KCNA2_HUMAN
ID KCNA2_HUMAN Reviewed; 499 AA.
AC P16389; A0A024R0D3; A8K1Z6; Q86XG6;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1996, sequence version 2.
DT 03-AUG-2022, entry version 208.
DE RecName: Full=Potassium voltage-gated channel subfamily A member 2;
DE AltName: Full=NGK1;
DE AltName: Full=Voltage-gated K(+) channel HuKIV {ECO:0000303|PubMed:19912772};
DE AltName: Full=Voltage-gated potassium channel HBK5;
DE AltName: Full=Voltage-gated potassium channel subunit Kv1.2;
GN Name=KCNA2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION,
RP ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Brain;
RX PubMed=19912772; DOI=10.1016/1044-7431(90)90004-n;
RA Ramaswami M., Gautam M., Kamb A., Rudy B., Tanouye M.A., Mathew M.K.;
RT "Human potassium channel genes: molecular cloning and functional
RT expression.";
RL Mol. Cell. Neurosci. 1:214-223(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Substantia nigra {ECO:0000312|EMBL:BAF82750.1};
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, AND INTERACTION WITH KCNA4.
RX PubMed=8495559; DOI=10.1161/01.res.72.6.1326;
RA Po S., Roberds S., Snyders D.J., Tamkun M.M., Bennett P.B.;
RT "Heteromultimeric assembly of human potassium channels. Molecular basis of
RT a transient outward current?";
RL Circ. Res. 72:1326-1336(1993).
RN [7]
RP INTERACTION WITH CNTNAP2.
RX PubMed=10624965; DOI=10.1016/s0896-6273(00)81049-1;
RA Poliak S., Gollan L., Martinez R., Custer A., Einheber S., Salzer J.L.,
RA Trimmer J.S., Shrager P., Peles E.;
RT "Caspr2, a new member of the neurexin superfamily, is localized at the
RT juxtaparanodes of myelinated axons and associates with K+ channels.";
RL Neuron 24:1037-1047(1999).
RN [8]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=11211111; DOI=10.1007/s004240000406;
RA Imbrici P., Tucker S.J., D'Adamo M.C., Pessia M.;
RT "Role of receptor protein tyrosine phosphatase alpha (RPTPalpha) and
RT tyrosine phosphorylation in the serotonergic inhibition of voltage-
RT dependent potassium channels.";
RL Pflugers Arch. 441:257-262(2000).
RN [9]
RP SUBCELLULAR LOCATION, INTERACTION WITH KCNA1 AND KCNAB2, SUBUNIT, AND
RP TISSUE SPECIFICITY.
RX PubMed=11086297;
RX DOI=10.1002/1096-9861(20000101)429:1<166::aid-cne13>3.0.co;2-y;
RA Rasband M.N., Trimmer J.S.;
RT "Subunit composition and novel localization of K+ channels in spinal
RT cord.";
RL J. Comp. Neurol. 429:166-176(2001).
RN [10]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=16473933; DOI=10.1073/pnas.0511197103;
RA Inda M.C., DeFelipe J., Munoz A.;
RT "Voltage-gated ion channels in the axon initial segment of human cortical
RT pyramidal cells and their relationship with chandelier cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:2920-2925(2006).
RN [11]
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 [12]
RP INTERACTION WITH KCNAB1.
RX PubMed=19713757; DOI=10.4161/chan.3.5.9558;
RA Peters C.J., Vaid M., Horne A.J., Fedida D., Accili E.A.;
RT "The molecular basis for the actions of Kvbeta1.2 on the opening and
RT closing of the Kv1.2 delayed rectifier channel.";
RL Channels 3:314-322(2009).
RN [13]
RP FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, AND ACTIVITY REGULATION.
