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Potassium voltage-gated channel subfamily A member 2 (NGK1) (Voltage-gated K( ) channel HuKIV) (Voltage-gated potassium channel HBK5) (Voltage-gated potassium channel subunit Kv1.2)

 KCNA2_HUMAN             Reviewed;         499 AA.
P16389; A0A024R0D3; A8K1Z6; Q86XG6;
01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
01-FEB-1996, sequence version 2.
23-MAY-2018, entry version 180.
RecName: Full=Potassium voltage-gated channel subfamily A member 2;
AltName: Full=NGK1;
AltName: Full=Voltage-gated K(+) channel HuKIV {ECO:0000303|PubMed:19912772};
AltName: Full=Voltage-gated potassium channel HBK5;
AltName: Full=Voltage-gated potassium channel subunit Kv1.2;
Name=KCNA2;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR
LOCATION, ENZYME REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
TISSUE=Brain;
PubMed=19912772; DOI=10.1016/1044-7431(90)90004-N;
Ramaswami M., Gautam M., Kamb A., Rudy B., Tanouye M.A., Mathew M.K.;
"Human potassium channel genes: molecular cloning and functional
expression.";
Mol. Cell. Neurosci. 1:214-223(1990).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
TISSUE=Substantia nigra {ECO:0000312|EMBL:BAF82750.1};
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=16710414; DOI=10.1038/nature04727;
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
Beck S., Rogers J., Bentley D.R.;
"The DNA sequence and biological annotation of human chromosome 1.";
Nature 441:315-321(2006).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
TISSUE=Blood;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[6]
FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, AND INTERACTION WITH KCNA4.
PubMed=8495559; DOI=10.1161/01.RES.72.6.1326;
Po S., Roberds S., Snyders D.J., Tamkun M.M., Bennett P.B.;
"Heteromultimeric assembly of human potassium channels. Molecular
basis of a transient outward current?";
Circ. Res. 72:1326-1336(1993).
[7]
INTERACTION WITH CNTNAP2.
PubMed=10624965; DOI=10.1016/S0896-6273(00)81049-1;
Poliak S., Gollan L., Martinez R., Custer A., Einheber S.,
Salzer J.L., Trimmer J.S., Shrager P., Peles E.;
"Caspr2, a new member of the neurexin superfamily, is localized at the
juxtaparanodes of myelinated axons and associates with K+ channels.";
Neuron 24:1037-1047(1999).
[8]
FUNCTION, AND SUBCELLULAR LOCATION.
PubMed=11211111; DOI=10.1007/s004240000406;
Imbrici P., Tucker S.J., D'Adamo M.C., Pessia M.;
"Role of receptor protein tyrosine phosphatase alpha (RPTPalpha) and
tyrosine phosphorylation in the serotonergic inhibition of voltage-
dependent potassium channels.";
Pflugers Arch. 441:257-262(2000).
[9]
SUBCELLULAR LOCATION, INTERACTION WITH KCNA1 AND KCNAB2, SUBUNIT, AND
TISSUE SPECIFICITY.
PubMed=11086297;
DOI=10.1002/1096-9861(20000101)429:1<166::AID-CNE13>3.0.CO;2-Y;
Rasband M.N., Trimmer J.S.;
"Subunit composition and novel localization of K+ channels in spinal
cord.";
J. Comp. Neurol. 429:166-176(2001).
[10]
SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
PubMed=16473933; DOI=10.1073/pnas.0511197103;
Inda M.C., DeFelipe J., Munoz A.;
"Voltage-gated ion channels in the axon initial segment of human
cortical pyramidal cells and their relationship with chandelier
cells.";
Proc. Natl. Acad. Sci. U.S.A. 103:2920-2925(2006).
[11]
REVIEW.
PubMed=17917103; DOI=10.1007/s12035-007-8001-0;
Baranauskas G.;
"Ionic channel function in action potential generation: current
perspective.";
Mol. Neurobiol. 35:129-150(2007).
[12]
INTERACTION WITH KCNAB1.
PubMed=19713757; DOI=10.4161/chan.3.5.9558;
Peters C.J., Vaid M., Horne A.J., Fedida D., Accili E.A.;
"The molecular basis for the actions of Kvbeta1.2 on the opening and
closing of the Kv1.2 delayed rectifier channel.";
Channels 3:314-322(2009).
