KCND2_RABIT
ID KCND2_RABIT Reviewed; 630 AA.
AC P59995;
DT 07-NOV-2003, integrated into UniProtKB/Swiss-Prot.
DT 07-NOV-2003, sequence version 1.
DT 03-AUG-2022, entry version 120.
DE RecName: Full=Potassium voltage-gated channel subfamily D member 2;
DE AltName: Full=Voltage-gated potassium channel subunit Kv4.2;
GN Name=KCND2;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=New Zealand white; TISSUE=Cornea;
RA Rae J.L.;
RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 15-614, AND TISSUE SPECIFICITY.
RX PubMed=12122138; DOI=10.1113/jphysiol.2002.018382;
RA Sanchez D., Lopez-Lopez J.R., Perez-Garcia M.T., Sanz-Alfayate G.,
RA Obeso A., Ganfornina M.D., Gonzalez C.;
RT "Molecular identification of Kv alpha subunits that contribute to the
RT oxygen-sensitive K(+) current of chemoreceptor cells of the rabbit carotid
RT body.";
RL J. Physiol. (Lond.) 542:369-382(2002).
RN [3]
RP REVIEW.
RX PubMed=17917103; DOI=10.1007/s12035-007-8001-0;
RA Baranauskas G.;
RT "Ionic channel function in action potential generation: current
RT perspective.";
RL Mol. Neurobiol. 35:129-150(2007).
RN [4]
RP REVIEW.
RX PubMed=18357523; DOI=10.1007/s11064-008-9650-8;
RA Covarrubias M., Bhattacharji A., De Santiago-Castillo J.A., Dougherty K.,
RA Kaulin Y.A., Na-Phuket T.R., Wang G.;
RT "The neuronal Kv4 channel complex.";
RL Neurochem. Res. 33:1558-1567(2008).
CC -!- FUNCTION: Voltage-gated potassium channel that mediates transmembrane
CC potassium transport in excitable membranes, primarily in the brain, but
CC also in rodent heart. Mediates the major part of the dendritic A-type
CC current I(SA) in brain neurons (By similarity). This current is
CC activated at membrane potentials that are below the threshold for
CC action potentials. It regulates neuronal excitability, prolongs the
CC latency before the first spike in a series of action potentials,
CC regulates the frequency of repetitive action potential firing, shortens
CC the duration of action potentials and regulates the back-propagation of
CC action potentials from the neuronal cell body to the dendrites.
CC Contributes to the regulation of the circadian rhythm of action
CC potential firing in suprachiasmatic nucleus neurons, which regulates
CC the circadian rhythm of locomotor activity (By similarity). Functions
CC downstream of the metabotropic glutamate receptor GRM5 and plays a role
CC in neuronal excitability and in nociception mediated by activation of
CC GRM5 (By similarity). Mediates the transient outward current I(to) in
CC rodent heart left ventricle apex cells, but not in human heart, where
CC this current is mediated by another family member. Forms tetrameric
CC potassium-selective channels through which potassium ions pass in
CC accordance with their electrochemical gradient. The channel alternates
CC between opened and closed conformations in response to the voltage
CC difference across the membrane. Can form functional homotetrameric
CC channels and heterotetrameric channels that contain variable
CC proportions of KCND2 and KCND3; channel properties depend on the type
CC of pore-forming alpha subunits that are part of the channel. In vivo,
CC membranes probably contain a mixture of heteromeric potassium channel
CC complexes. Interaction with specific isoforms of the regulatory
CC subunits KCNIP1, KCNIP2, KCNIP3 or KCNIP4 strongly increases expression
CC at the cell surface and thereby increases channel activity; it
CC modulates the kinetics of channel activation and inactivation, shifts
CC the threshold for channel activation to more negative voltage values,
CC shifts the threshold for inactivation to less negative voltages and
CC accelerates recovery after inactivation. Likewise, interaction with
CC DPP6 or DPP10 promotes expression at the cell membrane and regulates
CC both channel characteristics and activity (By similarity).
CC {ECO:0000250|UniProtKB:Q63881, ECO:0000250|UniProtKB:Q9Z0V2}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Note=Homotetrameric channels activate rapidly, i.e within a few msec.
CC After that, they inactivate rapidly, i.e within about 50-100 msec.
CC The voltage-dependence of activation and inactivation and other
CC channel characteristics vary depending on the experimental
CC conditions, the expression system and the presence or absence of
CC ancillary subunits. Homotetrameric channels have a unitary
CC conductance of about 4 pS when expressed in a heterologous system.
CC For the activation of homotetrameric channels expressed in xenopus
CC oocytes, the voltage at half-maximal amplitude is about -10 mV. The
CC time constant for inactivation is about 20 msec. For inactivation,
CC the voltage at half-maximal amplitude is -62 mV. The time constant
CC for recovery after inactivation is about 70 msec.
