KCNA2_CANLF
ID KCNA2_CANLF Reviewed; 499 AA.
AC Q28293;
DT 24-MAY-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 131.
DE RecName: Full=Potassium voltage-gated channel subfamily A member 2;
DE AltName: Full=CSMK1;
DE AltName: Full=Voltage-gated potassium channel subunit Kv1.2;
GN Name=KCNA2;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Colon smooth muscle;
RX PubMed=8415758; DOI=10.1073/pnas.90.20.9659;
RA Hart P.J., Overturf K.E., Russell S.N., Carl A., Hume J.R., Sanders K.M.,
RA Horowitz B.;
RT "Cloning and expression of a Kv1.2 class delayed rectifier K+ channel from
RT canine colonic smooth muscle.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:9659-9663(1993).
RN [2]
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).
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:8415758). Can form functional homotetrameric channels and
CC heterotetrameric channels that contain variable proportions of KCNA1,
CC KCNA2, KCNA4, KCNA5, KCNA6, KCNA7, and possibly other family members as
CC well; channel properties depend on the type of alpha subunits that are
CC part of the channel (By similarity). Channel properties are modulated
CC by cytoplasmic beta subunits that regulate the subcellular location of
CC the alpha subunits and promote rapid inactivation of delayed rectifier
CC potassium channels (By similarity). In vivo, membranes probably contain
CC 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:8415758). In contrast, a heteromultimer formed by KCNA2 and
CC KCNA4 shows rapid inactivation (By similarity). Regulates neuronal
CC excitability and plays a role as pacemaker in the regulation of
CC neuronal action potentials (By similarity). KCNA2-containing channels
CC play a presynaptic role and prevent hyperexcitability and aberrant
CC action potential firing (By similarity). Response to toxins that are
CC selective for KCNA2-containing potassium channels suggests that in
CC Purkinje cells, dendritic subthreshold KCNA2-containing potassium
CC channels prevent random spontaneous calcium spikes, suppressing
CC dendritic hyperexcitability without hindering the generation of somatic
CC action potentials, and thereby play an important role in motor
CC coordination (By similarity). Plays a role in the induction of long-
CC term potentiation of neuron excitability in the CA3 layer of the
CC hippocampus (By similarity). May function as down-stream effector for G
CC protein-coupled receptors and inhibit GABAergic inputs to basolateral
CC amygdala neurons (By similarity). May contribute to the regulation of
CC neurotransmitter release, such as gamma-aminobutyric acid (GABA) (By
CC similarity). Contributes to the regulation of the axonal release of the
CC neurotransmitter dopamine (By similarity). Reduced KCNA2 expression
CC plays a role in the perception of neuropathic pain after peripheral
CC nerve injury, but not acute pain (By similarity). Plays a role in the
CC regulation of the time spent in non-rapid eye movement (NREM) sleep (By
CC similarity). {ECO:0000250|UniProtKB:P63141,
CC ECO:0000250|UniProtKB:P63142, ECO:0000269|PubMed:8415758}.
CC -!- ACTIVITY REGULATION: Inhibited by 4-aminopyridine (4-AP)
CC (PubMed:8415758). Inhibited by dendrotoxin (DTX) and charybdotoxin
CC (CTX), but not by tetraethylammonium (TEA) (By similarity). Inhibited
CC by tityustoxin-K alpha (TsTX-Kalpha), a toxin that is highly specific
CC for KCNA2 (By similarity). Inhibited by maurotoxin (By similarity).
CC Inhibited by kappaM conotoxins kappaM-RIIIJ and kappaM-RIIIK (By
CC similarity). {ECO:0000250|UniProtKB:P16389,
CC ECO:0000250|UniProtKB:P63142, ECO:0000269|PubMed:8415758}.
