UniProt functional annotation for Q63881



	UniProt functional annotation for Q63881

UniProt code: Q63881.

Organism: Rattus norvegicus (Rat).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.

Function: 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). {ECO:0000250|UniProtKB:Q9Z0V2, ECO:0000269|PubMed:10676964, ECO:0000269|PubMed:11847232, ECO:0000269|PubMed:12451113, ECO:0000269|PubMed:12592409, ECO:0000269|PubMed:12754210, ECO:0000269|PubMed:14980206, ECO:0000269|PubMed:15452711, ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:16123112, ECO:0000269|PubMed:16207878, ECO:0000269|PubMed:16820361, ECO:0000269|PubMed:17026528, ECO:0000269|PubMed:1722463, ECO:0000269|PubMed:17582333, ECO:0000269|PubMed:1840649, ECO:0000269|PubMed:19279261, ECO:0000269|PubMed:19441798, ECO:0000269|PubMed:19901547, ECO:0000269|PubMed:24404150, ECO:0000269|PubMed:25352783, ECO:0000269|PubMed:9058605, ECO:0000269|PubMed:9093524, ECO:0000305}.

Activity regulation: 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 HpTx(1), HpTx(2), and HpTx(3) (PubMed:9058605). {ECO:0000269|PubMed:1722463, ECO:0000269|PubMed:1840649, ECO:0000269|PubMed:9058605, ECO:0000269|PubMed:9093524}.

Biophysicochemical properties: Kinetic parameters: Note=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). {ECO:0000269|PubMed:12451113, ECO:0000269|PubMed:1722463, ECO:0000269|PubMed:19279261, ECO:0000269|PubMed:19901547, ECO:0000269|PubMed:9093524, ECO:0000305|PubMed:15858231};

