KCNA1

KCNA1
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2AFL
Identifikatori
Aliasi	KCNA1
Vanjski ID-jevi	OMIM: 176260 MGI: 96654 HomoloGene: 183 GeneCards: KCNA1
Lokacija gena (čovjek)
Hrom.	Hromosom 12 (čovjek)
Kraj	4,918,256 bp
Lokacija gena (miš)
Hrom.	Hromosom 6 (miš)
Kraj	126,623,347 bp
Ontologija gena
Molekularna funkcija	• potassium channel activity; • delayed rectifier potassium channel activity; • voltage-gated ion channel activity; • GO:0015388 potassium ion transmembrane transporter activity; • ion channel activity; • GO:0001948, GO:0016582 vezivanje za proteine; • voltage-gated potassium channel activity; • disordered domain specific binding; • voltage-gated ion channel activity involved in regulation of presynaptic membrane potential; • voltage-gated ion channel activity involved in regulation of postsynaptic membrane potential;
Ćelijska komponenta	• axon terminus; • juxtaparanode region of axon; • integral component of membrane; • citosol; • perikaryon; • projekcija ćelije; • membrana; • ćelijska membrana; • sinapsa; • integral component of plasma membrane; • cell surface; • međućelijske veze; • soma; • dendrit; • Akson; • potassium channel complex; • apical plasma membrane; • Endoplazmatski retikulum; • paranode region of axon; • presynaptic membrane; • GO:0016023 citoplazmatska vezikula; • voltage-gated potassium channel complex; • calyx of Held; • glutamatergic synapse; • integral component of postsynaptic membrane; • integral component of presynaptic membrane;
Biološki proces	• regulation of muscle contraction; • detection of mechanical stimulus involved in sensory perception of pain; • cellular response to magnesium ion; • startle response; • regulation of membrane potential; • cell communication by electrical coupling; • neuronal signal transduction; • regulation of ion transmembrane transport; • ion transport; • magnesium ion homeostasis; • potassium ion transport; • brain development; • neuromuscular process; • transmembrane transport; • potassium ion transmembrane transport; • neuroblast proliferation; • detection of mechanical stimulus involved in sensory perception of touch; • protein homooligomerization; • hippocampus development; • neuronal action potential; • chemical synaptic transmission; • positive regulation of voltage-gated potassium channel activity; • regulation of postsynaptic membrane potential; • regulation of presynaptic membrane potential;
	Izvori:Amigo / QuickGO
Ortolozi
	3736
	16485
	ENSG00000111262
	ENSMUSG00000047976
	Q09470
	P16388
	NM_000217
	NM_010595
	NP_000208
	NP_034725
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Član 1 potporodice A kalijevog naponskog kanala, znan i kao K_v1.1 je gen vezan s tresalicom, kalijev kanal s naponskim upravljanjem, koji je kod ljudi kodiran genom KCNA1.^[5]^[6]^[7] Isaacov sindrom jest posljedica autoimunske reakcije protiv K_v1.1 knalskih iona.^[8]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 495 aminokiselina, a molekulska težina 56.466 Da.^[9].

10	20	30	40	50
MTVMSGENVD	EASAAPGHPQ	DGSYPRQADH	DDHECCERVV	INISGLRFET
QLKTLAQFPN	TLLGNPKKRM	RYFDPLRNEY	FFDRNRPSFD	AILYYYQSGG
RLRRPVNVPL	DMFSEEIKFY	ELGEEAMEKF	REDEGFIKEE	ERPLPEKEYQ
RQVWLLFEYP	ESSGPARVIA	IVSVMVILIS	IVIFCLETLP	ELKDDKDFTG
TVHRIDNTTV	IYNSNIFTDP	FFIVETLCII	WFSFELVVRF	FACPSKTDFF
KNIMNFIDIV	AIIPYFITLG	TEIAEQEGNQ	KGEQATSLAI	LRVIRLVRVF
RIFKLSRHSK	GLQILGQTLK	ASMRELGLLI	FFLFIGVILF	SSAVYFAEAE
EAESHFSSIP	DAFWWAVVSM	TTVGYGDMYP	VTIGGKIVGS	LCAIAGVLTI
ALPVPVIVSN	FNYFYHRETE	GEEQAQLLHV	SSPNLASDSD	LSRRSSSTMS
KSEYMEIEED	MNNSIAHYRQ	VNIRTANCTT	ANQNCVNKSK	LLTDV

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Genomika

Gen se nalazi na Watsonovom (plus) lancu kratkog kraka hromosoma 12 (12p13.32). Dug je 8.348 baznih parova i kodira protein od 495 aminokiselina (predviđena molekulska težina 56.466 kD).

