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Cav1.2

S Wikipedije, slobodne enciklopedije
Cav1.2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1T0J, 2BE6, 2F3Z, 2LQC, 3G43, 3OXQ

Identifikatori
AliasiCACNA1C
Vanjski ID-jeviOMIM: 114205 MGI: 103013 HomoloGene: 55484 GeneCards: CACNA1C
Lokacija gena (čovjek)
Hromosom 12 (čovjek)
Hrom.Hromosom 12 (čovjek)[1]
Hromosom 12 (čovjek)
Genomska lokacija za Cav1.2
Genomska lokacija za Cav1.2
Bend12p13.33Početak1,970,772 bp[1]
Kraj2,697,950 bp[1]
Lokacija gena (miš)
Hromosom 6 (miš)
Hrom.Hromosom 6 (miš)[2]
Hromosom 6 (miš)
Genomska lokacija za Cav1.2
Genomska lokacija za Cav1.2
Bend6 F1|6 55.86 cMPočetak118,564,201 bp[2]
Kraj119,173,851 bp[2]
Ontologija gena
Molekularna funkcija calcium channel activity
vezivanje iona metala
voltage-gated ion channel activity
ion channel activity
GO:0001948, GO:0016582 vezivanje za proteine
alpha-actinin binding
voltage-gated calcium channel activity
voltage-gated calcium channel activity involved in cardiac muscle cell action potential
high voltage-gated calcium channel activity
voltage-gated calcium channel activity involved in AV node cell action potential
calmodulin binding
Ćelijska komponenta citoplazma
Naponom kontrolirani kalcijev kanal
integral component of membrane
membrana
GO:0097483, GO:0097481 postsynaptic density
ćelijska membrana
Z disc
L-type voltage-gated calcium channel complex
integral component of plasma membrane
međućelijske veze
dendrit
Sarkolema
projekcija ćelije
perikaryon
sinapsa
postsynaptic membrane
T-tubule
Biološki proces calcium ion transport into cytosol
regulation of insulin secretion
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion
positive regulation of cytosolic calcium ion concentration
cell communication by electrical coupling involved in cardiac conduction
regulation of ion transmembrane transport
ion transport
calcium-mediated signaling using extracellular calcium source
transmembrane transport
calcium ion transport
regulation of ventricular cardiac muscle cell action potential
embryonic forelimb morphogenesis
immune system development
regulation of heart rate by cardiac conduction
membrane depolarization during cardiac muscle cell action potential
calcium ion transmembrane transport via high voltage-gated calcium channel
membrane depolarization during AV node cell action potential
heart development
membrane depolarization during atrial cardiac muscle cell action potential
cardiac muscle cell action potential involved in contraction
calcium ion transmembrane transport
camera-type eye development
cardiac conduction
calcium ion import
positive regulation of adenylate cyclase activity
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
NM_000719
NM_001129827
NM_001129829
NM_001129830
NM_001129831

NM_001129832
NM_001129833
NM_001129834
NM_001129835
NM_001129836
NM_001129837
NM_001129838
NM_001129839
NM_001129840
NM_001129841
NM_001129842
NM_001129843
NM_001129844
NM_001129846
NM_001167623
NM_001167624
NM_001167625
NM_199460

NM_001159533
NM_001159534
NM_001159535
NM_001255997
NM_001255998

NM_001255999
NM_001256000
NM_001256001
NM_001256002
NM_009781
NM_001290335

RefSeq (bjelančevina)
NP_000710
NP_001123299
NP_001123301
NP_001123302
NP_001123303

NP_001123304
NP_001123305
NP_001123306
NP_001123307
NP_001123308
NP_001123309
NP_001123310
NP_001123311
NP_001123312
NP_001123313
NP_001123314
NP_001123315
NP_001123316
NP_001123318
NP_001161095
NP_001161096
NP_001161097
NP_955630

