Ca_v1.2

Cav1.2
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1T0J, 2BE6, 2F3Z, 2LQC, 3G43, 3OXQ
Identifikatori
Aliasi	CACNA1C
Vanjski ID-jevi	OMIM: 114205 MGI: 103013 HomoloGene: 55484 GeneCards: CACNA1C
Lokacija gena (čovjek)
Hrom.	Hromosom 12 (čovjek)
Kraj	2,697,950 bp
Lokacija gena (miš)
Hrom.	Hromosom 6 (miš)
Kraj	119,173,851 bp
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 discdkac; • 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
	775
	12288
	ENSG00000151067; ENSG00000285479
	ENSMUSG00000051331
	Q13936
	Q01815
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
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
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Podjedinica alfa 1C L-tipa naponski ovisnog kalcijskog kanala (znana i kao Ca_v1.2) jest protein koji je kod ljudi kodiran genom CACNA1C sa hromosoma 12.^[5]^[6]

Aminokiselinska sekvenca

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

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

10	20	30	40	50
MVNENTRMYI	PEENHQGSNY	GSPRPAHANM	NANAAAGLAP	EHIPTPGAAL
SWQAAIDAAR	QAKLMGSAGN	ATISTVSSTQ	RKRQQYGKPK	KQGSTTATRP
PRALLCLTLK	NPIRRACISI	VEWKPFEIII	LLTIFANCVA	LAIYIPFPED
DSNATNSNLE	RVEYLFLIIF	TVEAFLKVIA	YGLLFHPNAY	LRNGWNLLDF
IIVVVGLFSA	ILEQATKADG	ANALGGKGAG	FDVKALRAFR	VLRPLRLVSG
VPSLQVVLNS	IIKAMVPLLH	IALLVLFVII	IYAIIGLELF	MGKMHKTCYN
QEGIADVPAE	DDPSPCALET	GHGRQCQNGT	VCKPGWDGPK	HGITNFDNFA
FAMLTVFQCI	TMEGWTDVLY	WVNDAVGRDW	PWIYFVTLII	IGSFFVLNLV
LGVLSGEFSK	EREKAKARGD	FQKLREKQQL	EEDLKGYLDW	ITQAEDIDPE
NEDEGMDEEK	PRNMSMPTSE	TESVNTENVA	GGDIEGENCG	ARLAHRISKS
KFSRYWRRWN	RFCRRKCRAA	VKSNVFYWLV	IFLVFLNTLT	IASEHYNQPN
WLTEVQDTAN	KALLALFTAE	MLLKMYSLGL	QAYFVSLFNR	FDCFVVCGGI
LETILVETKI	MSPLGISVLR	CVRLLRIFKI	TRYWNSLSNL	VASLLNSVRS
IASLLLLLFL	FIIIFSLLGM	QLFGGKFNFD	EMQTRRSTFD	NFPQSLLTVF
QILTGEDWNS	VMYDGIMAYG	GPSFPGMLVC	IYFIILFICG	NYILLNVFLA
IAVDNLADAE	SLTSAQKEEE	EEKERKKLAR	TASPEKKQEL	VEKPAVGESK
EEKIELKSIT	ADGESPPATK	INMDDLQPNE	NEDKSPYPNP	ETTGEEDEEE
PEMPVGPRPR	PLSELHLKEK	AVPMPEASAF	FIFSSNNRFR	LQCHRIVNDT
IFTNLILFFI	LLSSISLAAE	DPVQHTSFRN	HILFYFDIVF	TTIFTIEIAL
KILGNADYVF	TSIFTLEIIL	KMTAYGAFLH	KGSFCRNYFN	ILDLLVVSVS
LISFGIQSSA	INVVKILRVL	RVLRPLRAIN	RAKGLKHVVQ	CVFVAIRTIG
NIVIVTTLLQ	FMFACIGVQL	FKGKLYTCSD	SSKQTEAECK	GNYITYKDGE
VDHPIIQPRS	WENSKFDFDN	VLAAMMALFT	VSTFEGWPEL	LYRSIDSHTE
DKGPIYNYRV	EISIFFIIYI	IIIAFFMMNI	FVGFVIVTFQ	EQGEQEYKNC
ELDKNQRQCV	EYALKARPLR	RYIPKNQHQY	KVWYVVNSTY	FEYLMFVLIL
LNTICLAMQH	YGQSCLFKIA	MNILNMLFTG	LFTVEMILKL	IAFKPKGYFS
DPWNVFDFLI	VIGSIIDVIL	SETNHYFCDA	WNTFDALIVV	GSIVDIAITE
VNPAEHTQCS	PSMNAEENSR	ISITFFRLFR	VMRLVKLLSR	GEGIRTLLWT
FIKSFQALPY	VALLIVMLFF	IYAVIGMQVF	GKIALNDTTE	INRNNNFQTF
PQAVLLLFRC	ATGEAWQDIM	LACMPGKKCA	PESEPSNSTE	GETPCGSSFA
VFYFISFYML	CAFLIINLFV	AVIMDNFDYL	TRDWSILGPH	HLDEFKRIWA
EYDPEAKGRI	KHLDVVTLLR	RIQPPLGFGK	LCPHRVACKR	LVSMNMPLNS
DGTVMFNATL	FALVRTALRI	KTEGNLEQAN	EELRAIIKKI	WKRTSMKLLD
QVVPPAGDDE	VTVGKFYATF	LIQEYFRKFK	KRKEQGLVGK	PSQRNALSLQ
AGLRTLHDIG	PEIRRAISGD	LTAEEELDKA	MKEAVSAASE	DDIFRRAGGL
FGNHVSYYQS	DGRSAFPQTF	TTQRPLHINK	AGSSQGDTES	PSHEKLVDST
FTPSSYSSTG	SNANINNANN	TALGRLPRPA	GYPSTVSTVE	GHGPPLSPAI
RVQEVAWKLS	SNRERHVPMC	EDLELRRDSG	SAGTQAHCLL	LRKANPSRCH
SRESQAAMAG	QEETSQDETY	EVKMNHDTEA	CSEPSLLSTE	MLSYQDDENR
QLTLPEEDKR	DIRQSPKRGF	LRSASLGRRA	SFHLECLKRQ	KDRGGDISQK
TVLPLHLVHH	QALAVAGLSP	LLQRSHSPAS	FPRPFATPPA	TPGSRGWPPQ
PVPTLRLEGV	ESSEKLNSSF	PSIHCGSWAE	TTPGGGGSSA	ARRVRPVSLM
VPSQAGAPGR	QFHGSASSLV	EAVLISEGLG	QFAQDPKFIE	VTTQELADAC
DMTIEEMESA	ADNILSGGAP	QSPNGALLPF	VNCRDAGQDR	AGGEEDAGCV
RARGRPSEEE	LQDSRVYVSS	L