RX PubMed=20220134; DOI=10.1074/jbc.m109.068486;
RA Chen P., Dendorfer A., Finol-Urdaneta R.K., Terlau H., Olivera B.M.;
RT "Biochemical characterization of kappaM-RIIIJ, a Kv1.2 channel blocker:
RT evaluation of cardioprotective effects of kappaM-conotoxins.";
RL J. Biol. Chem. 285:14882-14889(2010).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=22649228; DOI=10.1523/jneurosci.0719-12.2012;
RA Zenker J., Poirot O., de Preux Charles A.S., Arnaud E., Medard J.J.,
RA Lacroix C., Kuntzer T., Chrast R.;
RT "Altered distribution of juxtaparanodal kv1.2 subunits mediates peripheral
RT nerve hyperexcitability in type 2 diabetes mellitus.";
RL J. Neurosci. 32:7493-7498(2012).
RN [15]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23769686; DOI=10.1016/j.neulet.2013.05.048;
RA Lee J.H., Choi S.H., Lee B.H., Hwang S.H., Kim H.J., Rhee J., Chung C.,
RA Nah S.Y.;
RT "Activation of lysophosphatidic acid receptor by gintonin inhibits Kv1.2
RT channel activity: involvement of tyrosine kinase and receptor protein
RT tyrosine phosphatase alpha.";
RL Neurosci. Lett. 548:143-148(2013).
RN [16]
RP INVOLVEMENT IN DEE32, AND VARIANT DEE32 GLN-297.
RX PubMed=25477152; DOI=10.1111/cge.12542;
RA Pena S.D., Coimbra R.L.;
RT "Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2:
RT proposal for a new channelopathy.";
RL Clin. Genet. 87:E1-E3(2015).
RN [17]
RP INVOLVEMENT IN DEE32, VARIANTS DEE32 THR-263; GLN-297; PHE-298 AND LEU-405,
RP AND CHARACTERIZATION OF VARIANTS DEE32 THR-263; GLN-297; PHE-298 AND
RP LEU-405.
RX PubMed=25751627; DOI=10.1038/ng.3239;
RA Syrbe S., Hedrich U.B., Riesch E., Djemie T., Mueller S., Moeller R.S.,
RA Maher B., Hernandez-Hernandez L., Synofzik M., Caglayan H.S., Arslan M.,
RA Serratosa J.M., Nothnagel M., May P., Krause R., Loeffler H., Detert K.,
RA Dorn T., Vogt H., Kraemer G., Schoels L., Mullis P.E., Linnankivi T.,
RA Lehesjoki A.E., Sterbova K., Craiu D.C., Hoffman-Zacharska D., Korff C.M.,
RA Weber Y.G., Steinlin M., Gallati S., Bertsche A., Bernhard M.K.,
RA Merkenschlager A., Kiess W., Gonzalez M., Zuechner S., Palotie A., Suls A.,
RA De Jonghe P., Helbig I., Biskup S., Wolff M., Maljevic S., Schuele R.,
RA Sisodiya S.M., Weckhuysen S., Lerche H., Lemke J.R.;
RT "De novo loss- or gain-of-function mutations in KCNA2 cause epileptic
RT encephalopathy.";
RL Nat. Genet. 47:393-399(2015).
RN [18]
RP VARIANT THR-324.
RX PubMed=27864847; DOI=10.1002/humu.23149;
RG Clinical Study Group;
RA Parrini E., Marini C., Mei D., Galuppi A., Cellini E., Pucatti D.,
RA Chiti L., Rutigliano D., Bianchini C., Virdo S., De Vita D., Bigoni S.,
RA Barba C., Mari F., Montomoli M., Pisano T., Rosati A., Guerrini R.;
RT "Diagnostic targeted resequencing in 349 patients with drug-resistant
RT pediatric epilepsies identifies causative mutations in 30 different
RT genes.";
RL Hum. Mutat. 38:216-225(2017).
RN [19]
RP VARIANT DEE32 LYS-236, AND CHARACTERIZATION OF VARIANT DEE32 LYS-236.
RX PubMed=34576077; DOI=10.3390/ijms22189913;
RA Imbrici P., Conte E., Blunck R., Stregapede F., Liantonio A., Tosi M.,
RA D'Adamo M.C., De Luca A., Brankovic V., Zanni G.;
RT "A novel KCNA2 variant in a patient with non-progressive congenital ataxia
RT and epilepsy: functional characterization and sensitivity to 4-
RT aminopyridine.";
RL Int. J. Mol. Sci. 22:0-0(2021).