Subunit: 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). {ECO:0000250|UniProtKB:Q9NZV8, ECO:0000250|UniProtKB:Q9Z0V2, ECO:0000269|PubMed:10676964, ECO:0000269|PubMed:11102480, ECO:0000269|PubMed:11805342, ECO:0000269|PubMed:11847232, ECO:0000269|PubMed:11923279, ECO:0000269|PubMed:12451113, ECO:0000269|PubMed:12575952, ECO:0000269|PubMed:12754210, ECO:0000269|PubMed:14559911, ECO:0000269|PubMed:14980206, ECO:0000269|PubMed:14980207, ECO:0000269|PubMed:15356203, ECO:0000269|PubMed:15452711, ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:15671030, ECO:0000269|PubMed:16123112, ECO:0000269|PubMed:16207878, ECO:0000269|PubMed:16820361, ECO:0000269|PubMed:19213956, ECO:0000269|PubMed:20224290, ECO:0000269|PubMed:24811166, ECO:0000269|PubMed:25352783, ECO:0000305|PubMed:19441798, ECO:0000305|PubMed:19901547}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:10676964, ECO:0000269|PubMed:10860776, ECO:0000269|PubMed:11102480, ECO:0000269|PubMed:11847232, ECO:0000269|PubMed:12451113, ECO:0000269|PubMed:12592409, ECO:0000269|PubMed:12754210, ECO:0000269|PubMed:12829703, ECO:0000269|PubMed:14559911, ECO:0000269|PubMed:14980206, ECO:0000269|PubMed:15452711, ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:15671030, ECO:0000269|PubMed:15736227, ECO:0000269|PubMed:16123112, ECO:0000269|PubMed:16820361, ECO:0000269|PubMed:1722463, ECO:0000269|PubMed:17582333, ECO:0000269|PubMed:18371079, ECO:0000269|PubMed:1840649, ECO:0000269|PubMed:18650329, ECO:0000269|PubMed:20045463, ECO:0000269|PubMed:22098631, ECO:0000269|PubMed:24793047, ECO:0000269|PubMed:25352783, ECO:0000269|PubMed:9070739, ECO:0000269|PubMed:9093524}; Multi-pass membrane protein {ECO:0000305}. Cell projection, dendrite {ECO:0000269|PubMed:10676964, ECO:0000269|PubMed:11102480, ECO:0000269|PubMed:12592409, ECO:0000269|PubMed:15736227, ECO:0000269|PubMed:16207878, ECO:0000269|PubMed:17582333, ECO:0000269|PubMed:18371079, ECO:0000269|PubMed:20224290, ECO:0000269|PubMed:22098631, ECO:0000269|PubMed:24037673, ECO:0000269|PubMed:24404150, ECO:0000269|PubMed:9070739}. Cell junction, synapse {ECO:0000269|PubMed:11102480, ECO:0000269|PubMed:15736227, ECO:0000269|PubMed:17582333, ECO:0000269|PubMed:9070739}. Perikaryon {ECO:0000269|PubMed:10676964, ECO:0000269|PubMed:15736227, ECO:0000269|PubMed:16207878, ECO:0000269|PubMed:18371079, ECO:0000269|PubMed:22098631, ECO:0000269|PubMed:9070739}. Cell junction, synapse, postsynaptic cell membrane {ECO:0000269|PubMed:15736227, ECO:0000269|PubMed:9070739}. Cell projection, dendritic spine {ECO:0000269|PubMed:17582333, ECO:0000269|PubMed:18650329, ECO:0000269|PubMed:22098631, ECO:0000269|PubMed:24037673, ECO:0000269|PubMed:9070739}. Cell membrane, sarcolemma {ECO:0000269|PubMed:10860776}. Cell junction {ECO:0000269|PubMed:18371079}. Membrane, caveola {ECO:0000269|PubMed:20224290}. Note=In neurons, primarily detected on dendrites, dendritic spines and on the neuron cell body, but not on axons (PubMed:9070739, PubMed:17582333, PubMed:16207878, PubMed:22098631). Localized preferentially at the dendrites of pyramidal cells in the hippocampus CA1 layer (PubMed:22098631). Detected at GABAergic synapses (By similarity). Detected at cell junctions that are distinct from synaptic cell contacts (PubMed:18371079). Detected in lipid rafts (PubMed:14559911, PubMed:20224290, PubMed:24793047). Detected primarily at the endoplasmic reticulum or Golgi when expressed by itself (PubMed:12829703, PubMed:12754210, PubMed:16820361, PubMed:19441798, PubMed:14980206). Interaction with KCNIP1, KCNIP2, KCNIP3 or KCNIP4 promotes expression at the cell membrane (PubMed:12829703, PubMed:15485870, PubMed:20045463, PubMed:14980206). Interaction with DPP6 or DPP10 promotes expression at the cell membrane (PubMed:19441798). 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 (PubMed:17582333, PubMed:18650329). Redistributed from dendritic spines to the main dendritic shaft in response to activation of AMPA-selective glutamate receptors and activation of PKA (PubMed:17582333, PubMed:18650329). {ECO:0000250|UniProtKB:Q9Z0V2, ECO:0000269|PubMed:12754210, ECO:0000269|PubMed:14559911, ECO:0000269|PubMed:14980206, ECO:0000269|PubMed:15485870, ECO:0000269|PubMed:16207878, ECO:0000269|PubMed:16820361, ECO:0000269|PubMed:17582333, ECO:0000269|PubMed:18650329, ECO:0000269|PubMed:19441798, ECO:0000269|PubMed:20045463, ECO:0000269|PubMed:20224290, ECO:0000269|PubMed:22098631, ECO:0000269|PubMed:24793047, ECO:0000269|PubMed:9070739, ECO:0000305}.

Tissue specificity: 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. {ECO:0000269|PubMed:10676964, ECO:0000269|PubMed:11102480, ECO:0000269|PubMed:15736227, ECO:0000269|PubMed:16123112, ECO:0000269|PubMed:16207878, ECO:0000269|PubMed:1705709, ECO:0000269|PubMed:18371079, ECO:0000269|PubMed:1840649, ECO:0000269|PubMed:22098631, ECO:0000269|PubMed:24793047, ECO:0000269|PubMed:9070739}.