Alternativni nazivi

Preporučeni naziv za ovaj protein je potporodica kanala s kalijevim naponom, član 1, ali u literaturi je korišten niz alternativa, uključujući HuK1 (ljudski K⁺kanal I), RBK1 (rubidij kalijev kanal 1), kanal MBK (mišji mozak K⁺), kalijev kanal s naponom, HBK1, podjedinica kalijevog kanala s naponom, K_vkanal 1.1, K⁺ kanal HuKI i AEMK (povezan sa miokimijom sa periodičnom ataksijom).

Struktura

Vjeruje se da protein ima šest domena (S1-S6) sa petljom između S5 i S6 koja formira pore kanala. Ova regija također ima očuvani motiv filtera selektivnosti. Funkcionalni kanal je homotetramer. N-kraj proteina asocira na β podjedinice. Ove podjedinice reguliraju inaktivaciju kanala, kao i njegovu ekspresiju. C-terminal je povezan sa PDZ-domenskim proteinom, uključenim u ciljanje kanala^[10]^[11]

Editiranje RNK

Pre-iRNK ovog proteina podliježe editiranju RNK.^[12]

Tip

Editiranje RNK iz A u I katalizira porodica adenozin-deaminaza koja djeluje na RNK (ADAR) koje specifično prepoznaju adenozine unutar dvolančanih regija pre-iRNK (npr. editiranje RNK iz kalijevog kanalnog signala) i deaminira ih na inozin. U mehanizmima za ćelijsku translaciju, inozini su prepoznati kao gvanozin. Tri su člana ADAR porodice: ADAR 1-3, pri čemu su ADAR1 i ADAR2 jedini enzimski aktivni članovi. Smatra se da u mozgu ADAR3 ima regulatornu ulogu. ADAR1 i ADAR2 su široko eksprimirani u tkivima, dok je ADAR3 ograničen na mozak. Dvolančane regije RNK nastaju uparivanjem baza između ostataka u regiji blizu mjesta editiranja s ostacima obično u susjednom intronu, ali ponekad mogu biti i egzonska sekvenca. Područje uparivanja baza sa regijom editiranje poznato je kao editiranje komplementarne sekvence (eng. Editing Complementary Sequence: ECS).

Lokacija

Modifikovani ostatak se nalazi u aminokiselini 400 konačnog proteina. Ovo se nalazi u šestoj transmembrana regiji koja odgovara unutrašnjem predvorju pora. Struktura ukosnice sa matičnom omčom posreduje u editiranju RNK. Preferirani enzim za editiranje na I/V mjestu vjerovatno je ADAR2. Eitiranje rezultira promjenom kodona iz ATT u GTT, što rezultira promjenom aminokiseline iz izoleucina u valin. Glavni enzim za editiranje je enzim ADAR2. Program MFOLD je predvidio da će minimalno područje potrebno za editiranje formirati nesavršeno obrnuto ponavljanje ukosnica. Ova regija se sastoji od 114 parova baza. Slične regije identificirane su kod miševa i pacova. Editirani adenozin nalazi se u dupleksnoj regiji od šest parova baza. Eksperiment mutacije u tom području blizu dupleksa pokazao je da su specifične baze u ovoj regiji također bitne za početak editiranja. Područje potrebno za uređivanje neobično je po tome što strukturu ukosnice tvore samo egzonske sekvence. U većini editiranja A do I, ECS nalazi se unutar intronske sekvence.^[12]

Editirana regija je visoko konzervirana kod lignji, vinskih mušica, miševa i pacova.^[12]

Regulacija

Razine editiranja se razlikuju u različitim tkivima: 17% u repnom jezgru, 68% u kičmenoj i 77% u produženoj moždini.^[13]

Struktura

Editiranje rezultira promjenom kodona (I/V) iz (ATT) u (GTT) što na mjestu editiranja mijenja translaciju izoleucina u valin. Valin ima duži bočni lanac. Editiranje RNK na ovoj poziciji događa se kod visoko konzerviranih pora ionskih provodnih kanala. To može uticati na ulogu kanala u procesu brze inaktivacije.^[14]