CC -!- FUNCTION: Voltage-gated potassium channel that mediates transmembrane
CC potassium transport in excitable membranes, primarily in the brain and
CC the central nervous system, but also in the cardiovascular system.
CC Prevents aberrant action potential firing and regulates neuronal
CC output. Forms tetrameric potassium-selective channels through which
CC potassium ions pass in accordance with their electrochemical gradient.
CC The channel alternates between opened and closed conformations in
CC response to the voltage difference across the membrane
CC (PubMed:19912772, PubMed:8495559, PubMed:11211111, PubMed:23769686).
CC Can form functional homotetrameric channels and heterotetrameric
CC channels that contain variable proportions of KCNA1, KCNA2, KCNA4,
CC KCNA5, KCNA6, KCNA7, and possibly other family members as well; channel
CC properties depend on the type of alpha subunits that are part of the
CC channel (PubMed:8495559, PubMed:20220134). Channel properties are
CC modulated by cytoplasmic beta subunits that regulate the subcellular
CC location of the alpha subunits and promote rapid inactivation of
CC delayed rectifier potassium channels. In vivo, membranes probably
CC contain a mixture of heteromeric potassium channel complexes, making it
CC difficult to assign currents observed in intact tissues to any
CC particular potassium channel family member. Homotetrameric KCNA2 forms
CC a delayed-rectifier potassium channel that opens in response to
CC membrane depolarization, followed by slow spontaneous channel closure
CC (PubMed:19912772, PubMed:23769686). In contrast, a heteromultimer
CC formed by KCNA2 and KCNA4 shows rapid inactivation (PubMed:8495559).
CC Regulates neuronal excitability and plays a role as pacemaker in the
CC regulation of neuronal action potentials (By similarity). KCNA2-
CC containing channels play a presynaptic role and prevent
CC hyperexcitability and aberrant action potential firing (By similarity).
CC Response to toxins that are selective for KCNA2-containing potassium
CC channels suggests that in Purkinje cells, dendritic subthreshold KCNA2-
CC containing potassium channels prevent random spontaneous calcium
CC spikes, suppressing dendritic hyperexcitability without hindering the
CC generation of somatic action potentials, and thereby play an important
CC role in motor coordination (By similarity). Plays a role in the
CC induction of long-term potentiation of neuron excitability in the CA3
CC layer of the hippocampus (By similarity). May function as down-stream
CC effector for G protein-coupled receptors and inhibit GABAergic inputs
CC to basolateral amygdala neurons (By similarity). May contribute to the
CC regulation of neurotransmitter release, such as gamma-aminobutyric acid
CC (GABA) (By similarity). Contributes to the regulation of the axonal
CC release of the neurotransmitter dopamine (By similarity). Reduced KCNA2
CC expression plays a role in the perception of neuropathic pain after
CC peripheral nerve injury, but not acute pain (By similarity). Plays a
CC role in the regulation of the time spent in non-rapid eye movement
CC (NREM) sleep (By similarity). {ECO:0000250|UniProtKB:P63141,
CC ECO:0000250|UniProtKB:P63142, ECO:0000269|PubMed:11211111,
CC ECO:0000269|PubMed:19912772, ECO:0000269|PubMed:20220134,
CC ECO:0000269|PubMed:23769686, ECO:0000269|PubMed:8495559, ECO:0000305}.
CC -!- ACTIVITY REGULATION: Inhibited by 4-aminopyridine (4-AP) and
CC charybdotoxin (CTX), but not by tetraethylammonium (TEA)
CC (PubMed:19912772). Inhibited by dendrotoxin (DTX) (By similarity).
CC Inhibited by tityustoxin-K alpha (TsTX-Kalpha), a toxin that is highly
CC specific for KCNA2 (By similarity). Inhibited by maurotoxin (By
CC similarity). Inhibited by kappaM conotoxins kappaM-RIIIJ and kappaM-
CC RIIIK; kappaM-RIIIJ has much higher affinity for channels containing
CC KCNA2 than kappaM-RIIIK, with the exception of heterodimers formed by
CC KCNA2 and KCNA7 where the opposite is true (PubMed:20220134).