Induction: Down-regulated in response to hypoxia lasting about 15 min, a treatment that leads to spontaneous convulsive seizures in these pups. {ECO:0000269|PubMed:25352783}.

Domain: 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. {ECO:0000250|UniProtKB:P63142}.

Domain: 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. {ECO:0000250|UniProtKB:Q9NZV8, ECO:0000269|PubMed:12754210, ECO:0000269|PubMed:16820361, ECO:0000305|PubMed:14980206, ECO:0000305|PubMed:15452711, ECO:0000305|PubMed:18357523}.

Domain: 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. {ECO:0000269|PubMed:16820361}.

Ptm: 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). {ECO:0000250|UniProtKB:Q9Z0V2, ECO:0000269|PubMed:12451113, ECO:0000269|PubMed:17582333, ECO:0000269|PubMed:19441798, ECO:0000269|PubMed:24404150}.

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. {ECO:0000269|PubMed:9093524, ECO:0000305|PubMed:17917103, ECO:0000305|PubMed:18357523}.

Miscellaneous: Is specifically and reversibly inhibited by the scorpion toxin Ts8 (AC P69940). {ECO:0000269|PubMed:27346450}.

Similarity: Belongs to the potassium channel family. D (Shal) (TC 1.A.1.2) subfamily. Kv4.2/KCND2 sub-subfamily. {ECO:0000305}.

Sequence caution: Sequence=AAA40929.1; Type=Frameshift; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Rattus norvegicus (Rat).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.



Function:		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). {ECO:0000250\|UniProtKB:Q9Z0V2, ECO:0000269\|PubMed:10676964, ECO:0000269\|PubMed:11847232, ECO:0000269\|PubMed:12451113, ECO:0000269\|PubMed:12592409, ECO:0000269\|PubMed:12754210, ECO:0000269\|PubMed:14980206, ECO:0000269\|PubMed:15452711, ECO:0000269\|PubMed:15485870, ECO:0000269\|PubMed:16123112, ECO:0000269\|PubMed:16207878, ECO:0000269\|PubMed:16820361, ECO:0000269\|PubMed:17026528, ECO:0000269\|PubMed:1722463, ECO:0000269\|PubMed:17582333, ECO:0000269\|PubMed:1840649, ECO:0000269\|PubMed:19279261, ECO:0000269\|PubMed:19441798, ECO:0000269\|PubMed:19901547, ECO:0000269\|PubMed:24404150, ECO:0000269\|PubMed:25352783, ECO:0000269\|PubMed:9058605, ECO:0000269\|PubMed:9093524, ECO:0000305}.


