 180 190 200
      DADTDTAGES ALPTMTARQR VWRAFENPHT STMALVFYYV TGFFIAVSVI
      210 220 230 240 250
      ANVVETVPCG SSPGHIKELP CGERYAVAFF CLDTACVMIF TVEYLLRLAA
      260 270 280 290 300
      APSRYRFVRS VMSIIDVVAI LPYYIGLVMT DNEDVSGAFV TLRVFRVFRI
      310 320 330 340 350
      FKFSRHSQGL RILGYTLKSC ASELGFLLFS LTMAIIIFAT VMFYAEKGSS
      360 370 380 390 400
      ASKFTSIPAA FWYTIVTMTT LGYGDMVPKT IAGKIFGSIC SLSGVLVIAL
      410 420 430 440 450
      PVPVIVSNFS RIYHQNQRAD KRRAQKKARL ARIRAAKSGS ANAYMQSKRN
      460 470 480 490 500
      GLLSNQLQSS EDEQAFVSKS GSSFETQHHH LLHCLEKTTN HEFVDEQVFE
      510 520 530 540 550
      ESCMEVATVN RPSSHSPSLS SQQGVTSTCC SRRHKKTFRI PNANVSGSHQ
      560 570 580 590 600
      GSIQELSTIQ IRCVERTPLS NSRSSLNAKM EECVKLNCEQ PYVTTAIISI
      610 620 630
      PTPPVTTPEG DDRPESPEYS GGNIVRVSAL
      Length:630
      Mass (Da):70,537
      Last modified:November 7, 2003 - v2
      Checksum:i0C11E62FFA220421
      GO

      Sequence cautioni

      The sequence BAA82996.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

      Experimental Info

      Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
      Sequence conflicti450 – 4501N → S in AAD22053 (PubMed:9843794).Curated
      Sequence conflicti464 – 4641Q → P in AAD22053 (PubMed:9843794).Curated
      Sequence conflicti550 – 5501Q → R in AAD22053 (PubMed:9843794).Curated
      Sequence conflicti553 – 5531I → V in AAD22053 (PubMed:9843794).Curated

      Natural variant

      Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
      Natural varianti404 – 4041V → M Probable disease-associated mutation found in a family with atypical autism and severe epilepsy; disrupts potassium current inactivation. 1 Publication
      VAR_072076

      Sequence databases

      Select the link destinations:
      EMBLi
      GenBanki
      DDBJi
      Links Updated
      AF121104 mRNA. Translation: AAD22053.1.
      AB028967 mRNA. Translation: BAA82996.2. Different initiation.
      AJ010969 mRNA. Translation: CAB56841.1.
      AF166008, AF166007 Genomic DNA. Translation: AAF65618.1.
      AC004888 Genomic DNA. Translation: AAC83405.1.
      AC004946 Genomic DNA. No translation available.
      AF142568 Genomic DNA. Translation: AAD52159.1.
      BC110449 mRNA. Translation: AAI10450.1.
      BC110450 mRNA. Translation: AAI10451.1.
      CCDSiCCDS5776.1.
      RefSeqiNP_036413.1. NM_012281.2.
      UniGeneiHs.654739.

      Genome annotation databases

      EnsembliENST00000331113; ENSP00000333496; ENSG00000184408.
      GeneIDi3751.
      KEGGihsa:3751.
      UCSCiuc003vjj.2. human.

      Cross-referencesi

      Sequence databases

      Select the link destinations:
      EMBLi
      GenBanki
      DDBJi
      Links Updated
      AF121104 mRNA. Translation: AAD22053.1.
      AB028967 mRNA. Translation: BAA82996.2. Different initiation.
      AJ010969 mRNA. Translation: CAB56841.1.
      AF166008, AF166007 Genomic DNA. Translation: AAF65618.1.
      AC004888 Genomic DNA. Translation: AAC83405.1.
      AC004946 Genomic DNA. No translation available.
      AF142568 Genomic DNA. Translation: AAD52159.1.
      BC110449 mRNA. Translation: AAI10450.1.
      BC110450 mRNA. Translation: AAI10451.1.
      CCDSiCCDS5776.1.
      RefSeqiNP_036413.1. NM_012281.2.
      UniGeneiHs.654739.

      3D structure databases

      ProteinModelPortaliQ9NZV8.
      SMRiQ9NZV8. Positions 6-415.
      ModBaseiSearch...
      MobiDBiSearch...