CC {ECO:0000250|UniProtKB:P63141, ECO:0000250|UniProtKB:P63142,
CC ECO:0000269|PubMed:19912772, ECO:0000269|PubMed:20220134}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Note=Homotetrameric channels activate rapidly, i.e within a few msec,
CC but inactivation is very slow, with only a marginal decrease in
CC conductance over several seconds. The voltage-dependence of
CC activation and inactivation and other channel characteristics vary
CC depending on the experimental conditions, the expression system,
CC post-translational modifications and the presence or absence of
CC ancillary subunits. For the activation of homotetrameric channels
CC expressed in xenopus oocytes, the threshold is at about -30 mV and
CC the midpoint at about -5 mV. {ECO:0000269|PubMed:19912772};
CC -!- SUBUNIT: Homotetramer and heterotetramer with other channel-forming
CC alpha subunits, such as KCNA1, KCNA4, KCNA5, KCNA6 and KCNA7. Channel
CC activity is regulated by interaction with the beta subunits, including
CC KCNAB1 and KCNAB2. Identified in a complex with KCNA1 and KCNAB2
CC (PubMed:11086297). Identified in a complex with KCNA5 and KCNAB1 (By
CC similarity). Identified in a complex with KCNA4 and FYN (By
CC similarity). Interacts with the beta subunit KCNAB1 (PubMed:19713757).
CC Interacts with PTK2B (By similarity). Interacts (via C-terminus) with
CC CTTN (By similarity). Interacts (via N-terminal cytoplasmic domain)
CC with RHOA (GTP-bound form); this regulates channel activity by reducing
CC location at the cell surface in response to CHRM1 activation (By
CC similarity). Interacts with DRD2 (By similarity). Interacts with
CC SIGMAR1; cocaine consumption leads to increased interaction (By
CC similarity). Interacts with ADAM22 (By similarity). Interacts (via C-
CC terminus) with the PDZ domains of DLG1, DLG2 and DLG4 (By similarity).
CC Interacts with CNTNAP2 (PubMed:10624965).
CC {ECO:0000250|UniProtKB:P63141, ECO:0000250|UniProtKB:P63142,
CC ECO:0000250|UniProtKB:Q09081, ECO:0000269|PubMed:10624965,
CC ECO:0000269|PubMed:11086297, ECO:0000269|PubMed:19713757,
CC ECO:0000269|PubMed:8495559, ECO:0000305}.
CC -!- INTERACTION:
CC P16389; P49069: CAMLG; NbExp=3; IntAct=EBI-10210559, EBI-1748958;
CC P16389-2; P49069: CAMLG; NbExp=3; IntAct=EBI-11987131, EBI-1748958;
CC P16389-2; Q92520: FAM3C; NbExp=3; IntAct=EBI-11987131, EBI-2876774;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11211111,
CC ECO:0000269|PubMed:19912772, ECO:0000269|PubMed:20220134,
CC ECO:0000269|PubMed:23769686, ECO:0000269|PubMed:8495559}; Multi-pass
CC membrane protein {ECO:0000250|UniProtKB:P63142, ECO:0000305}. Membrane
CC {ECO:0000250|UniProtKB:P63142}. Cell projection, axon
CC {ECO:0000269|PubMed:16473933}. Synapse {ECO:0000250|UniProtKB:P63142}.
CC Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:P63142}. Cell
CC projection, lamellipodium membrane {ECO:0000250|UniProtKB:P63142}.
CC Synapse, synaptosome {ECO:0000250|UniProtKB:P63141}. Presynaptic cell
CC membrane {ECO:0000250|UniProtKB:P63141}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:P63141}. Cell junction, paranodal septate
CC junction {ECO:0000250|UniProtKB:P63141}. Note=KCNA2 by itself is
CC detected both at the endoplasmic reticulum and at the cell membrane.