CC {ECO:0000305|PubMed:17917103};
CC -!- SUBUNIT: Homotetramer or heterotetramer with KCND1 or KCND3. Associates
CC with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4.
CC Interacts with DPP6, DPP10, DLG4 and DLG1. In vivo, probably exists as
CC heteromeric complex containing variable proportions of KCND1, KCND2,
CC KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (By similarity).
CC The tetrameric channel can associate with up to four regulatory
CC subunits, such as KCNIP2 or KCNIP4 (By similarity). Interaction with
CC KCNIP3 promotes tetramerization and formation of a functional potassium
CC channel (By similarity). Interaction with four KCNIP4 chains does not
CC reduce interaction with DPP10 (By similarity). Probably part of a
CC complex consisting of KCNIP1, KCNIP2 isoform 3 and KCND2 (By
CC similarity). Interacts with FLNA and FLNC (By similarity). Interacts
CC with NCS1/FREQ (By similarity). Identified in a complex with cAMP-
CC dependent protein kinase (PKA), CAV3, AKAP6 and KCND3 in cardiac
CC myocytes (By similarity). {ECO:0000250|UniProtKB:Q63881,
CC ECO:0000250|UniProtKB:Q9NZV8, ECO:0000250|UniProtKB:Q9Z0V2}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q63881};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q63881}. Cell
CC projection, dendrite {ECO:0000250|UniProtKB:Q63881}. Synapse
CC {ECO:0000250|UniProtKB:Q63881}. Perikaryon
CC {ECO:0000250|UniProtKB:Q63881}. Postsynaptic cell membrane
CC {ECO:0000250|UniProtKB:Q63881}. Cell projection, dendritic spine
CC {ECO:0000250|UniProtKB:Q63881}. Cell membrane, sarcolemma
CC {ECO:0000250|UniProtKB:Q63881}. Cell junction
CC {ECO:0000250|UniProtKB:Q63881}. Membrane, caveola
CC {ECO:0000250|UniProtKB:Q63881}. Note=In neurons, primarily detected on
CC dendrites, dendritic spines and on the neuron cell body, but not on
CC axons. Localized preferentially at the dendrites of pyramidal cells in
CC the hippocampus CA1 layer. Detectedat GABAergic synapses. Detected at
CC cell junctions that are distinct from synaptic cell contacts. Detected
CC in lipid rafts. Detected primarily at the endoplasmic reticulum or
CC Golgi when expressed by itself. Interaction with KCNIP1, KCNIP2, KCNIP3
CC or KCNIP4 promotes expression at the cell membrane. Interaction with
CC DPP6 or DPP10 promotes expression at the cell membrane (By similarity).
CC Internalized from the cell membrane by clathrin-dependent endocytosis
CC in response to activation of AMPA-selective glutamate receptors and
CC PKA-mediated phosphorylation at Ser-552. Redistributed from dendritic
CC spines to the main dendritic shaft in response to activation of AMPA-
CC selective glutamate receptors and activation of PKA (By similarity).
CC {ECO:0000250|UniProtKB:Q63881, ECO:0000250|UniProtKB:Q9Z0V2}.
CC -!- TISSUE SPECIFICITY: Detected in brain frontal cortex.
CC {ECO:0000269|PubMed:12122138}.
CC -!- DOMAIN: The transmembrane segment S4 functions as voltage-sensor and is
CC characterized by a series of positively charged amino acids at every
CC third position. Channel opening and closing is effected by a
CC conformation change that affects the position and orientation of the
CC voltage-sensor paddle formed by S3 and S4 within the membrane. A
CC transmembrane electric field that is positive inside would push the
CC positively charged S4 segment outwards, thereby opening the pore, while
CC a field that is negative inside would pull the S4 segment inwards and
CC close the pore. Changes in the position and orientation of S4 are then
CC transmitted to the activation gate formed by the inner helix bundle via
CC the S4-S5 linker region. {ECO:0000250|UniProtKB:P63142}.
CC -!- DOMAIN: The N-terminal cytoplasmic region can mediate N-type
CC inactivation by physically blocking the channel (By similarity). This
CC probably does not happen in vivo, where the N-terminal region mediates
CC interaction with regulatory subunits, such as KCNIP1 and KCNIP2 (By
CC similarity). The zinc binding sites in the N-terminal domain are
CC important for tetramerization and assembly of a functional channel
CC complex (By similarity). Most likely, the channel undergoes closed-
CC state inactivation, where a subtle conformation change would render the
CC protein less sensitive to activation. {ECO:0000250|UniProtKB:Q63881,
CC ECO:0000250|UniProtKB:Q9NZV8, ECO:0000305|PubMed:18357523}.