[13]
FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, AND ENZYME REGULATION.
PubMed=20220134; DOI=10.1074/jbc.M109.068486;
Chen P., Dendorfer A., Finol-Urdaneta R.K., Terlau H., Olivera B.M.;
"Biochemical characterization of kappaM-RIIIJ, a Kv1.2 channel
blocker: evaluation of cardioprotective effects of kappaM-
conotoxins.";
J. Biol. Chem. 285:14882-14889(2010).
[14]
TISSUE SPECIFICITY.
PubMed=22649228; DOI=10.1523/JNEUROSCI.0719-12.2012;
Zenker J., Poirot O., de Preux Charles A.S., Arnaud E., Medard J.J.,
Lacroix C., Kuntzer T., Chrast R.;
"Altered distribution of juxtaparanodal kv1.2 subunits mediates
peripheral nerve hyperexcitability in type 2 diabetes mellitus.";
J. Neurosci. 32:7493-7498(2012).
[15]
FUNCTION, AND SUBCELLULAR LOCATION.
PubMed=23769686; DOI=10.1016/j.neulet.2013.05.048;
Lee J.H., Choi S.H., Lee B.H., Hwang S.H., Kim H.J., Rhee J.,
Chung C., Nah S.Y.;
"Activation of lysophosphatidic acid receptor by gintonin inhibits
Kv1.2 channel activity: involvement of tyrosine kinase and receptor
protein tyrosine phosphatase alpha.";
Neurosci. Lett. 548:143-148(2013).
[16]
INVOLVEMENT IN EIEE32, AND VARIANT EIEE32 GLN-297.
PubMed=25477152; DOI=10.1111/cge.12542;
Pena S.D., Coimbra R.L.;
"Ataxia and myoclonic epilepsy due to a heterozygous new mutation in
KCNA2: proposal for a new channelopathy.";
Clin. Genet. 87:E1-E3(2015).
[17]
INVOLVEMENT IN EIEE32, VARIANTS EIEE32 THR-263; GLN-297; PHE-298 AND
LEU-405, AND CHARACTERIZATION OF VARIANTS EIEE32 THR-263; GLN-297;
PHE-298 AND LEU-405.
PubMed=25751627; DOI=10.1038/ng.3239;
Syrbe S., Hedrich U.B., Riesch E., Djemie T., Mueller S.,
Moeller R.S., Maher B., Hernandez-Hernandez L., Synofzik M.,
Caglayan H.S., Arslan M., Serratosa J.M., Nothnagel M., May P.,
Krause R., Loeffler H., Detert K., Dorn T., Vogt H., Kraemer G.,
Schoels L., Mullis P.E., Linnankivi T., Lehesjoki A.E., Sterbova K.,
Craiu D.C., Hoffman-Zacharska D., Korff C.M., Weber Y.G., Steinlin M.,
Gallati S., Bertsche A., Bernhard M.K., Merkenschlager A., Kiess W.,
Gonzalez M., Zuechner S., Palotie A., Suls A., De Jonghe P.,
Helbig I., Biskup S., Wolff M., Maljevic S., Schuele R.,
Sisodiya S.M., Weckhuysen S., Lerche H., Lemke J.R.;
"De novo loss- or gain-of-function mutations in KCNA2 cause epileptic
encephalopathy.";
Nat. Genet. 47:393-399(2015).
[18]
VARIANT THR-324.
PubMed=27864847; DOI=10.1002/humu.23149;
Clinical Study Group;
Parrini E., Marini C., Mei D., Galuppi A., Cellini E., Pucatti D.,
Chiti L., Rutigliano D., Bianchini C., Virdo S., De Vita D.,
Bigoni S., Barba C., Mari F., Montomoli M., Pisano T., Rosati A.,
Guerrini R.;
"Diagnostic targeted resequencing in 349 patients with drug-resistant
pediatric epilepsies identifies causative mutations in 30 different
genes.";
Hum. Mutat. 38:216-225(2017).