CC Coexpression with KCNA4 or with beta subunits promotes expression at
CC the cell membrane. Coexpression with KCNA1 inhibits cell surface
CC expression. In myelinated peripheral axons, clustered in the
CC juxtaparadonal region and at an internodal line located along the
CC mesaxon and below the Schmidt-Lanterman incisures (By similarity).
CC {ECO:0000250|UniProtKB:P63141, ECO:0000250|UniProtKB:P63142}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P16389-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P16389-2; Sequence=VSP_043077;
CC -!- TISSUE SPECIFICITY: Detected in brain cortex (PubMed:16473933).
CC Detected in peroneal nerve in the juxtaparanodal regions of the node of
CC Ranvier; expression is decreased in patients with diabetes mellitus
CC that suffer from axonal neuropathy (PubMed:22649228). Detected in
CC paranodal and juxtanodal zones in myelinated spinal cord (at protein
CC level) (PubMed:11086297). {ECO:0000269|PubMed:11086297,
CC ECO:0000269|PubMed:16473933, ECO:0000269|PubMed:22649228}.
CC -!- DOMAIN: The cytoplasmic N-terminus is important for tetramerization.
CC Interactions between the different subunits modulate the gating
CC characteristics (By similarity). Besides, the cytoplasmic N-terminal
CC domain mediates interaction with RHOA and thus is required for RHOA-
CC mediated endocytosis (By similarity). {ECO:0000250|UniProtKB:P63142}.
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 -!- PTM: Phosphorylated on tyrosine residues; phosphorylation increases in
CC response to ischemia (By similarity). Phosphorylated on tyrosine
CC residues by activated PTK2B/PYK2 (By similarity). Phosphorylation on
CC tyrosine residues suppresses ion channel activity (By similarity).
CC Phosphorylated on tyrosine residues in response to CHRM1 activation;
CC this abolishes interaction with CTTN. This is probably due to
CC endocytosis of the phosphorylated channel subunits (By similarity).
CC Phosphorylated on serine residues in response to increased cAMP levels;
CC phosphorylation is apparently not catalyzed by PKA (By similarity).
CC {ECO:0000250|UniProtKB:P63142}.
CC -!- PTM: N-glycosylated, with complex, sialylated N-glycans.
CC {ECO:0000250|UniProtKB:P63142}.
CC -!- DISEASE: Developmental and epileptic encephalopathy 32 (DEE32)
CC [MIM:616366]: A form of epileptic encephalopathy, a heterogeneous group
CC of severe early-onset epilepsies characterized by refractory seizures,
CC neurodevelopmental impairment, and poor prognosis. Development is
CC normal prior to seizure onset, after which cognitive and motor delays
CC become apparent. DEE32 inheritance is autosomal dominant.
CC {ECO:0000269|PubMed:25477152, ECO:0000269|PubMed:25751627,
CC ECO:0000269|PubMed:34576077}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: The delay or D-type current observed in hippocampus
CC pyramidal neurons is probably mediated by potassium channels containing
CC KCNA2 plus KCNA1 or other family members. It is activated at about -50
CC mV, i.e. below the action potential threshold, and is characterized by
CC slow inactivation, extremely slow recovery from inactivation,
CC sensitivity to dendrotoxin (DTX) and to 4-aminopyridine (4-AP).
CC {ECO:0000305|PubMed:17917103}.
CC -!- SIMILARITY: Belongs to the potassium channel family. A (Shaker) (TC
CC 1.A.1.2) subfamily. Kv1.2/KCNA2 sub-subfamily. {ECO:0000305}.
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DR EMBL; L02752; AAA36141.1; -; mRNA.
DR EMBL; AK290061; BAF82750.1; -; mRNA.
DR EMBL; AL365361; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471122; EAW56455.1; -; Genomic_DNA.
DR EMBL; CH471122; EAW56456.1; -; Genomic_DNA.
DR EMBL; BC043564; AAH43564.1; -; mRNA.
DR CCDS; CCDS55625.1; -. [P16389-2]
DR CCDS; CCDS827.1; -. [P16389-1]
DR PIR; I77466; I77466.