Activity regulation:		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 HpTx(1), HpTx(2), and HpTx(3) (PubMed:9058605). {ECO:0000269\|PubMed:1722463, ECO:0000269\|PubMed:1840649, ECO:0000269\|PubMed:9058605, ECO:0000269\|PubMed:9093524}.
Biophysicochemical properties:		Kinetic parameters: Note=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). {ECO:0000269\|PubMed:12451113, ECO:0000269\|PubMed:1722463, ECO:0000269\|PubMed:19279261, ECO:0000269\|PubMed:19901547, ECO:0000269\|PubMed:9093524, ECO:0000305\|PubMed:15858231};
Subunit:		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). {ECO:0000250\|UniProtKB:Q9NZV8, ECO:0000250\|UniProtKB:Q9Z0V2, ECO:0000269\|PubMed:10676964, ECO:0000269\|PubMed:11102480, ECO:0000269\|PubMed:11805342, ECO:0000269\|PubMed:11847232, ECO:0000269\|PubMed:11923279, ECO:0000269\|PubMed:12451113, ECO:0000269\|PubMed:12575952, ECO:0000269\|PubMed:12754210, ECO:0000269\|PubMed:14559911, ECO:0000269\|PubMed:14980206, ECO:0000269\|PubMed:14980207, ECO:0000269\|PubMed:15356203, ECO:0000269\|PubMed:15452711, ECO:0000269\|PubMed:15485870, ECO:0000269\|PubMed:15671030, ECO:0000269\|PubMed:16123112, ECO:0000269\|PubMed:16207878, ECO:0000269\|PubMed:16820361, ECO:0000269\|PubMed:19213956, ECO:0000269\|PubMed:20224290, ECO:0000269\|PubMed:24811166, ECO:0000269\|PubMed:25352783, ECO:0000305\|PubMed:19441798, ECO:0000305\|PubMed:19901547}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:10676964, ECO:0000269\|PubMed:10860776, ECO:0000269\|PubMed:11102480, ECO:0000269\|PubMed:11847232, ECO:0000269\|PubMed:12451113, ECO:0000269\|PubMed:12592409, ECO:0000269\|PubMed:12754210, ECO:0000269\|PubMed:12829703, ECO:0000269\|PubMed:14559911, ECO:0000269\|PubMed:14980206, ECO:0000269\|PubMed:15452711, ECO:0000269\|PubMed:15485870, ECO:0000269\|PubMed:15671030, ECO:0000269\|PubMed:15736227, ECO:0000269\|PubMed:16123112, ECO:0000269\|PubMed:16820361, ECO:0000269\|PubMed:1722463, ECO:0000269\|PubMed:17582333, ECO:0000269\|PubMed:18371079, ECO:0000269\|PubMed:1840649, ECO:0000269\|PubMed:18650329, ECO:0000269\|PubMed:20045463, ECO:0000269\|PubMed:22098631, ECO:0000269\|PubMed:24793047, ECO:0000269\|PubMed:25352783, ECO:0000269\|PubMed:9070739, ECO:0000269\|PubMed:9093524}; Multi-pass membrane protein {ECO:0000305}. Cell projection, dendrite {ECO:0000269\|PubMed:10676964, ECO:0000269\|PubMed:11102480, ECO:0000269\|PubMed:12592409, ECO:0000269\|PubMed:15736227, ECO:0000269\|PubMed:16207878, ECO:0000269\|PubMed:17582333, ECO:0000269\|PubMed:18371079, ECO:0000269\|PubMed:20224290, ECO:0000269\|PubMed:22098631, ECO:0000269\|PubMed:24037673, ECO:0000269\|PubMed:24404150, ECO:0000269\|PubMed:9070739}. Cell junction, synapse {ECO:0000269\|PubMed:11102480, ECO:0000269\|PubMed:15736227, ECO:0000269\|PubMed:17582333, ECO:0000269\|PubMed:9070739}. Perikaryon {ECO:0000269\|PubMed:10676964, ECO:0000269\|PubMed:15736227, ECO:0000269\|PubMed:16207878, ECO:0000269\|PubMed:18371079, ECO:0000269\|PubMed:22098631, ECO:0000269\|PubMed:9070739}. Cell junction, synapse, postsynaptic cell membrane {ECO:0000269\|PubMed:15736227, ECO:0000269\|PubMed:9070739}. Cell projection, dendritic spine {ECO:0000269\|PubMed:17582333, ECO:0000269\|PubMed:18650329, ECO:0000269\|PubMed:22098631, ECO:0000269\|PubMed:24037673, ECO:0000269\|PubMed:9070739}. Cell membrane, sarcolemma {ECO:0000269\|PubMed:10860776}. Cell junction {ECO:0000269\|PubMed:18371079}. Membrane, caveola {ECO:0000269\|PubMed:20224290}. Note=In neurons, primarily detected on dendrites, dendritic spines and on the neuron cell body, but not on axons (PubMed:9070739, PubMed:17582333, PubMed:16207878, PubMed:22098631). Localized preferentially at the dendrites of pyramidal cells in the hippocampus CA1 layer (PubMed:22098631). Detected at GABAergic synapses (By similarity). Detected at cell junctions that are distinct from synaptic cell contacts (PubMed:18371079). Detected in lipid rafts (PubMed:14559911, PubMed:20224290, PubMed:24793047). Detected primarily at the endoplasmic reticulum or Golgi when expressed by itself (PubMed:12829703, PubMed:12754210, PubMed:16820361, PubMed:19441798, PubMed:14980206). Interaction with KCNIP1, KCNIP2, KCNIP3 or KCNIP4 promotes expression at the cell membrane (PubMed:12829703, PubMed:15485870, PubMed:20045463, PubMed:14980206). Interaction with DPP6 or DPP10 promotes expression at the cell membrane (PubMed:19441798). 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 (PubMed:17582333, PubMed:18650329). Redistributed from dendritic spines to the main dendritic shaft in response to activation of AMPA-selective glutamate receptors and activation of PKA (PubMed:17582333, PubMed:18650329). {ECO:0000250\|UniProtKB:Q9Z0V2, ECO:0000269\|PubMed:12754210, ECO:0000269\|PubMed:14559911, ECO:0000269\|PubMed:14980206, ECO:0000269\|PubMed:15485870, ECO:0000269\|PubMed:16207878, ECO:0000269\|PubMed:16820361, ECO:0000269\|PubMed:17582333, ECO:0000269\|PubMed:18650329, ECO:0000269\|PubMed:19441798, ECO:0000269\|PubMed:20045463, ECO:0000269\|PubMed:20224290, ECO:0000269\|PubMed:22098631, ECO:0000269\|PubMed:24793047, ECO:0000269\|PubMed:9070739, ECO:0000305}.
Tissue specificity:		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. {ECO:0000269\|PubMed:10676964, ECO:0000269\|PubMed:11102480, ECO:0000269\|PubMed:15736227, ECO:0000269\|PubMed:16123112, ECO:0000269\|PubMed:16207878, ECO:0000269\|PubMed:1705709, ECO:0000269\|PubMed:18371079, ECO:0000269\|PubMed:1840649, ECO:0000269\|PubMed:22098631, ECO:0000269\|PubMed:24793047, ECO:0000269\|PubMed:9070739}.
Induction:		Down-regulated in response to hypoxia lasting about 15 min, a treatment that leads to spontaneous convulsive seizures in these pups. {ECO:0000269\|PubMed:25352783}.
Domain:		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. {ECO:0000250\|UniProtKB:P63142}.
Domain:		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. {ECO:0000250\|UniProtKB:Q9NZV8, ECO:0000269\|PubMed:12754210, ECO:0000269\|PubMed:16820361, ECO:0000305\|PubMed:14980206, ECO:0000305\|PubMed:15452711, ECO:0000305\|PubMed:18357523}.
Domain:		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. {ECO:0000269\|PubMed:16820361}.
Ptm:		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). {ECO:0000250\|UniProtKB:Q9Z0V2, ECO:0000269\|PubMed:12451113, ECO:0000269\|PubMed:17582333, ECO:0000269\|PubMed:19441798, ECO:0000269\|PubMed:24404150}.
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. {ECO:0000269\|PubMed:9093524, ECO:0000305\|PubMed:17917103, ECO:0000305\|PubMed:18357523}.
Miscellaneous:		Is specifically and reversibly inhibited by the scorpion toxin Ts8 (AC P69940). {ECO:0000269\|PubMed:27346450}.
Similarity:		Belongs to the potassium channel family. D (Shal) (TC 1.A.1.2) subfamily. Kv4.2/KCND2 sub-subfamily. {ECO:0000305}.
Sequence caution:		Sequence=AAA40929.1; Type=Frameshift; Evidence={ECO:0000305};