-!- FUNCTION: Voltage-gated potassium channel that mediates
transmembrane potassium transport in excitable membranes,
primarily in the brain and the central nervous system, but also in
the cardiovascular system. Prevents aberrant action potential
firing and regulates neuronal output. 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:19912772, PubMed:8495559,
PubMed:11211111, PubMed:23769686). Can form functional
homotetrameric channels and heterotetrameric channels that contain
variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNA7,
and possibly other family members as well; channel properties
depend on the type of alpha subunits that are part of the channel
(PubMed:8495559, PubMed:20220134). Channel properties are
modulated by cytoplasmic beta subunits that regulate the
subcellular location of the alpha subunits and promote rapid
inactivation of delayed rectifier potassium channels. In vivo,
membranes probably contain a mixture of heteromeric potassium
channel complexes, making it difficult to assign currents observed
in intact tissues to any particular potassium channel family
member. Homotetrameric KCNA2 forms a delayed-rectifier potassium
channel that opens in response to membrane depolarization,
followed by slow spontaneous channel closure (PubMed:19912772,
PubMed:23769686). In contrast, a heteromultimer formed by KCNA2
and KCNA4 shows rapid inactivation (PubMed:8495559). Regulates
neuronal excitability and plays a role as pacemaker in the
regulation of neuronal action potentials (By similarity). KCNA2-
containing channels play a presynaptic role and prevent
hyperexcitability and aberrant action potential firing (By
similarity). Response to toxins that are selective for KCNA2-
containing potassium channels suggests that in Purkinje cells,
dendritic subthreshold KCNA2-containing potassium channels prevent
random spontaneous calcium spikes, suppressing dendritic
hyperexcitability without hindering the generation of somatic
action potentials, and thereby play an important role in motor
coordination (By similarity). Plays a role in the induction of
long-term potentiation of neuron excitability in the CA3 layer of
the hippocampus (By similarity). May function as down-stream
effector for G protein-coupled receptors and inhibit GABAergic
inputs to basolateral amygdala neurons (By similarity). May
contribute to the regulation of neurotransmitter release, such as
gamma-aminobutyric acid (GABA) (By similarity). Contributes to the
regulation of the axonal release of the neurotransmitter dopamine
(By similarity). Reduced KCNA2 expression plays a role in the
perception of neuropathic pain after peripheral nerve injury, but
not acute pain (By similarity). Plays a role in the regulation of
the time spent in non-rapid eye movement (NREM) sleep (By
similarity). {ECO:0000250|UniProtKB:P63141,
ECO:0000250|UniProtKB:P63142, ECO:0000269|PubMed:11211111,
ECO:0000269|PubMed:19912772, ECO:0000269|PubMed:20220134,
ECO:0000269|PubMed:23769686, ECO:0000269|PubMed:8495559,
ECO:0000305}.
-!- ENZYME REGULATION: Inhibited by 4-aminopyridine (4-AP) and
charybdotoxin (CTX), but not by tetraethylammonium (TEA)
(PubMed:19912772). Inhibited by dendrotoxin (DTX) (By similarity).
Inhibited by tityustoxin-K alpha (TsTX-Kalpha), a toxin that is
highly specific for KCNA2 (By similarity). Inhibited by maurotoxin
(By similarity). Inhibited by kappaM conotoxins kappaM-RIIIJ and
kappaM-RIIIK; kappaM-RIIIJ has much higher affinity for channels
containing KCNA2 than kappaM-RIIIK, with the exception of
heterodimers formed by KCNA2 and KCNA7 where the opposite is true
(PubMed:20220134). {ECO:0000250|UniProtKB:P63141,
ECO:0000250|UniProtKB:P63142, ECO:0000269|PubMed:19912772,
ECO:0000269|PubMed:20220134}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
Note=Homotetrameric channels activate rapidly, i.e within a few
msec, but inactivation is very slow, with only a marginal
decrease in conductance over several seconds. The voltage-
dependence of activation and inactivation and other channel
characteristics vary depending on the experimental conditions,
the expression system, post-translational modifications and the
presence or absence of ancillary subunits. For the activation of
homotetrameric channels expressed in xenopus oocytes, the
threshold is at about -30 mV and the midpoint at about -5 mV.