DR RefSeq; NP_001191198.1; NM_001204269.1. [P16389-2]
DR RefSeq; NP_004965.1; NM_004974.3. [P16389-1]
DR RefSeq; XP_011539698.1; XM_011541396.2. [P16389-1]
DR RefSeq; XP_011539699.1; XM_011541397.2. [P16389-1]
DR RefSeq; XP_011539700.1; XM_011541398.2. [P16389-1]
DR RefSeq; XP_011539701.1; XM_011541399.2. [P16389-1]
DR RefSeq; XP_011539702.1; XM_011541400.2. [P16389-1]
DR RefSeq; XP_016856702.1; XM_017001213.1. [P16389-1]
DR AlphaFoldDB; P16389; -.
DR SMR; P16389; -.
DR BioGRID; 109940; 116.
DR CORUM; P16389; -.
DR IntAct; P16389; 3.
DR STRING; 9606.ENSP00000433109; -.
DR BindingDB; P16389; -.
DR ChEMBL; CHEMBL2086; -.
DR DrugBank; DB06637; Dalfampridine.
DR DrugBank; DB00228; Enflurane.
DR DrugBank; DB01110; Miconazole.
DR DrugBank; DB01069; Promethazine.
DR DrugCentral; P16389; -.
DR GuidetoPHARMACOLOGY; 539; -.
DR TCDB; 1.A.1.2.10; the voltage-gated ion channel (vic) superfamily.
DR GlyGen; P16389; 1 site.
DR iPTMnet; P16389; -.
DR PhosphoSitePlus; P16389; -.
DR BioMuta; KCNA2; -.
DR DMDM; 1345813; -.
DR jPOST; P16389; -.
DR MassIVE; P16389; -.
DR MaxQB; P16389; -.
DR PaxDb; P16389; -.
DR PeptideAtlas; P16389; -.
DR PRIDE; P16389; -.
DR ProteomicsDB; 53349; -. [P16389-1]
DR ProteomicsDB; 53350; -. [P16389-2]
DR ABCD; P16389; 3 sequenced antibodies.
DR Antibodypedia; 4539; 291 antibodies from 31 providers.
DR DNASU; 3737; -.
DR Ensembl; ENST00000316361.10; ENSP00000314520.4; ENSG00000177301.16. [P16389-1]
DR Ensembl; ENST00000369770.7; ENSP00000358785.3; ENSG00000177301.16. [P16389-2]
DR Ensembl; ENST00000485317.6; ENSP00000433109.1; ENSG00000177301.16. [P16389-1]
DR Ensembl; ENST00000633222.1; ENSP00000487785.1; ENSG00000177301.16. [P16389-1]
DR Ensembl; ENST00000638532.1; ENSP00000491613.1; ENSG00000177301.16. [P16389-1]
DR Ensembl; ENST00000638616.2; ENSP00000491977.1; ENSG00000177301.16. [P16389-1]
DR Ensembl; ENST00000675391.1; ENSP00000502642.1; ENSG00000177301.16. [P16389-1]
DR GeneID; 3737; -.
DR KEGG; hsa:3737; -.
DR MANE-Select; ENST00000316361.10; ENSP00000314520.4; NM_004974.4; NP_004965.1.
DR UCSC; uc009wfv.2; human. [P16389-1]
DR CTD; 3737; -.
DR DisGeNET; 3737; -.
DR GeneCards; KCNA2; -.
DR HGNC; HGNC:6220; KCNA2.
DR HPA; ENSG00000177301; Tissue enriched (brain).
DR MalaCards; KCNA2; -.
DR MIM; 176262; gene.
DR MIM; 616366; phenotype.
DR neXtProt; NX_P16389; -.
DR OpenTargets; ENSG00000177301; -.
DR Orphanet; 442835; Non-specific early-onset epileptic encephalopathy.
DR PharmGKB; PA206; -.
DR VEuPathDB; HostDB:ENSG00000177301; -.
DR eggNOG; KOG1545; Eukaryota.
DR GeneTree; ENSGT00940000158688; -.
DR InParanoid; P16389; -.