CC -!- DOMAIN: The C-terminal cytoplasmic region is important for normal
CC expression at the cell membrane and modulates the voltage-dependence of
CC channel activation and inactivation. It is required for interaction
CC with KCNIP2, and probably other family members as well.
CC {ECO:0000250|UniProtKB:Q63881}.
CC -!- PTM: Phosphorylation at Ser-438 in response to MAPK activation is
CC increased in stimulated dendrites. Interaction with KCNIP2 and DPP6
CC propomtes phosphorylation by PKA at Ser-552. Phosphorylation at Ser-552
CC has no effect on interaction with KCNIP3, but is required for the
CC regulation of channel activity by KCNIP3. Phosphorylation at Ser-552
CC leads to KCND2 internalization (By similarity). Phosphorylated by MAPK
CC in response to signaling via the metabotropic glutamate receptor GRM5
CC (By similarity). Phosphorylation at Ser-616 is required for the down-
CC regulation of neuronal A-type currents in response to signaling via
CC GRM5 (By similarity). {ECO:0000250|UniProtKB:Q63881,
CC ECO:0000250|UniProtKB:Q9Z0V2}.
CC -!- MISCELLANEOUS: The transient neuronal A-type potassium current called
CC I(SA) is triggered at membrane potentials that are below the threshold
CC for action potentials. It inactivates rapidly and recovers rapidly from
CC inactivation. It regulates the firing of action potentials and plays a
CC role in synaptic integration and plasticity. Potassium channels
CC containing KCND2 account for about 80% of the neuronal A-type potassium
CC current. In contrast, the potassium channel responsible for the cardiac
CC I(to) current differs between species; it is mediated by KCND2 in
CC rodents. In human and other non-rodents KCND3 may play an equivalent
CC role. {ECO:0000250|UniProtKB:Q63881, ECO:0000305|PubMed:17917103,
CC ECO:0000305|PubMed:18357523}.
CC -!- MISCELLANEOUS: Is specifically and reversibly inhibited by the scorpion
CC toxin Ts8 (AC P69940). {ECO:0000250|UniProtKB:Q63881}.
CC -!- SIMILARITY: Belongs to the potassium channel family. D (Shal) (TC
CC 1.A.1.2) subfamily. Kv4.2/KCND2 sub-subfamily. {ECO:0000305}.
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DR EMBL; AF508735; AAM46929.1; -; mRNA.
DR EMBL; AF493547; AAM46841.1; -; mRNA.
DR RefSeq; NP_001075587.1; NM_001082118.1.
DR AlphaFoldDB; P59995; -.
DR SMR; P59995; -.
DR STRING; 9986.ENSOCUP00000003587; -.
DR Ensembl; ENSOCUT00000004147; ENSOCUP00000003587; ENSOCUG00000004149.
DR GeneID; 100008841; -.
DR KEGG; ocu:100008841; -.
DR CTD; 3751; -.
DR eggNOG; KOG4390; Eukaryota.
DR GeneTree; ENSGT00940000155472; -.
DR InParanoid; P59995; -.
DR OrthoDB; 469107at2759; -.
DR Proteomes; UP000001811; Chromosome 7.
DR Bgee; ENSOCUG00000004149; Expressed in prefrontal cortex and 4 other tissues.
DR ExpressionAtlas; P59995; baseline.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-SubCell.
DR GO; GO:0005901; C:caveola; ISS:UniProtKB.
DR GO; GO:0043197; C:dendritic spine; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0032809; C:neuronal cell body membrane; ISS:UniProtKB.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0044853; C:plasma membrane raft; ISS:UniProtKB.
DR GO; GO:0045211; C:postsynaptic membrane; ISS:UniProtKB.
DR GO; GO:0042383; C:sarcolemma; ISS:UniProtKB.
DR GO; GO:0030315; C:T-tubule; ISS:UniProtKB.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; ISS:UniProtKB.
DR GO; GO:0005250; F:A-type (transient outward) potassium channel activity; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005249; F:voltage-gated potassium channel activity; ISS:UniProtKB.
DR GO; GO:0086001; P:cardiac muscle cell action potential; ISS:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; ISS:UniProtKB.
DR GO; GO:0071805; P:potassium ion transmembrane transport; ISS:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IEA:InterPro.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR Gene3D; 1.20.120.350; -; 1.
DR Gene3D; 3.30.710.10; -; 1.
DR InterPro; IPR000210; BTB/POZ_dom.
DR InterPro; IPR005821; Ion_trans_dom.
DR InterPro; IPR003968; K_chnl_volt-dep_Kv.
DR InterPro; IPR003975; K_chnl_volt-dep_Kv4.
DR InterPro; IPR004055; K_chnl_volt-dep_Kv4.2.
DR InterPro; IPR024587; K_chnl_volt-dep_Kv4_C.