      Protein-protein interaction databases

      BioGridi109953. 18 interactions.
      IntActiQ9NZV8. 2 interactions.
      STRINGi9606.ENSP00000333496.

      Chemistry

      ChEMBLiCHEMBL2362996.
      DrugBankiDB00321. Amitriptyline.
      DB06637. Dalfampridine.
      DB00280. Disopyramide.
      DB00458. Imipramine.

      Protein family/group databases

      TCDBi1.A.1.2.5. the voltage-gated ion channel (vic) superfamily.

      PTM databases

      iPTMnetiQ9NZV8.
      PhosphoSiteiQ9NZV8.

      Polymorphism and mutation databases

      BioMutaiKCND2.
      DMDMi38258257.

      Proteomic databases

      PaxDbiQ9NZV8.
      PRIDEiQ9NZV8.

      Protocols and materials databases

      Structural Biology KnowledgebaseSearch...

      Genome annotation databases

      EnsembliENST00000331113; ENSP00000333496; ENSG00000184408.
      GeneIDi3751.
      KEGGihsa:3751.
      UCSCiuc003vjj.2. human.

      Organism-specific databases

      CTDi3751.
      GeneCardsiKCND2.
      HGNCiHGNC:6238. KCND2.
      HPAiHPA029068.
      MIMi605410. gene.
      neXtProtiNX_Q9NZV8.
      PharmGKBiPA30030.
      HUGEiSearch...
      GenAtlasiSearch...

      Phylogenomic databases

      eggNOGiKOG4390. Eukaryota.
      COG1226. LUCA.
      GeneTreeiENSGT00760000118846.
      HOVERGENiHBG106687.
      InParanoidiQ9NZV8.
      KOiK04892.
      OMAiIPYNGQP.
      OrthoDBiEOG7SR4MG.
      PhylomeDBiQ9NZV8.
      TreeFamiTF313103.

      Enzyme and pathway databases

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

      Miscellaneous databases

      ChiTaRSiKCND2. human.
      GeneWikiiKCND2.
      GenomeRNAii3751.
      NextBioi14687.
      PROiQ9NZV8.
      SOURCEiSearch...

      Gene expression databases

      BgeeiQ9NZV8.
      CleanExiHS_KCND2.
      ExpressionAtlasiQ9NZV8. baseline and differential.
      GenevisibleiQ9NZV8. HS.

      Family and domain databases

      Gene3Di1.20.120.350. 1 hit.
      InterProiIPR000210. BTB/POZ_dom.
      IPR027359. Channel_four-helix_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.
      [Graphical view]
      PANTHERiPTHR11537. PTHR11537. 1 hit.
      PfamiPF02214. BTB_2. 1 hit.
      PF11879. DUF3399. 1 hit.
      PF00520. Ion_trans. 1 hit.
      PF11601. Shal-type. 1 hit.
      [Graphical view]
      PRINTSiPR00169. KCHANNEL.
      PR01517. KV42CHANNEL.
      PR01491. KVCHANNEL.
      PR01497. SHALCHANNEL.
      SMARTiSM00225. BTB. 1 hit.
      [Graphical view]
      SUPFAMiSSF54695. SSF54695. 1 hit.
      ProtoNetiSearch...