Struktura i funkcija

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]

Ca_V1. 2 je inhibiran djelovanjem STIM1.^[14]

Regulacija

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

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

Šablon:NicotineChromaffinActivity WP1603

Također pogledajte

Reference

^ ^a ^b ^c ENSG00000285479 GRCh38: Ensembl release 89: ENSG00000151067, ENSG00000285479 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000051331 - 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.
^ ^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.
^ 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.
^ Shaw RM, Colecraft HM (maj 2013). "L-type calcium channel targeting and local signalling in cardiac myocytes". Cardiovascular Research. 98 (2): 177–86. doi:10.1093/cvr/cvt021. PMC 3633156. PMID 23417040.
^ ^a ^b Lipscombe D, Helton TD, Xu W (Nov 2004). "L-type calcium channels: the low down". Journal of Neurophysiology. 92 (5): 2633–41. doi:10.1152/jn.00486.2004. PMID 15486420. S2CID 52887174.
^ Christel C, Lee A (Aug 2012). "Ca2+-dependent modulation of voltage-gated Ca2+ channels". Biochimica et Biophysica Acta (BBA) - General Subjects. 1820 (8): 1243–52. doi:10.1016/j.bbagen.2011.12.012. PMC 3345169. PMID 22223119.
^ Berger SM, Bartsch D (Aug 2014). "The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function". Cell and Tissue Research. 357 (2): 463–76. doi:10.1007/s00441-014-1936-3. PMID 24996399. S2CID 15914718.
^ "Entrez Gene: voltage-dependent, L type, alpha 1C subunit".
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ ^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.
^ 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.
^ ^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.
^ 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.
^
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.
- "Channeling Mental Illness: GWAS Links Ion Channels, Bipolar Disorder". Schizophrenia Research Forum. Arhivirano s originala, 18. 12. 2010.
^ 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.
^ 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.
^ 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.
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Dopunska literatura

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Vanjski linkovi

GeneReviews/NIH/NCBI/UW entry on Brugada syndrome
CACNA1C protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
GeneReviews/NIH/NCBI/UW entry on Timothy Syndrome

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

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