{ECO:0000269|PubMed:19912772};
-!- SUBUNIT: Homotetramer and heterotetramer with other channel-
forming alpha subunits, such as KCNA1, KCNA4, KCNA5, KCNA6 and
KCNA7. Channel activity is regulated by interaction with the beta
subunits, including KCNAB1 and KCNAB2. Identified in a complex
with KCNA1 and KCNAB2 (PubMed:11086297). Identified in a complex
with KCNA5 and KCNAB1 (By similarity). Identified in a complex
with KCNA4 and FYN (By similarity). Interacts with the beta
subunit KCNAB1 (PubMed:19713757). Interacts with PTK2B (By
similarity). Interacts (via C-terminus) with CTTN (By similarity).
Interacts (via N-terminal cytoplasmic domain) with RHOA (GTP-bound
form); this regulates channel activity by reducing location at the
cell surface in response to CHRM1 activation (By similarity).
Interacts with DRD2 (By similarity). Interacts with SIGMAR1;
cocaine consumption leads to increased interaction (By
similarity). Interacts with ADAM22 (By similarity). Interacts (via
C-terminus) with the PDZ domains of DLG1, DLG2 and DLG4 (By
similarity). Interacts with CNTNAP2 (PubMed:10624965).
{ECO:0000250|UniProtKB:P63141, ECO:0000250|UniProtKB:P63142,
ECO:0000250|UniProtKB:Q09081, ECO:0000269|PubMed:10624965,
ECO:0000269|PubMed:11086297, ECO:0000269|PubMed:19713757,
ECO:0000269|PubMed:8495559, ECO:0000305}.
-!- INTERACTION:
P49069:CAMLG; NbExp=4; IntAct=EBI-11987131, EBI-1748958;
-!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11211111,
ECO:0000269|PubMed:19912772, ECO:0000269|PubMed:20220134,
ECO:0000269|PubMed:23769686, ECO:0000269|PubMed:8495559}; Multi-
pass membrane protein {ECO:0000250|UniProtKB:P63142, ECO:0000305}.
Membrane {ECO:0000250|UniProtKB:P63142}. Cell projection, axon
{ECO:0000269|PubMed:16473933}. Cell junction, synapse
{ECO:0000250|UniProtKB:P63142}. Endoplasmic reticulum membrane
{ECO:0000250|UniProtKB:P63142}. Cell projection, lamellipodium
membrane {ECO:0000250|UniProtKB:P63142}. Cell junction, synapse,
synaptosome {ECO:0000250|UniProtKB:P63141}. Cell junction,
synapse, presynaptic cell membrane {ECO:0000250|UniProtKB:P63141}.
Cell projection, dendrite {ECO:0000250|UniProtKB:P63141}. Cell
junction, paranodal septate junction
{ECO:0000250|UniProtKB:P63141}. Note=KCNA2 by itself is detected
both at the endoplasmic reticulum and at the cell membrane.
Coexpression with KCNA4 or with beta subunits promotes expression
at the cell membrane. Coexpression with KCNA1 inhibits cell
surface expression. In myelinated peripheral axons, clustered in
the juxtaparadonal region and at an internodal line located along
the mesaxon and below the Schmidt-Lanterman incisures (By
similarity). {ECO:0000250|UniProtKB:P63141,
ECO:0000250|UniProtKB:P63142}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1;
IsoId=P16389-1; Sequence=Displayed;
Name=2;
IsoId=P16389-2; Sequence=VSP_043077;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: Detected in brain cortex (PubMed:16473933).
Detected in peroneal nerve in the juxtaparanodal regions of the
node of Ranvier; expression is decreased in patients with diabetes
mellitus that suffer from axonal neuropathy (PubMed:22649228).
Detected in paranodal and juxtanodal zones in myelinated spinal
cord (at protein level) (PubMed:11086297).
{ECO:0000269|PubMed:11086297, ECO:0000269|PubMed:16473933,
ECO:0000269|PubMed:22649228}.
-!- DOMAIN: The cytoplasmic N-terminus is important for
tetramerization. Interactions between the different subunits
modulate the gating characteristics (By similarity). Besides, the
cytoplasmic N-terminal domain mediates interaction with RHOA and
thus is required for RHOA-mediated endocytosis (By similarity).
{ECO:0000250|UniProtKB:P63142}.
