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 24-JAN-2024, entry version 216. 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). Interacts with ADAM11 (By CC similarity). {ECO:0000250|UniProtKB:P63141, CC ECO:0000250|UniProtKB:P63142, ECO:0000250|UniProtKB:Q09081, CC ECO:0000269|PubMed:10624965, ECO:0000269|PubMed:11086297, CC ECO:0000269|PubMed:19713757, 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 a voltage-sensor and CC is 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. DR RefSeq; XP_011539700.1; XM_011541398.2. [P16389-1] DR RefSeq; XP_011539701.1; XM_011541399.2. 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.ENSP00000487785; -. 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 GlyCosmos; P16389; 1 site, No reported glycans. 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; 9606-ENSP00000433109; -. DR PeptideAtlas; P16389; -. DR ProteomicsDB; 53349; -. [P16389-1] DR ProteomicsDB; 53350; -. [P16389-2] DR ABCD; P16389; 3 sequenced antibodies. DR Antibodypedia; 4539; 312 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 AGR; HGNC:6220; -. DR CTD; 3737; -. DR DisGeNET; 3737; -. DR GeneCards; KCNA2; -. DR HGNC; HGNC:6220; KCNA2. DR HPA; ENSG00000177301; Group enriched (brain, retina). 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; NDEDEMH; -. DR OrthoDB; 1478695at2759; -. 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; 20 hits in 1155 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 144 other cell types or 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:0098978; C:glutamatergic synapse; 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; IMP:UniProtKB. DR GO; GO:0045211; C:postsynaptic membrane; IEA:Ensembl. DR GO; GO:0042734; C:presynaptic membrane; IEA:UniProtKB-SubCell. 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:1905030; F:voltage-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential; IEA:Ensembl. DR GO; GO:0099508; F:voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential; IEA:Ensembl. DR GO; GO:0005249; F:voltage-gated potassium channel activity; IMP:UniProtKB. DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl. DR GO; GO:0022038; P:corpus callosum development; IEA:Ensembl. 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:0019233; P:sensory perception of pain; ISS:UniProtKB. DR Gene3D; 1.10.287.70; -; 1. DR Gene3D; 1.20.120.350; Voltage-gated potassium channels. Chain C; 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; IPR027359; Volt_channel_dom_sf. DR PANTHER; PTHR11537:SF23; POTASSIUM VOLTAGE-GATED CHANNEL SUBFAMILY A MEMBER 2; 1. DR PANTHER; PTHR11537; VOLTAGE-GATED POTASSIUM CHANNEL; 1. DR Pfam; PF02214; BTB_2; 1. DR Pfam; PF00520; Ion_trans; 1. DR PRINTS; PR00169; KCHANNEL. DR PRINTS; PR01509; KV12CHANNEL. DR PRINTS; PR01491; KVCHANNEL. DR PRINTS; PR01496; SHAKERCHANEL. DR SMART; SM00225; BTB; 1. DR SUPFAM; SSF54695; POZ domain; 1. DR SUPFAM; SSF81324; Voltage-gated potassium channels; 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 (found in a patient with drug-resistant FT epilepsy; likely pathogenic)" 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 //