Funkcija

Kalijevi kanali ovisni o naponu moduliraju ekscitabilnost, otvaranjem i zatvaranjem selektivnih pora za kalij, kao odgovor na napon. Protok kalijevih iona prekida se interakcijom inaktivirajuće čestice, pomoćnog proteina kod ljudi, ali unutrašnjeg dijela kanala kod drugih vrsta. Smatra se da promjena aminokiseline I u V narušava hidrofobnu interakciju između inaktivirajuće čestice i obloge pora. Time se prekida proces brze inaktivacije. Editiranje RNK ne utiče na kinetiku aktivacije. Promjene u kinetici inaktivacije utiču na trajanje i učestalost akcijskog potencijala. Editirani kanal propuđta više struje i ima kraći akcijski potencijal od neuređenog tipa, zbog nemogućnosti inaktivirajuće čestice da stupi u interakciju s ostatkom u porama kanala koji provode ione, što je utvrđeno elektrofiziološkom analizom.^[15] Smanjuje se vrijeme depolarizacije membrane, što također smanjuje efikasnost otpuštanja odašiljača.^[13] Budući da editiranje može uzrokovati promjene aminokiselina u 1- 4 u tetramerima kalijevih kanala, to može imati različite efekte na inaktivaciju kanala.

Disregulacija

Poznato je da promjene u procesu brze inaktivacije imaju etološke i nervne posljedice in vivo.^[12]

Klinički značaj

Mutacije u ovom genu uzrokuju epizodnu ataksiju tip 1.

Također pogledajte

GABRA3 - podjedinica kanala koja prolazi kroz slično editiranje RNK

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000111262 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000047976 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Curran ME, Landes GM, Keating MT (1992). "Molecular cloning, characterization, and genomic localization of a human potassium channel gene". Genomics. 12 (4): 729–37. doi:10.1016/0888-7543(92)90302-9. PMID 1349297.
^ Albrecht B, Weber K, Pongs O (1995). "Characterization of a voltage-activated K-channel gene cluster on human chromosome 12p13". Recept. Channels. 3 (3): 213–20. PMID 8821794.
^ Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stühmer W, Wang X (2005). "International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels". Pharmacol. Rev. 57 (4): 473–508. doi:10.1124/pr.57.4.10. PMID 16382104. S2CID 219195192.
^ Newsom-Davis J (1997). "Autoimmune neuromyotonia (Isaacs' syndrome): an antibody-mediated potassium channelopathy". Ann. N. Y. Acad. Sci. 835 (1): 111–9. Bibcode:1997NYASA.835..111N. doi:10.1111/j.1749-6632.1997.tb48622.x. PMID 9616766. S2CID 13231594.^{[trajno mrtav link]}
^ "UniProt, Q09470". Pristupljeno 10. 8. 2021.
^ "Entrez Gene: KCNA1 potassium voltage-gated channel".
^ "KCNA1 - Potassium voltage-gated channel subfamily A member 1 - Homo sapiens (Human) - KCNA1 gene & protein". www.uniprot.org.
^ ^a ^b ^c ^d Bhalla T, Rosenthal JJ, Holmgren M, Reenan R (oktobar 2004). "Control of human potassium channel inactivation by editing of a small mRNA hairpin". Nat. Struct. Mol. Biol. 11 (10): 950–6. doi:10.1038/nsmb825. PMID 15361858. S2CID 34081059.
^ ^a ^b Hoopengardner B, Bhalla T, Staber C, Reenan R (august 2003). "Nervous system targets of RNA editing identified by comparative genomics". Science. 301 (5634): 832–6. Bibcode:2003Sci...301..832H. doi:10.1126/science.1086763. PMID 12907802. S2CID 782642.
^ Bhalla, Tarun; Rosenthal, Joshua J C; Holmgren, Miguel; Reenan, Robert (2004). "Control of human potassium channel inactivation by editing of a small mRNA hairpin". Nature Structural & Molecular Biology. 11 (10): 950–956. doi:10.1038/nsmb825. ISSN 1545-9993. PMID 15361858. S2CID 34081059.
^ Bezanilla, Francisco (2004). "RNA editing of a human potassium channel modifies its inactivation". Nature Structural & Molecular Biology. 11 (10): 915–916. doi:10.1038/nsmb1004-915. ISSN 1545-9993. PMID 15452561. S2CID 40545616.