CC -!- SUBUNIT: Homotetramer and heterotetramer with other channel-forming
CC alpha subunits, such as KCNA1, KCNA4, KCNA5, KCNA6 and KCNA7 (By
CC similarity). Channel activity is regulated by interaction with the beta
CC subunits, including KCNAB1 and KCNAB2 (By similarity). Identified in a
CC complex with KCNA1 and KCNAB2 (By similarity). Identified in a complex
CC with KCNA5 and KCNAB1 (By similarity). Interacts with the beta subunit
CC KCNAB1 (By similarity). Identified in a complex with KCNA4 and FYN (By
CC similarity). Interacts with PTK2B (By similarity). Interacts (via C-
CC terminus) with CTTN (By similarity). Interacts (via N-terminal
CC cytoplasmic domain) with RHOA (GTP-bound form); this regulates channel
CC activity by reducing location at the cell surface in response to CHRM1
CC activation (By similarity). Interacts with DRD2 (By similarity).
CC Interacts with SIGMAR1; cocaine consumption leads to increased
CC interaction (By similarity). Interacts with ADAM22 (By similarity).
CC Interacts with CNTNAP2 (By similarity). Interacts (via C-terminus) with
CC the PDZ domains of DLG1, DLG2 and DLG4 (By similarity).
CC {ECO:0000250|UniProtKB:P16389, ECO:0000250|UniProtKB:P63141,
CC ECO:0000250|UniProtKB:P63142, ECO:0000250|UniProtKB:Q09081}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:8415758};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:P63142,
CC ECO:0000305}. Membrane {ECO:0000250|UniProtKB:P63142}. Cell projection,
CC axon {ECO:0000250|UniProtKB:P63142}. Synapse
CC {ECO:0000250|UniProtKB:P63142}. Presynaptic cell membrane
CC {ECO:0000250|UniProtKB:P63141}. Synapse, synaptosome
CC {ECO:0000250|UniProtKB:P63141}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P63142}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:P63141}. Cell projection, lamellipodium membrane
CC {ECO:0000250|UniProtKB:P63142}. 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 -!- TISSUE SPECIFICITY: Expressed in a wide variety of gastrointestinal
CC smooth muscles. Not expressed in portal vein, renal artery, and uterus.
CC {ECO:0000269|PubMed:8415758}.
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 -!- 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; L19740; AAA03607.1; -; mRNA.
DR PIR; A48672; A48672.
DR RefSeq; NP_001003329.1; NM_001003329.1.
DR AlphaFoldDB; Q28293; -.
DR SMR; Q28293; -.
DR STRING; 9612.ENSCAFP00000029266; -.
DR PaxDb; Q28293; -.
DR GeneID; 404022; -.
DR KEGG; cfa:404022; -.
DR CTD; 3737; -.
DR eggNOG; KOG1545; Eukaryota.
DR InParanoid; Q28293; -.
DR OrthoDB; 695337at2759; -.
DR Proteomes; UP000002254; Unplaced.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0043679; C:axon terminus; ISS:UniProtKB.
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; ISS:UniProtKB.
DR GO; GO:0044224; C:juxtaparanode region of axon; ISS:UniProtKB.
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:0042734; C:presynaptic membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; ISS:UniProtKB.
DR GO; GO:0005251; F:delayed rectifier potassium channel activity; ISS:UniProtKB.
DR GO; GO:0005249; F:voltage-gated potassium channel activity; ISS:UniProtKB.
DR GO; GO:0019228; P:neuronal action potential; ISS:UniProtKB.
DR GO; GO:0071805; P:potassium ion transmembrane transport; ISS:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IEA:InterPro.
DR GO; GO: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 2: Evidence at transcript level;
KW Cell junction; Cell membrane; Cell projection; Endoplasmic reticulum;
KW Glycoprotein; 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_0000053971"
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..27
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"
SQ SEQUENCE 499 AA; 56607 MW; 394FDA7D04CA8EC8 CRC64;
MTVATGEPAD EAAALPGHPQ DTYDPEADHE CCERVVTNIS GLRFETQLKT LAQFPETLLG
DPKKRMRFFD PLRNEIFFVR NRPSFDAILY YYQSGGRLRR PVNVPLDIFS EEIRFYELGE
EAMEMFREDE GYIKEEERPL PENEFQRQVW LLFEYPESSG PARIIAIVSV MVILISIVSF
CLETLPIFRD ENEDMHGGGV 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