      Publicationsi

      « Hide 'large scale' publications
      1. "Isolation and characterization of the human gene encoding Ito: further diversity by alternative mRNA splicing."
        Kong W., Po S., Yamagishi T., Ashen M.D., Stetten G., Tomaselli G.F.
        Am. J. Physiol. 275:H1963-H1970(1998) [PubMed] [Europe PMC] [Abstract]
        Cited for: NUCLEOTIDE SEQUENCE [MRNA].
        Tissue: Brain.
      2. "Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro."
        Kikuno R., Nagase T., Ishikawa K., Hirosawa M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
        DNA Res. 6:197-205(1999) [PubMed] [Europe PMC] [Abstract]
        Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
        Tissue: Brain.
      3. "Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current."
        Zhu X.-R., Wulf A., Schwarz M., Isbrandt D., Pongs O.
        Recept. Channels 6:387-400(1999) [PubMed] [Europe PMC] [Abstract]
        Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, FUNCTION.
      4. "Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(TO) and I(SA)."
        Isbrandt D., Leicher T., Waldschuetz R., Zhu X.-R., Luhmann U., Michel U., Sauter K., Pongs O.
        Genomics 64:144-154(2000) [PubMed] [Europe PMC] [Abstract]
        Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY.
        Tissue: Brain cortex.
      5. "The DNA sequence of human chromosome 7."
        Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L.
        , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K.
        Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract]
        Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
        The MGC Project Team
        Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
        Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      7. "Localization and enhanced current density of the Kv4.2 potassium channel by interaction with the actin-binding protein filamin."
        Petrecca K., Miller D.M., Shrier A.
        J. Neurosci. 20:8736-8744(2000) [PubMed] [Europe PMC] [Abstract]
        Cited for: MUTAGENESIS OF 601-PRO--PRO-604, SUBCELLULAR LOCATION, INTERACTION WITH FLNA AND FLNC.
      8. Cited for: INTERACTION WITH KCNIP1.
      9. "Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating."
        Baehring R., Dannenberg J., Peters H.C., Leicher T., Pongs O., Isbrandt D.
        J. Biol. Chem. 276:23888-23894(2001) [PubMed] [Europe PMC] [Abstract]
        Cited for: INTERACTION WITH KCNIP2.
      10. "Kinetic analysis of open- and closed-state inactivation transitions in human Kv4.2 A-type potassium channels."
        Baehring R., Boland L.M., Varghese A., Gebauer M., Pongs O.
        J. Physiol. (Lond.) 535:65-81(2001) [PubMed] [Europe PMC] [Abstract]
        Cited for: FUNCTION, SUBCELLULAR LOCATION, BIOPHYSICOCHEMICAL PROPERTIES, DOMAIN.
      11. "Expression of voltage-gated K+ channels in human atrium."
        Bertaso F., Sharpe C.C., Hendry B.M., James A.F.
        Basic Res. Cardiol. 97:424-433(2002) [PubMed] [Europe PMC] [Abstract]
        Cited for: TISSUE SPECIFICITY.
      12. "Molecular cloning and characterization of CALP/KChIP4, a novel EF-hand protein interacting with presenilin 2 and voltage-gated potassium channel subunit Kv4."
        Morohashi Y., Hatano N., Ohya S., Takikawa R., Watabiki T., Takasugi N., Imaizumi Y., Tomita T., Iwatsubo T.
        J. Biol. Chem. 277:14965-14975(2002) [PubMed] [Europe PMC] [Abstract]
        Cited for: INTERACTION WITH KCNIP4.
      13. "PKA modulation of Kv4.2-encoded A-type potassium channels requires formation of a supramolecular complex."
        Schrader L.A., Anderson A.E., Mayne A., Pfaffinger P.J., Sweatt J.D.
        J. Neurosci. 22:10123-10133(2002) [PubMed] [Europe PMC] [Abstract]
        Cited for: INTERACTION WITH KCNIP3.
      14. Cited for: FUNCTION, SUBCELLULAR LOCATION, DOMAIN.
      15. "Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10)."
        Jerng H.H., Qian Y., Pfaffinger P.J.
        Biophys. J. 87:2380-2396(2004) [PubMed] [Europe PMC] [Abstract]
        Cited for: FUNCTION, INTERACTION WITH DPP10 AND DPP6, SUBCELLULAR LOCATION.
      16. "Protein-protein interactions of KChIP proteins and Kv4.2."
        Lin Y.-L., Chen C.Y., Cheng C.P., Chang L.S.
        Biochem. Biophys. Res. Commun. 321:606-610(2004) [PubMed] [Europe PMC] [Abstract]
        Cited for: INTERACTION WITH KCNIP1 AND KCNIP2, SUBUNIT, DOMAIN.
      17. "A Kv4.2 truncation mutation in a patient with temporal lobe epilepsy."
        Singh B., Ogiwara I., Kaneda M., Tokonami N., Mazaki E., Baba K., Matsuda K., Inoue Y., Yamakawa K.