DR OMA; HPLDYDP; -.
DR OrthoDB; 695337at2759; -.
DR PhylomeDB; P16389; -.
DR TreeFam; TF313103; -.
DR PathwayCommons; P16389; -.
DR Reactome; R-HSA-1296072; Voltage gated Potassium channels.
DR SignaLink; P16389; -.
DR BioGRID-ORCS; 3737; 19 hits in 1065 CRISPR screens.
DR ChiTaRS; KCNA2; human.
DR GeneWiki; KCNA2; -.
DR GenomeRNAi; 3737; -.
DR Pharos; P16389; Tclin.
DR PRO; PR:P16389; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P16389; protein.
DR Bgee; ENSG00000177301; Expressed in Brodmann (1909) area 23 and 143 other tissues.
DR ExpressionAtlas; P16389; baseline and differential.
DR Genevisible; P16389; HS.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0043194; C:axon initial segment; IEA:Ensembl.
DR GO; GO:0043679; C:axon terminus; ISS:UniProtKB.
DR GO; GO:0044305; C:calyx of Held; IEA:Ensembl.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IBA:GO_Central.
DR GO; GO:0005887; C:integral component of plasma membrane; IMP:UniProtKB.
DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl.
DR GO; GO:0044224; C:juxtaparanode region of axon; ISS:BHF-UCL.
DR GO; GO:0030027; C:lamellipodium; ISS:UniProtKB.
DR GO; GO:0031258; C:lamellipodium membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0032809; C:neuronal cell body membrane; ISS:UniProtKB.
DR GO; GO:0033010; C:paranodal junction; IEA:UniProtKB-SubCell.
DR GO; GO:0043204; C:perikaryon; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; IDA:UniProtKB.
DR GO; GO:0005251; F:delayed rectifier potassium channel activity; ISS:UniProtKB.
DR GO; GO:0019894; F:kinesin binding; IEA:Ensembl.
DR GO; GO:0015271; F:outward rectifier potassium channel activity; IEA:Ensembl.
DR GO; GO:0005267; F:potassium channel activity; TAS:ProtInc.
DR GO; GO:0005249; F:voltage-gated potassium channel activity; IMP:UniProtKB.
DR GO; GO:0019228; P:neuronal action potential; ISS:UniProtKB.
DR GO; GO:0021633; P:optic nerve structural organization; IEA:Ensembl.
DR GO; GO:0097623; P:potassium ion export across plasma membrane; IEA:Ensembl.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:0006813; P:potassium ion transport; TAS:ProtInc.
DR GO; GO:0051260; P:protein homooligomerization; IEA:InterPro.
DR GO; GO:0045188; P:regulation of circadian sleep/wake cycle, non-REM sleep; IEA:Ensembl.
DR GO; GO:0014059; P:regulation of dopamine secretion; ISS:UniProtKB.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR GO; GO:0019233; P:sensory perception of pain; ISS:UniProtKB.
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; IPR003972; K_chnl_volt-dep_Kv1.
DR InterPro; IPR004049; K_chnl_volt-dep_Kv1.2.
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 PANTHER; PTHR11537:SF23; PTHR11537:SF23; 1.
DR Pfam; PF02214; BTB_2; 1.
DR Pfam; PF00520; Ion_trans; 1.
DR PRINTS; PR01509; KV12CHANNEL.
DR PRINTS; PR01491; KVCHANNEL.
DR PRINTS; PR01496; SHAKERCHANEL.
DR SMART; SM00225; BTB; 1.
DR SUPFAM; SSF54695; SSF54695; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell junction; Cell membrane; Cell projection;
KW Disease variant; Endoplasmic reticulum; Epilepsy; Glycoprotein;
KW Ion channel; Ion transport; Lipoprotein; Membrane; Palmitate;
KW Phosphoprotein; Potassium; Potassium channel; Potassium transport;
KW Reference proteome; Synapse; Synaptosome; Transmembrane;
KW Transmembrane helix; Transport; Voltage-gated channel.