-!- 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}.
-!- PTM: Phosphorylated on tyrosine residues; phosphorylation
increases in response to ischemia (By similarity). Phosphorylated
on tyrosine residues by activated PTK2B/PYK2 (By similarity).
Phosphorylation on tyrosine residues suppresses ion channel
activity (By similarity). Phosphorylated on tyrosine residues in
response to CHRM1 activation; this abolishes interaction with
CTTN. This is probably due to endocytosis of the phosphorylated
channel subunits (By similarity). Phosphorylated on serine
residues in response to increased cAMP levels; phosphorylation is
apparently not catalyzed by PKA (By similarity).
{ECO:0000250|UniProtKB:P63142}.
-!- PTM: N-glycosylated, with complex, sialylated N-glycans.
{ECO:0000250|UniProtKB:P63142}.
-!- DISEASE: Epileptic encephalopathy, early infantile, 32 (EIEE32)
[MIM:616366]: A form of epileptic encephalopathy, a heterogeneous
group of severe childhood onset epilepsies characterized by
refractory seizures, neurodevelopmental impairment, and poor
prognosis. Development is normal prior to seizure onset, after
which cognitive and motor delays become apparent.
{ECO:0000269|PubMed:25477152, ECO:0000269|PubMed:25751627}.
Note=The disease is caused by mutations affecting the gene
represented in this entry.
-!- MISCELLANEOUS: The delay or D-type current observed in hippocampus
pyramidal neurons is probably mediated by potassium channels
containing KCNA2 plus KCNA1 or other family members. It is
activated at about -50 mV, i.e. below the action potential
threshold, and is characterized by slow inactivation, extremely
slow recovery from inactivation, sensitivity to dendrotoxin (DTX)
and to 4-aminopyridine (4-AP). {ECO:0000305|PubMed:17917103}.
-!- SIMILARITY: Belongs to the potassium channel family. A (Shaker)
(TC 1.A.1.2) subfamily. Kv1.2/KCNA2 sub-subfamily. {ECO:0000305}.
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EMBL; L02752; AAA36141.1; -; mRNA.
EMBL; AK290061; BAF82750.1; -; mRNA.
EMBL; AL365361; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CH471122; EAW56455.1; -; Genomic_DNA.
EMBL; CH471122; EAW56456.1; -; Genomic_DNA.
EMBL; BC043564; AAH43564.1; -; mRNA.
CCDS; CCDS55625.1; -. [P16389-2]
CCDS; CCDS827.1; -. [P16389-1]
PIR; I77466; I77466.
RefSeq; NP_001191198.1; NM_001204269.1. [P16389-2]
RefSeq; NP_004965.1; NM_004974.3. [P16389-1]
RefSeq; XP_011539698.1; XM_011541396.2. [P16389-1]
RefSeq; XP_011539699.1; XM_011541397.2. [P16389-1]
RefSeq; XP_011539700.1; XM_011541398.2. [P16389-1]
RefSeq; XP_011539701.1; XM_011541399.2. [P16389-1]
RefSeq; XP_011539702.1; XM_011541400.2. [P16389-1]
RefSeq; XP_016856702.1; XM_017001213.1. [P16389-1]
UniGene; Hs.248139; -.
UniGene; Hs.657199; -.
UniGene; Hs.731191; -.
ProteinModelPortal; P16389; -.
BioGrid; 109940; 17.
CORUM; P16389; -.
IntAct; P16389; 2.
STRING; 9606.ENSP00000314520; -.
BindingDB; P16389; -.
ChEMBL; CHEMBL2086; -.
DrugBank; DB06637; Dalfampridine.
GuidetoPHARMACOLOGY; 539; -.
TCDB; 1.A.1.2.10; the voltage-gated ion channel (vic) superfamily.
iPTMnet; P16389; -.
PhosphoSitePlus; P16389; -.
BioMuta; KCNA2; -.
DMDM; 1345813; -.
MaxQB; P16389; -.
PaxDb; P16389; -.
PeptideAtlas; P16389; -.
PRIDE; P16389; -.