NP_001153005
NP_001153006
NP_001153007
NP_001242926
NP_001242927

NP_001242928
NP_001242929
NP_001242930
NP_001242931
NP_001277264
NP_033911

Lokacija (UCSC)Chr 12: 1.97 – 2.7 MbChr 6: 118.56 – 119.17 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Podjedinica alfa 1C L-tipa naponski ovisnog kalcijskog kanala (znana i kao Cav1.2) jest protein koji je kod ljudi kodiran genom CACNA1C sa hromosoma 12.[5][6]

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 2.221 aminokiselina, a molekulska težina 248.977 Da.[5]

1020304050
MVNENTRMYIPEENHQGSNYGSPRPAHANMNANAAAGLAPEHIPTPGAAL
SWQAAIDAARQAKLMGSAGNATISTVSSTQRKRQQYGKPKKQGSTTATRP
PRALLCLTLKNPIRRACISIVEWKPFEIIILLTIFANCVALAIYIPFPED
DSNATNSNLERVEYLFLIIFTVEAFLKVIAYGLLFHPNAYLRNGWNLLDF
IIVVVGLFSAILEQATKADGANALGGKGAGFDVKALRAFRVLRPLRLVSG
VPSLQVVLNSIIKAMVPLLHIALLVLFVIIIYAIIGLELFMGKMHKTCYN
QEGIADVPAEDDPSPCALETGHGRQCQNGTVCKPGWDGPKHGITNFDNFA
FAMLTVFQCITMEGWTDVLYWVNDAVGRDWPWIYFVTLIIIGSFFVLNLV
LGVLSGEFSKEREKAKARGDFQKLREKQQLEEDLKGYLDWITQAEDIDPE
NEDEGMDEEKPRNMSMPTSETESVNTENVAGGDIEGENCGARLAHRISKS
KFSRYWRRWNRFCRRKCRAAVKSNVFYWLVIFLVFLNTLTIASEHYNQPN
WLTEVQDTANKALLALFTAEMLLKMYSLGLQAYFVSLFNRFDCFVVCGGI
LETILVETKIMSPLGISVLRCVRLLRIFKITRYWNSLSNLVASLLNSVRS
IASLLLLLFLFIIIFSLLGMQLFGGKFNFDEMQTRRSTFDNFPQSLLTVF
QILTGEDWNSVMYDGIMAYGGPSFPGMLVCIYFIILFICGNYILLNVFLA
IAVDNLADAESLTSAQKEEEEEKERKKLARTASPEKKQELVEKPAVGESK
EEKIELKSITADGESPPATKINMDDLQPNENEDKSPYPNPETTGEEDEEE
PEMPVGPRPRPLSELHLKEKAVPMPEASAFFIFSSNNRFRLQCHRIVNDT
IFTNLILFFILLSSISLAAEDPVQHTSFRNHILFYFDIVFTTIFTIEIAL
KILGNADYVFTSIFTLEIILKMTAYGAFLHKGSFCRNYFNILDLLVVSVS
LISFGIQSSAINVVKILRVLRVLRPLRAINRAKGLKHVVQCVFVAIRTIG
NIVIVTTLLQFMFACIGVQLFKGKLYTCSDSSKQTEAECKGNYITYKDGE
VDHPIIQPRSWENSKFDFDNVLAAMMALFTVSTFEGWPELLYRSIDSHTE
DKGPIYNYRVEISIFFIIYIIIIAFFMMNIFVGFVIVTFQEQGEQEYKNC
ELDKNQRQCVEYALKARPLRRYIPKNQHQYKVWYVVNSTYFEYLMFVLIL
LNTICLAMQHYGQSCLFKIAMNILNMLFTGLFTVEMILKLIAFKPKGYFS
DPWNVFDFLIVIGSIIDVILSETNHYFCDAWNTFDALIVVGSIVDIAITE
VNPAEHTQCSPSMNAEENSRISITFFRLFRVMRLVKLLSRGEGIRTLLWT
FIKSFQALPYVALLIVMLFFIYAVIGMQVFGKIALNDTTEINRNNNFQTF
PQAVLLLFRCATGEAWQDIMLACMPGKKCAPESEPSNSTEGETPCGSSFA
VFYFISFYMLCAFLIINLFVAVIMDNFDYLTRDWSILGPHHLDEFKRIWA
EYDPEAKGRIKHLDVVTLLRRIQPPLGFGKLCPHRVACKRLVSMNMPLNS
DGTVMFNATLFALVRTALRIKTEGNLEQANEELRAIIKKIWKRTSMKLLD
QVVPPAGDDEVTVGKFYATFLIQEYFRKFKKRKEQGLVGKPSQRNALSLQ
AGLRTLHDIGPEIRRAISGDLTAEEELDKAMKEAVSAASEDDIFRRAGGL
FGNHVSYYQSDGRSAFPQTFTTQRPLHINKAGSSQGDTESPSHEKLVDST
FTPSSYSSTGSNANINNANNTALGRLPRPAGYPSTVSTVEGHGPPLSPAI
RVQEVAWKLSSNRERHVPMCEDLELRRDSGSAGTQAHCLLLRKANPSRCH
SRESQAAMAGQEETSQDETYEVKMNHDTEACSEPSLLSTEMLSYQDDENR
QLTLPEEDKRDIRQSPKRGFLRSASLGRRASFHLECLKRQKDRGGDISQK
TVLPLHLVHHQALAVAGLSPLLQRSHSPASFPRPFATPPATPGSRGWPPQ
PVPTLRLEGVESSEKLNSSFPSIHCGSWAETTPGGGGSSAARRVRPVSLM
VPSQAGAPGRQFHGSASSLVEAVLISEGLGQFAQDPKFIEVTTQELADAC
DMTIEEMESAADNILSGGAPQSPNGALLPFVNCRDAGQDRAGGEEDAGCV
RARGRPSEEELQDSRVYVSSL