FT CHAIN 1..499
FT /note="Potassium voltage-gated channel subfamily A member
FT 2"
FT /id="PRO_0000053972"
FT TOPO_DOM 1..160
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 161..182
FT /note="Helical; Name=Segment S1"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 183..221
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 222..243
FT /note="Helical; Name=Segment S2"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 244..254
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 255..275
FT /note="Helical; Name=Segment S3"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 276..289
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 290..310
FT /note="Helical; Voltage-sensor; Name=Segment S4"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 311..325
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 326..347
FT /note="Helical; Name=Segment S5"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 348..361
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT INTRAMEM 362..373
FT /note="Helical; Name=Pore helix"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT INTRAMEM 374..381
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 382..388
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TRANSMEM 389..417
FT /note="Helical; Name=Segment S6"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT TOPO_DOM 418..499
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT REGION 1..125
FT /note="Tetramerization domain"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT REGION 1..26
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 312..325
FT /note="S4-S5 linker"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT MOTIF 374..379
FT /note="Selectivity filter"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT MOTIF 497..499
FT /note="PDZ-binding"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT SITE 252
FT /note="Important for normal, slow channel gating"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT SITE 381
FT /note="Important for binding with the scorpion
FT mesomartoxin; when the scorpion mesomartoxin-rKv1.2/KCNA2
FT interaction is modeled, this residue is close to the 'Y-57'
FT residue of the toxin"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT MOD_RES 429
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P63141"
FT MOD_RES 434
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P63141"
FT MOD_RES 440
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P63141"
FT MOD_RES 441
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q09081"
FT MOD_RES 449
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q09081"
FT MOD_RES 458
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P63142"
FT MOD_RES 468
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P63141"
FT LIPID 244
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000255"
FT CARBOHYD 207
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 299..499
FT /note="VRVFRIFKLSRHSKGLQILGQTLKASMRELGLLIFFLFIGVILFSSAVYFAE
FT ADERESQFPSIPDAFWWAVVSMTTVGYGDMVPTTIGGKIVGSLCAIAGVLTIALPVPVI
FT VSNFNYFYHRETEGEEQAQYLQVTSCPKIPSSPDLKKSRSASTISKSDYMEIQEGVNNS
FT NEDFREENLKTANCTLANTNYVNITKMLTDV -> ERRPLQSQKSKRGRQHLNTSHDCT
FT LGINLVAGMTVQWTRASGPDDRQTPAVTTLHRMY (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_043077"
FT VARIANT 236
FT /note="E -> K (in DEE32; affects channel activity; mutant
FT channels display voltage-dependent activation significantly
FT shifted toward negative potentials compared to wild-type;
FT no effect on channel sensitivity to 4-aminopyridine)"
FT /evidence="ECO:0000269|PubMed:34576077"
FT /id="VAR_085682"
FT VARIANT 263
FT /note="I -> T (in DEE32; dominant-negative mutation; loss
FT of channel function; dbSNP:rs786205231)"
FT /evidence="ECO:0000269|PubMed:25751627"
FT /id="VAR_073704"
FT VARIANT 297
FT /note="R -> Q (in DEE32; causes a gain of function;
FT dbSNP:rs786205232)"
FT /evidence="ECO:0000269|PubMed:25477152,
FT ECO:0000269|PubMed:25751627"
FT /id="VAR_073705"
FT VARIANT 298
FT /note="L -> F (in DEE32; causes a gain of function;
FT dbSNP:rs876657390)"
FT /evidence="ECO:0000269|PubMed:25751627"
FT /id="VAR_073706"
FT VARIANT 324
FT /note="S -> T (probable disease-associated variant found in
FT a patient with drug-resistant epilepsy)"
FT /evidence="ECO:0000269|PubMed:27864847"
FT /id="VAR_078206"
FT VARIANT 405
FT /note="P -> L (in DEE32; loss of channel function;
FT dbSNP:rs876657389)"
FT /evidence="ECO:0000269|PubMed:25751627"
FT /id="VAR_073707"
FT CONFLICT 230
FT /note="I -> V (in Ref. 2; BAF82750)"
FT /evidence="ECO:0000305"
SQ 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