        Neurobiol. Dis. 24:245-253(2006) [PubMed] [Europe PMC] [Abstract]
        Cited for: FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, DOMAIN, ROLE IN DISEASE.
      18. "Ionic channel function in action potential generation: current perspective."
        Baranauskas G.
        Mol. Neurobiol. 35:129-150(2007) [PubMed] [Europe PMC] [Abstract]
        Cited for: REVIEW.
      19. Cited for: REVIEW.
      20. "Dynamic coupling of voltage sensor and gate involved in closed-state inactivation of Kv4.2 channels."
        Barghaan J., Baehring R.
        J. Gen. Physiol. 133:205-224(2009) [PubMed] [Europe PMC] [Abstract]
        Cited for: FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, MUTAGENESIS OF GLY-309; ARG-311; ILE-312; LEU-313; GLY-314; TYR-315; THR-316; LEU-317; LYS-318; SER-319; CYS-320; SER-322; GLU-323; LEU-324; LEU-327; LEU-328; VAL-397; ILE-398; ALA-399; PRO-401; 402-VAL--VAL-404; PRO-403; ILE-405; VAL-406; SER-407; ASN-408 AND PHE-409.
      21. "The stoichiometry and biophysical properties of the Kv4 potassium channel complex with K+ channel-interacting protein (KChIP) subunits are variable, depending on the relative expression level."
        Kitazawa M., Kubo Y., Nakajo K.
        J. Biol. Chem. 289:17597-17609(2014) [PubMed] [Europe PMC] [Abstract]
        Cited for: FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, INTERACTION WITH KCNIP4.
      22. "Three-dimensional structure of I(to); Kv4.2-KChIP2 ion channels by electron microscopy at 21 Angstrom resolution."
        Kim L.A., Furst J., Gutierrez D., Butler M.H., Xu S., Goldstein S.A., Grigorieff N.
        Neuron 41:513-519(2004) [PubMed] [Europe PMC] [Abstract]
        Cited for: STRUCTURE BY ELECTRON MICROSCOPY (21 ANGSTROMS) OF THE KCND2-KCNIP2 COMPLEX, FUNCTION, SUBCELLULAR LOCATION, SUBUNIT.
      23. "Ito channels are octameric complexes with four subunits of each Kv4.2 and K+ channel-interacting protein 2."
        Kim L.A., Furst J., Butler M.H., Xu S., Grigorieff N., Goldstein S.A.
        J. Biol. Chem. 279:5549-5554(2004) [PubMed] [Europe PMC] [Abstract]
        Cited for: INTERACTION WITH KCNIP2, FUNCTION, SUBCELLULAR LOCATION, SUBUNIT.
      24. "Voltage-dependent K+ channel acts as sex steroid sensor in endocrine cells of the human ovary."
        Kunz L., Ramsch R., Krieger A., Young K.A., Dissen G.A., Stouffer R.L., Ojeda S.R., Mayerhofer A.
        J. Cell. Physiol. 206:167-174(2006) [PubMed] [Europe PMC] [Abstract]
        Cited for: TISSUE SPECIFICITY.
      25. Cited for: INTERACTION WITH KCNIP1.
      26. "Kv4 potassium channels form a tripartite complex with the anchoring protein SAP97 and CaMKII in cardiac myocytes."
        El-Haou S., Balse E., Neyroud N., Dilanian G., Gavillet B., Abriel H., Coulombe A., Jeromin A., Hatem S.N.
        Circ. Res. 104:758-769(2009) [PubMed] [Europe PMC] [Abstract]
        Cited for: INTERACTION WITH DLG1.
      27. "Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation."
        Lee H., Lin M.C., Kornblum H.I., Papazian D.M., Nelson S.F.
        Hum. Mol. Genet. 23:3481-3489(2014) [PubMed] [Europe PMC] [Abstract]
        Cited for: VARIANT MET-404, CHARACTERIZATION OF VARIANT MET-404, FUNCTION, SUBCELLULAR LOCATION.

      Entry informationi

      Entry nameiKCND2_HUMAN
      AccessioniPrimary (citable) accession number: Q9NZV8
      Secondary accession number(s): O95012
      , O95021, Q2TBD3, Q9UBY7, Q9UN98, Q9UNH9
      Entry historyi
      Integrated into UniProtKB/Swiss-Prot: November 7, 2003
      Last sequence update: November 7, 2003
      Last modified: May 11, 2016
      This is version 149 of the entry and version 2 of the sequence. [Complete history]
      Entry statusiReviewed (UniProtKB/Swiss-Prot)
      Annotation programChordata Protein Annotation Program
      DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

      Miscellaneousi

      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.2 Publications1 Publication

      Keywords - Technical termi

      Complete proteome, Reference proteome

      Documents

      1. Human chromosome 7
        Human chromosome 7: entries, gene names and cross-references to MIM
      2. Human entries with polymorphisms or disease mutations
        List of human entries with polymorphisms or disease mutations
      3. Human polymorphisms and disease mutations
        Index of human polymorphisms and disease mutations
      4. MIM cross-references
        Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
      5. SIMILARITY comments
        Index of protein domains and families

      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.