Struktura i funkcija

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Ovaj gen kodira alfa-1 podjedinicu naponsko-ovisnog kalcijevog kanala. Kalcijski kanali posreduju priliv kalcijevih iona (Ca2+) u ćeliju nakon polarizacije membrane (vidi membranski potencijal i kalciju biologiji).[7]

Podjedinica alfa-1 sastoji se od 24 transmembranska segmenta i formira pore kroz koje ioni prolaze u ćeliju. Kalcijski kanal se sastoji od kompleksa alfa-1, alfa-2/delta i beta podjedinica u omjeru 1:1:1. S3-S4 linkeri Cav1.2 određuju fenotip sajta i moduliranu kinetiku kanala.[8] Cav1.2 je široko eksprimiran u glatkim mišićima, ćelijama pankreasa, fibroblastima i neuronima.[9][10] Međutim, posebno je važan i poznat po svojoj ekspresiji u srcu, gdje posreduje struje L-tipa, što uzrokuje oslobađanje kalcija izazvano kalcijem iz ER skladišta preko rijanodinskih receptora. Depolarizuje se na -30mV i pomaže u definiranju oblika akcijskog potencijala u srčanom i glatkim mišićima.[8] Protein kodiran ovim genom vezuje se za dihidropiridin i inhibira ga.[11] In the arteries of the brain, high levels of calcium in mitochondria elevates activity of nuclear factor kappa B NF-κB and transcription of CACNA1c and functional Cav1.2 expression increases.[12] Cav1.2 also regulates levels of osteoprotegerin.[13]

CaV1. 2 je inhibiran djelovanjem STIM1.[14]