Ensembl; ENST00000316361; ENSP00000314520; ENSG00000177301. [P16389-1]
Ensembl; ENST00000369770; ENSP00000358785; ENSG00000177301. [P16389-2]
Ensembl; ENST00000485317; ENSP00000433109; ENSG00000177301. [P16389-1]
Ensembl; ENST00000633222; ENSP00000487785; ENSG00000177301. [P16389-1]
Ensembl; ENST00000638532; ENSP00000491613; ENSG00000177301. [P16389-1]
Ensembl; ENST00000638616; ENSP00000491977; ENSG00000177301. [P16389-1]
GeneID; 3737; -.
KEGG; hsa:3737; -.
UCSC; uc009wfv.2; human. [P16389-1]
CTD; 3737; -.
DisGeNET; 3737; -.
EuPathDB; HostDB:ENSG00000177301.13; -.
GeneCards; KCNA2; -.
HGNC; HGNC:6220; KCNA2.
HPA; CAB001976; -.
MalaCards; KCNA2; -.
MIM; 176262; gene.
MIM; 616366; phenotype.
neXtProt; NX_P16389; -.
OpenTargets; ENSG00000177301; -.
PharmGKB; PA206; -.
eggNOG; KOG1545; Eukaryota.
eggNOG; COG1226; LUCA.
GeneTree; ENSGT00760000118846; -.
HOGENOM; HOG000231015; -.
HOVERGEN; HBG052230; -.
InParanoid; P16389; -.
KO; K04875; -.
OMA; PEPDHEC; -.
OrthoDB; EOG091G10NU; -.
PhylomeDB; P16389; -.
TreeFam; TF313103; -.
Reactome; R-HSA-1296072; Voltage gated Potassium channels.
ChiTaRS; KCNA2; human.
GeneWiki; KCNA2; -.
GenomeRNAi; 3737; -.
PRO; PR:P16389; -.
Proteomes; UP000005640; Chromosome 1.
Bgee; ENSG00000177301; -.
CleanEx; HS_KCNA2; -.
ExpressionAtlas; P16389; baseline and differential.
Genevisible; P16389; HS.
GO; GO:0030424; C:axon; ISS:UniProtKB.
GO; GO:0043679; C:axon terminus; ISS:UniProtKB.
GO; GO:0030425; C:dendrite; ISS:UniProtKB.
GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
GO; GO:0005887; C:integral component of plasma membrane; IMP:UniProtKB.
GO; GO:0044224; C:juxtaparanode region of axon; ISS:BHF-UCL.
GO; GO:0030027; C:lamellipodium; ISS:UniProtKB.
GO; GO:0031258; C:lamellipodium membrane; IEA:UniProtKB-SubCell.
GO; GO:0032809; C:neuronal cell body membrane; ISS:UniProtKB.
GO; GO:0033010; C:paranodal junction; IEA:UniProtKB-SubCell.
GO; GO:0043204; C:perikaryon; ISS:UniProtKB.
GO; GO:0005886; C:plasma membrane; TAS:Reactome.
GO; GO:0042734; C:presynaptic membrane; IEA:UniProtKB-SubCell.
GO; GO:0008076; C:voltage-gated potassium channel complex; IDA:UniProtKB.
GO; GO:0005251; F:delayed rectifier potassium channel activity; ISS:UniProtKB.
GO; GO:0015271; F:outward rectifier potassium channel activity; IEA:Ensembl.
GO; GO:0005267; F:potassium channel activity; TAS:ProtInc.
GO; GO:0005249; F:voltage-gated potassium channel activity; IMP:UniProtKB.
GO; GO:0019228; P:neuronal action potential; ISS:UniProtKB.
GO; GO:0021633; P:optic nerve structural organization; IEA:Ensembl.
GO; GO:0071805; P:potassium ion transmembrane transport; IMP:UniProtKB.
GO; GO:0006813; P:potassium ion transport; TAS:ProtInc.
GO; GO:0051260; P:protein homooligomerization; IEA:InterPro.
GO; GO:0045188; P:regulation of circadian sleep/wake cycle, non-REM sleep; IEA:Ensembl.
GO; GO:0014059; P:regulation of dopamine secretion; ISS:UniProtKB.
GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
GO; GO:0019233; P:sensory perception of pain; ISS:UniProtKB.
Gene3D; 1.20.120.350; -; 1.