Dopunska literatura

Grunnet M, Rasmussen HB, Hay-Schmidt A, et al. (2003). "KCNE4 is an inhibitory subunit to Kv1.1 and Kv1.3 potassium channels". Biophys. J. 85 (3): 1525–37. Bibcode:2003BpJ....85.1525G. doi:10.1016/S0006-3495(03)74585-8. PMC 1303329. PMID 12944270.
Nie DY, Zhou ZH, Ang BT, et al. (2003). "Nogo-A at CNS paranodes is a ligand of Caspr: possible regulation of K(+) channel localization". EMBO J. 22 (21): 5666–78. doi:10.1093/emboj/cdg570. PMC 275427. PMID 14592966.
Imbrici P, Cusimano A, D'Adamo MC, et al. (2003). "Functional characterization of an episodic ataxia type-1 mutation occurring in the S1 segment of hKv1.1 channels". Pflügers Arch. 446 (3): 373–9. doi:10.1007/s00424-002-0962-2. PMID 12799903. S2CID 21478393.
Glaudemans B, van der Wijst J, Scola RH, et al. (2009). "A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia". J. Clin. Invest. 119 (4): 936–42. doi:10.1172/JCI36948. PMC 2662556. PMID 19307729.
Shook SJ, Mamsa H, Jen JC, et al. (2008). "Novel mutation in KCNA1 causes episodic ataxia with paroxysmal dyspnea". Muscle Nerve. 37 (3): 399–402. doi:10.1002/mus.20904. PMID 17912752. S2CID 26175513.
Gubitosi-Klug RA, Mancuso DJ, Gross RW (2005). "The human Kv1.1 channel is palmitoylated, modulating voltage sensing: Identification of a palmitoylation consensus sequence". Proc. Natl. Acad. Sci. U.S.A. 102 (17): 5964–8. Bibcode:2005PNAS..102.5964G. doi:10.1073/pnas.0501999102. PMC 1087951. PMID 15837928.
Zhang ZH, Rhodes KJ, Childers WE, et al. (2004). "Disinactivation of N-type inactivation of voltage-gated K channels by an erbstatin analogue". J. Biol. Chem. 279 (28): 29226–30. doi:10.1074/jbc.M403290200. PMID 15136567.
Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
Jow F, Zhang ZH, Kopsco DC, et al. (2004). "Functional coupling of intracellular calcium and inactivation of voltage-gated Kv1.1/Kvbeta1.1 A-type K+ channels". Proc. Natl. Acad. Sci. U.S.A. 101 (43): 15535–40. Bibcode:2004PNAS..10115535J. doi:10.1073/pnas.0402081101. PMC 524431. PMID 15486093.
Imbrici P, Grottesi A, D'Adamo MC, et al. (2009). "Contribution of the central hydrophobic residue in the PXP motif of voltage-dependent K+ channels to S6 flexibility and gating properties". Channels (Austin). 3 (1): 39–45. doi:10.4161/chan.3.1.7548. PMID 19202350.
Kinali M, Jungbluth H, Eunson LH, et al. (2004). "Expanding the phenotype of potassium channelopathy: severe neuromyotonia and skeletal deformities without prominent Episodic Ataxia". Neuromuscul. Disord. 14 (10): 689–93. doi:10.1016/j.nmd.2004.06.007. PMID 15351427. S2CID 44972020.
Demos MK, Macri V, Farrell K, et al. (2009). "A novel KCNA1 mutation associated with global delay and persistent cerebellar dysfunction". Mov. Disord. 24 (5): 778–82. doi:10.1002/mds.22467. PMID 19205071. S2CID 25655998.
Imbrici P, Gualandi F, D'Adamo MC, et al. (2008). "A novel KCNA1 mutation identified in an Italian family affected by episodic ataxia type 1". Neuroscience. 157 (3): 577–87. doi:10.1016/j.neuroscience.2008.09.022. PMID 18926884. S2CID 15772885.
Tan KM, Lennon VA, Klein CJ, et al. (2008). "Clinical spectrum of voltage-gated potassium channel autoimmunity". Neurology. 70 (20): 1883–90. doi:10.1212/01.wnl.0000312275.04260.a0. PMID 18474843. S2CID 34815377.
Chen H, von Hehn C, Kaczmarek LK, et al. (2007). "Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia". Neurogenetics. 8 (2): 131–5. doi:10.1007/s10048-006-0071-z. PMC 1820748. PMID 17136396.
Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Gutman GA, Chandy KG, Grissmer S, et al. (2005). "International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels". Pharmacol. Rev. 57 (4): 473–508. doi:10.1124/pr.57.4.10. PMID 16382104. S2CID 219195192.
Lee H, Wang H, Jen JC, et al. (2004). "A novel mutation in KCNA1 causes episodic ataxia without myokymia". Hum. Mutat. 24 (6): 536. doi:10.1002/humu.9295. PMID 15532032. S2CID 2542180.
Gu C, Jan YN, Jan LY (2003). "A conserved domain in axonal targeting of Kv1 (Shaker) voltage-gated potassium channels". Science. 301 (5633): 646–9. Bibcode:2003Sci...301..646G. doi:10.1126/science.1086998. PMID 12893943. S2CID 9924760.