Regulacija

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Aktivnost CaV1.2 kanala je strogo regulirana Ca2+ signalima koje oni proizvode. Povećanje unutarćelijske koncentracije Ca2+ uključeno u Cav1.2 facilitaciju, oblik pozitivne povratne informacije koji se zove Ca2+-ovisna facilitacija, koja pojačava priliv Ca2+ . Osim toga, povećanje influksne unutarćelijske koncentracije Ca2+ je impliciralo da ima suprotan efekat inaktivacije ovisne od Ca2+.[15] Ovi mehanizmi aktivacije i inaktivacije uključuju vezivanje Ca2+ za kalmodulin (CaM) u IQ domen u C-terminalnom repu ovih kanala.[16] Cav1.2 kanali su raspoređeni u ćelijskoj membrani, u prosjeku u klasteru od po osam. Kada se ioni kalcija vežu za kalmodulin, koji se zauzvrat veže za Cav1.2 kanal, omogućava Cav1.2 kanalima unutar klastera da međusobno komuniciraju.[17] Ovo dovodi do toga da kanali rade zajedno kada se istovremeno otvore, kako bi omogućili ulazak više iona kalcija, a zatim se zatvaraju zajedno kako bi se ćelija opustila.[17]

Zbog jednostavnosti, prikazana su samo dva kalcijska kanala koja prikazuju grupisanje. Kada dođe do depolarizacije, ioni kalcija teku kroz kanal i neki se vežu za kalmodulin. Vezivanje kalcija/kalmodulina za C-terminalni pre-IQ domen Cav1.2 kanala promoviše interakciju između kanala koji su jedan pored drugog.

Klinički značaj

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Mutacija gena CACNA1C, jednonukleotidni polimorfizam (SNP) koji se nalazi u trećem intronu Cav1.2 gena,[18] povezana s varijantom sindromas dugog QT koja se naziva Timothyjev sindrom[19] i šire sa drugim CACNA1C-vezanim poremećajima,[19] kao i sa Brugadaovim sindromom.[20] Genetićke analize velikih razmjera pokazale su mogućnost da je CACNA1C povezan sa bipolarnim poremećajem[21] a posljedično i sa shizofrenijom.[22][23][24] Također, alel rizika CACNA1C povezan je s poremećajem moždane povezanosti kod pacijenata s bipolarnim poremećajem, iako ne ili samo u manjem stepenu, kod njihovih netaknutih rođaka ili zdravih kontrola.[25]

Interaktivna mapa puta

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Šablon:NicotineChromaffinActivity WP1603