InterPro; IPR000210; BTB/POZ_dom.
InterPro; IPR005821; Ion_trans_dom.
InterPro; IPR003968; K_chnl_volt-dep_Kv.
InterPro; IPR003972; K_chnl_volt-dep_Kv1.
InterPro; IPR004049; K_chnl_volt-dep_Kv1.2.
InterPro; IPR011333; SKP1/BTB/POZ_sf.
InterPro; IPR003131; T1-type_BTB.
InterPro; IPR028325; VG_K_chnl.
InterPro; IPR027359; Volt_channel_dom_sf.
PANTHER; PTHR11537; PTHR11537; 1.
PANTHER; PTHR11537:SF23; PTHR11537:SF23; 1.
Pfam; PF02214; BTB_2; 1.
Pfam; PF00520; Ion_trans; 1.
PRINTS; PR00169; KCHANNEL.
PRINTS; PR01509; KV12CHANNEL.
PRINTS; PR01491; KVCHANNEL.
PRINTS; PR01496; SHAKERCHANEL.
SMART; SM00225; BTB; 1.
SUPFAM; SSF54695; SSF54695; 1.
1: Evidence at protein level;
Alternative splicing; Cell junction; Cell membrane; Cell projection;
Complete proteome; Disease mutation; Endoplasmic reticulum; Epilepsy;
Glycoprotein; Ion channel; Ion transport; Lipoprotein; Membrane;
Palmitate; Phosphoprotein; Potassium; Potassium channel;
Potassium transport; Reference proteome; Synapse; Synaptosome;
Transmembrane; Transmembrane helix; Transport; Voltage-gated channel.
CHAIN 1 499 Potassium voltage-gated channel subfamily
A member 2.
/FTId=PRO_0000053972.
TOPO_DOM 1 160 Cytoplasmic.
{ECO:0000250|UniProtKB:P63142}.
TRANSMEM 161 182 Helical; Name=Segment S1.
{ECO:0000250|UniProtKB:P63142}.
TOPO_DOM 183 221 Extracellular.
{ECO:0000250|UniProtKB:P63142}.
TRANSMEM 222 243 Helical; Name=Segment S2.
{ECO:0000250|UniProtKB:P63142}.
TOPO_DOM 244 254 Cytoplasmic.
{ECO:0000250|UniProtKB:P63142}.
TRANSMEM 255 275 Helical; Name=Segment S3.
{ECO:0000250|UniProtKB:P63142}.
TOPO_DOM 276 289 Extracellular.
{ECO:0000250|UniProtKB:P63142}.
TRANSMEM 290 310 Helical; Voltage-sensor; Name=Segment S4.
{ECO:0000250|UniProtKB:P63142}.
TOPO_DOM 311 325 Cytoplasmic.
{ECO:0000250|UniProtKB:P63142}.
TRANSMEM 326 347 Helical; Name=Segment S5.
{ECO:0000250|UniProtKB:P63142}.
TOPO_DOM 348 361 Extracellular.
{ECO:0000250|UniProtKB:P63142}.
INTRAMEM 362 373 Helical; Name=Pore helix.
{ECO:0000250|UniProtKB:P63142}.
INTRAMEM 374 381 {ECO:0000250|UniProtKB:P63142}.
TOPO_DOM 382 388 Extracellular.
{ECO:0000250|UniProtKB:P63142}.
TRANSMEM 389 417 Helical; Name=Segment S6.
{ECO:0000250|UniProtKB:P63142}.
TOPO_DOM 418 499 Cytoplasmic.
{ECO:0000250|UniProtKB:P63142}.
REGION 1 125 Tetramerization domain.
{ECO:0000250|UniProtKB:P63142}.
REGION 312 325 S4-S5 linker.
{ECO:0000250|UniProtKB:P63142}.
MOTIF 374 379 Selectivity filter.
{ECO:0000250|UniProtKB:P63142}.
MOTIF 497 499 PDZ-binding.
{ECO:0000250|UniProtKB:P63142}.
SITE 252 252 Important for normal, slow channel
gating. {ECO:0000250|UniProtKB:P63142}.