Vanjski linkovi

GeneReviews/NCBI/NIH/UW entry on Episodic Ataxia Type 1, Episodic Ataxia with Myokymia, Hereditary Cerebellar Ataxia with Neuromyotonia
Kv1.1 Potassium Channel na US National Library of Medicine Medical Subject Headings (MeSH)
KCNA1 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000111262 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000047976 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid1349297-5] Curran ME, Landes GM, Keating MT (1992). "Molecular cloning, characterization, and genomic localization of a human potassium channel gene". Genomics. 12 (4): 729–37. doi:10.1016/0888-7543(92)90302-9. PMID 1349297.

[pmid8821794-6] Albrecht B, Weber K, Pongs O (1995). "Characterization of a voltage-activated K-channel gene cluster on human chromosome 12p13". Recept. Channels. 3 (3): 213–20. PMID 8821794.

[pmid16382104-7] Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stühmer W, Wang X (2005). "International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels". Pharmacol. Rev. 57 (4): 473–508. doi:10.1124/pr.57.4.10. PMID 16382104. S2CID 219195192.

[pmid9616766-8] Newsom-Davis J (1997). "Autoimmune neuromyotonia (Isaacs' syndrome): an antibody-mediated potassium channelopathy". Ann. N. Y. Acad. Sci. 835 (1): 111–9. Bibcode:1997NYASA.835..111N. doi:10.1111/j.1749-6632.1997.tb48622.x. PMID 9616766. S2CID 13231594.^{[trajno mrtav link]}

[UniProt-9] "UniProt, Q09470". Pristupljeno 10. 8. 2021.

[entrez-10] "Entrez Gene: KCNA1 potassium voltage-gated channel".

[11] "KCNA1 - Potassium voltage-gated channel subfamily A member 1 - Homo sapiens (Human) - KCNA1 gene & protein". www.uniprot.org.

[pmid15361858-12] Bhalla T, Rosenthal JJ, Holmgren M, Reenan R (oktobar 2004). "Control of human potassium channel inactivation by editing of a small mRNA hairpin". Nat. Struct. Mol. Biol. 11 (10): 950–6. doi:10.1038/nsmb825. PMID 15361858. S2CID 34081059.

[pmid12907802-13] Hoopengardner B, Bhalla T, Staber C, Reenan R (august 2003). "Nervous system targets of RNA editing identified by comparative genomics". Science. 301 (5634): 832–6. Bibcode:2003Sci...301..832H. doi:10.1126/science.1086763. PMID 12907802. S2CID 782642.

[BhallaRosenthal2004-14] Bhalla, Tarun; Rosenthal, Joshua J C; Holmgren, Miguel; Reenan, Robert (2004). "Control of human potassium channel inactivation by editing of a small mRNA hairpin". Nature Structural & Molecular Biology. 11 (10): 950–956. doi:10.1038/nsmb825. ISSN 1545-9993. PMID 15361858. S2CID 34081059.

[Bezanilla2004-15] Bezanilla, Francisco (2004). "RNA editing of a human potassium channel modifies its inactivation". Nature Structural & Molecular Biology. 11 (10): 915–916. doi:10.1038/nsmb1004-915. ISSN 1545-9993. PMID 15452561. S2CID 40545616.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]