DR InterPro; IPR021645; Shal-type_N.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR InterPro; IPR003131; T1-type_BTB.
DR InterPro; IPR028325; VG_K_chnl.
DR InterPro; IPR027359; Volt_channel_dom_sf.
DR PANTHER; PTHR11537; PTHR11537; 1.
DR Pfam; PF02214; BTB_2; 1.
DR Pfam; PF11879; DUF3399; 1.
DR Pfam; PF00520; Ion_trans; 1.
DR Pfam; PF11601; Shal-type; 1.
DR PRINTS; PR01517; KV42CHANNEL.
DR PRINTS; PR01491; KVCHANNEL.
DR PRINTS; PR01497; SHALCHANNEL.
DR SMART; SM00225; BTB; 1.
DR SUPFAM; SSF54695; SSF54695; 1.
PE 2: Evidence at transcript level;
KW Cell junction; Cell membrane; Cell projection; Ion channel; Ion transport;
KW Membrane; Metal-binding; Phosphoprotein; Postsynaptic cell membrane;
KW Potassium; Potassium channel; Potassium transport; Reference proteome;
KW Synapse; Transmembrane; Transmembrane helix; Transport;
KW Voltage-gated channel; Zinc.
FT CHAIN 1..630
FT /note="Potassium voltage-gated channel subfamily D member
FT 2"
FT /id="PRO_0000054066"
FT TOPO_DOM 1..182
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 183..204
FT /note="Helical; Name=Segment S1"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 205..228
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 229..250
FT /note="Helical; Name=Segment S2"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 251..261
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 262..279
FT /note="Helical; Name=Segment S3"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 280..286
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 287..306
FT /note="Helical; Voltage-sensor; Name=Segment S4"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 307..321
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 322..343
FT /note="Helical; Name=Segment S5"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 344..357
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT INTRAMEM 358..369
FT /note="Helical; Name=Pore helix"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT INTRAMEM 370..377
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 378..384
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 385..413
FT /note="Helical; Name=Segment S6"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 414..630
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT REGION 2..20
FT /note="Interaction with KCNIP1, KCNIP2, and other family
FT members"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT REGION 71..90
FT /note="Interaction with KCNIP1"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT REGION 308..321
FT /note="S4-S5 linker"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT REGION 474..630
FT /note="Important for normal channel activation and
FT inactivation, for interaction with KCNIP2, and probably
FT other family members as well"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT REGION 474..489
FT /note="Required for dendritic targeting"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT REGION 600..623
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 370..375
FT /note="Selectivity filter"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT MOTIF 627..630
FT /note="PDZ-binding"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT BINDING 105
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT BINDING 132
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT BINDING 133
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT MOD_RES 38
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT MOD_RES 438
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT MOD_RES 548
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT MOD_RES 552
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0V2"
FT MOD_RES 572
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0V2"
FT MOD_RES 575
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0V2"
FT MOD_RES 602
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT MOD_RES 607
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q63881"
FT MOD_RES 616
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0V2"
FT CONFLICT 118
FT /note="E -> K (in Ref. 2; AAM46841)"
FT /evidence="ECO:0000305"
FT CONFLICT 379
FT /note="K -> R (in Ref. 2; AAM46841)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 630 AA; 70614 MW; 5981C87A5E4C41D1 CRC64;
MAAGVAAWLP FARAAAIGWM PVASGPMPAP PRQERKRTQD ALIVLNVSGT RFQTWQDTLE
RYPDTLLGSS ERDFFYHPET QQYFFDRDPD IFRHILNFYR TGKLHYPRHE CISAYDEELA
FFGLIPEIIG DCCYEEYKDR RRENAERLQD DADTDNTCES ALPTMTARQR VWRAFENPHT
STMALVFYYV TGFFIAVSVI ANVVETVPCG SSPGHIKELP CGERYAVAFF CLDTACVMIF
TVEYLLRLAA APSRYRFVRS VMSIIDVVAI LPYYIGLVMT DNEDVSGAFV TLRVFRVFRI
FKFSRHSQGL RILGYTLKSC ASELGFLLFS LTMAIIIFAT VMFYAEKGSS ASKFTSIPAA
FWYTIVTMTT LGYGDMVPKT IAGKIFGSIC SLSGVLVIAL PVPVIVSNFS RIYHQNQRAD
KRRAQKKARL ARIRAAKSGS ANAYMQSKRN GLLSNQLQSS EEEPAFVSKS GSSFETQHHH
LLHCLEKTTN HEFVDEQVFE ESCMEVATVN RPSSHSPSLS SQQGVTSTCC SRRHKKTFRI
PNANVSGSQR GSVQELSTIQ IRCVERTPLS NSRSSLNAKM EECVKLNCEQ PYVTTAIISI
PTPPVTTPEG DDRPESPEYS GGNIVRVSAL