SITE 381 381 Important for binding with the scorpion
mesomartoxin; when the scorpion
mesomartoxin-rKv1.2/KCNA2 interaction is
modeled, this residue is close to the 'Y-
57' residue of the toxin.
{ECO:0000250|UniProtKB:P63142}.
MOD_RES 429 429 Phosphotyrosine.
{ECO:0000250|UniProtKB:P63141}.
MOD_RES 434 434 Phosphoserine.
{ECO:0000250|UniProtKB:P63141}.
MOD_RES 440 440 Phosphoserine.
{ECO:0000250|UniProtKB:P63141}.
MOD_RES 441 441 Phosphoserine.
{ECO:0000250|UniProtKB:Q09081}.
MOD_RES 449 449 Phosphoserine.
{ECO:0000250|UniProtKB:Q09081}.
MOD_RES 458 458 Phosphotyrosine.
{ECO:0000250|UniProtKB:P63142}.
MOD_RES 468 468 Phosphoserine.
{ECO:0000250|UniProtKB:P63141}.
LIPID 244 244 S-palmitoyl cysteine. {ECO:0000255}.
CARBOHYD 207 207 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
VAR_SEQ 299 499 VRVFRIFKLSRHSKGLQILGQTLKASMRELGLLIFFLFIGV
ILFSSAVYFAEADERESQFPSIPDAFWWAVVSMTTVGYGDM
VPTTIGGKIVGSLCAIAGVLTIALPVPVIVSNFNYFYHRET
EGEEQAQYLQVTSCPKIPSSPDLKKSRSASTISKSDYMEIQ
EGVNNSNEDFREENLKTANCTLANTNYVNITKMLTDV ->
ERRPLQSQKSKRGRQHLNTSHDCTLGINLVAGMTVQWTRAS
GPDDRQTPAVTTLHRMY (in isoform 2).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_043077.
VARIANT 263 263 I -> T (in EIEE32; dominant-negative
mutation; loss of channel function;
dbSNP:rs786205231).
{ECO:0000269|PubMed:25751627}.
/FTId=VAR_073704.
VARIANT 297 297 R -> Q (in EIEE32; causes a gain of
function; dbSNP:rs786205232).
{ECO:0000269|PubMed:25477152,
ECO:0000269|PubMed:25751627}.
/FTId=VAR_073705.
VARIANT 298 298 L -> F (in EIEE32; causes a gain of
function; dbSNP:rs876657390).
{ECO:0000269|PubMed:25751627}.
/FTId=VAR_073706.
VARIANT 324 324 S -> T (probable disease-associated
mutation found in a patient with drug-
resistant epilepsy).
{ECO:0000269|PubMed:27864847}.
/FTId=VAR_078206.
VARIANT 405 405 P -> L (in EIEE32; loss of channel
function; dbSNP:rs876657389).
{ECO:0000269|PubMed:25751627}.
/FTId=VAR_073707.
CONFLICT 230 230 I -> V (in Ref. 2; BAF82750).
{ECO:0000305}.
SEQUENCE 499 AA; 56717 MW; 4B03F1B46A826C39 CRC64;
MTVATGDPAD EAAALPGHPQ DTYDPEADHE CCERVVINIS GLRFETQLKT LAQFPETLLG
DPKKRMRYFD PLRNEYFFDR NRPSFDAILY YYQSGGRLRR PVNVPLDIFS EEIRFYELGE
EAMEMFREDE GYIKEEERPL PENEFQRQVW LLFEYPESSG PARIIAIVSV MVILISIVSF
CLETLPIFRD ENEDMHGSGV TFHTYSNSTI GYQQSTSFTD PFFIVETLCI IWFSFEFLVR
FFACPSKAGF FTNIMNIIDI VAIIPYFITL GTELAEKPED AQQGQQAMSL AILRVIRLVR
VFRIFKLSRH SKGLQILGQT LKASMRELGL LIFFLFIGVI LFSSAVYFAE ADERESQFPS
IPDAFWWAVV SMTTVGYGDM VPTTIGGKIV GSLCAIAGVL TIALPVPVIV SNFNYFYHRE
TEGEEQAQYL QVTSCPKIPS SPDLKKSRSA STISKSDYME IQEGVNNSNE DFREENLKTA
NCTLANTNYV NITKMLTDV


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