Također pogledajte

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Reference

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  1. ^ a b c ENSG00000285479 GRCh38: Ensembl release 89: ENSG00000151067, ENSG00000285479 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051331 - 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.
  5. ^ a b Lacerda AE, Kim HS, Ruth P, Perez-Reyes E, Flockerzi V, Hofmann F, Birnbaumer L, Brown AM (Aug 1991). "Normalization of current kinetics by interaction between the alpha 1 and beta subunits of the skeletal muscle dihydropyridine-sensitive Ca2+ channel". Nature. 352 (6335): 527–30. Bibcode:1991Natur.352..527L. doi:10.1038/352527a0. PMID 1650913. S2CID 4246540.
  6. ^ Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (Dec 2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels". Pharmacological Reviews. 57 (4): 411–25. doi:10.1124/pr.57.4.5. PMID 16382099. S2CID 10386627.
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  11. ^ "Entrez Gene: voltage-dependent, L type, alpha 1C subunit".
  12. ^ Narayanan D, Xi Q, Pfeffer LM, Jaggar JH (Sep 2010). "Mitochondria control functional CaV1.2 expression in smooth muscle cells of cerebral arteries". Circulation Research. 107 (5): 631–41. doi:10.1161/CIRCRESAHA.110.224345. PMC 3050675. PMID 20616314.
  13. ^ Bergh JJ, Xu Y, Farach-Carson MC (Jan 2004). "Osteoprotegerin expression and secretion are regulated by calcium influx through the L-type voltage-sensitive calcium channel". Endocrinology. 145 (1): 426–36. doi:10.1210/en.2003-0319. PMID 14525906.
  14. ^ Cahalan MD (Oct 2010). "Cell biology. How to STIMulate calcium channels". Science. 330 (6000): 43–4. doi:10.1126/science.1196348. PMC 3133971. PMID 20929798.
  15. ^ Isaev D, Solt K, Gurtovaya O, Reeves JP, Shirokov R (maj 2004). "Modulation of the voltage sensor of L-type Ca2+ channels by intracellular Ca2+". The Journal of General Physiology. 123 (5): 555–71. doi:10.1085/jgp.200308876. PMC 2234499. PMID 15111645.
  16. ^ Kim EY, Rumpf CH, Van Petegem F, Arant RJ, Findeisen F, Cooley ES, Isacoff EY, Minor DL (Dec 2010). "Multiple C-terminal tail Ca(2+)/CaMs regulate Ca(V)1.2 function but do not mediate channel dimerization". The EMBO Journal. 29 (23): 3924–38. doi:10.1038/emboj.2010.260. PMC 3020648. PMID 20953164.
  17. ^ a b Dixon RE, Moreno CM, Yuan C, Opitz-Araya X, Binder MD, Navedo MF, Santana LF (2015). "Graded Ca²⁺/calmodulin-dependent coupling of voltage-gated CaV1.2 channels". eLife. 4. doi:10.7554/eLife.05608. PMC 4360655. PMID 25714924.
  18. ^ Imbrici P, Camerino DC, Tricarico D (7. 5. 2013). "Major channels involved in neuropsychiatric disorders and therapeutic perspectives". Frontiers in Genetics. 4: 76. doi:10.3389/fgene.2013.00076. PMC 3646240. PMID 23675382.
  19. ^ a b Napolitano C, Timothy KW, Bloise R, Priori SG (1993). Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A (ured.). CACNA1C-Related Disorders. GeneReviews®. Seattle (WA): University of Washington, Seattle. PMID 20301577. Pristupljeno 12. 12. 2022.
  20. ^ Hedley PL, Jørgensen P, Schlamowitz S, Moolman-Smook J, Kanters JK, Corfield VA, Christiansen M (Sep 2009). "The genetic basis of Brugada syndrome: a mutation update". Human Mutation. 30 (9): 1256–66. doi:10.1002/humu.21066. PMID 19606473. S2CID 25207473.
  21. ^ Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, et al. (Sep 2008). "Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder". Nature Genetics. 40 (9): 1056–8. doi:10.1038/ng.209. PMC 2703780. PMID 18711365.
  22. ^ Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S, Gordon-Smith K, Fraser C, Forty L, Russell E, Hamshere ML, Moskvina V, Nikolov I, Farmer A, McGuffin P, Holmans PA, Owen MJ, O'Donovan MC, Craddock N (Oct 2010). "The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia". Molecular Psychiatry. 15 (10): 1016–22. doi:10.1038/mp.2009.49. PMC 3011210. PMID 19621016.
  23. ^ Curtis D, Vine AE, McQuillin A, Bass NJ, Pereira A, Kandaswamy R, Lawrence J, Anjorin A, Choudhury K, Datta SR, Puri V, Krasucki R, Pimm J, Thirumalai S, Quested D, Gurling HM (Feb 2011). "Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes". Psychiatric Genetics. 21 (1): 1–4. doi:10.1097/YPG.0b013e3283413382. PMC 3024533. PMID 21057379.
  24. ^ Schizophrenia Working Group of the Psychiatric Genomics Consortium (24. 7. 2014). "Biological insights from 108 schizophrenia-associated genetic loci". Nature. 511 (7510): 421–427. Bibcode:2014Natur.511..421S. doi:10.1038/nature13595. ISSN 1476-4687. PMC 4112379. PMID 25056061.
  25. ^ Radua J, Surguladze SA, Marshall N, Walshe M, Bramon E, Collier DA, Prata DP, Murray RM, McDonald C (maj 2013). "The impact of CACNA1C allelic variation on effective connectivity during emotional processing in bipolar disorder". Molecular Psychiatry. 18 (5): 526–7. doi:10.1038/mp.2012.61. PMID 22614292.

Dopunska literatura

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Vanjski linkovi

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Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.