Cav1.1
Cav1.1 , znan i kao podjedinica 1S L tipa naponski ovisnog kalcijskog kanala (CACNA1S), jest protein koji je kod ljudi kodiran genom CACNA1S sa hromosoma 1.[5] Također je poznat kao CACNL1A3 i dihidropiridinski receptor (DHPR, nazvan tako zbog blokirajućeg dejstva DHP-a na njega).
Aminokiselinska sekvenca[uredi | uredi izvor]
Dužina polipeptidnog lanca je 18.73 aminokiseline, a molekulska težina 212.350 Da.[5]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MEPSSPQDEG | LRKKQPKKPV | PEILPRPPRA | LFCLTLENPL | RKACISIVEW | ||||
| KPFETIILLT | IFANCVALAV | YLPMPEDDNN | SLNLGLEKLE | YFFLIVFSIE | ||||
| AAMKIIAYGF | LFHQDAYLRS | GWNVLDFTIV | FLGVFTVILE | QVNVIQSHTA | ||||
| PMSSKGAGLD | VKALRAFRVL | RPLRLVSGVP | SLQVVLNSIF | KAMLPLFHIA | ||||
| LLVLFMVIIY | AIIGLELFKG | KMHKTCYFIG | TDIVATVENE | EPSPCARTGS | ||||
| GRRCTINGSE | CRGGWPGPNH | GITHFDNFGF | SMLTVYQCIT | MEGWTDVLYW | ||||
| VNDAIGNEWP | WIYFVTLILL | GSFFILNLVL | GVLSGEFTKE | REKAKSRGTF | ||||
| QKLREKQQLD | EDLRGYMSWI | TQGEVMDVED | FREGKLSLDE | GGSDTESLYE | ||||
| IAGLNKIIQF | IRHWRQWNRI | FRWKCHDIVK | SKVFYWLVIL | IVALNTLSIA | ||||
| SEHHNQPLWL | TRLQDIANRV | LLSLFTTEML | MKMYGLGLRQ | YFMSIFNRFD | ||||
| CFVVCSGILE | ILLVESGAMT | PLGISVLRCI | RLLRIFKITK | YWTSLSNLVA | ||||
| SLLNSIRSIA | SLLLLLFLFI | VIFALLGMQL | FGGRYDFEDT | EVRRSNFDNF | ||||
| PQALISVFQV | LTGEDWTSMM | YNGIMAYGGP | SYPGMLVCIY | FIILFVCGNY | ||||
| ILLNVFLAIA | VDNLAEAESL | TSAQKAKAEE | KKRRKMSKGL | PDKSEEEKST | ||||
| MAKKLEQKPK | GEGIPTTAKL | KIDEFESNVN | EVKDPYPSAD | FPGDDEEDEP | ||||
| EIPLSPRPRP | LAELQLKEKA | VPIPEASSFF | IFSPTNKIRV | LCHRIVNATW | ||||
| FTNFILLFIL | LSSAALAAED | PIRADSMRNQ | ILKHFDIGFT | SVFTVEIVLK | ||||
| MTTYGAFLHK | GSFCRNYFNM | LDLLVVAVSL | ISMGLESSAI | SVVKILRVLR | ||||
| VLRPLRAINR | AKGLKHVVQC | MFVAISTIGN | IVLVTTLLQF | MFACIGVQLF | ||||
| KGKFFRCTDL | SKMTEEECRG | YYYVYKDGDP | MQIELRHREW | VHSDFHFDNV | ||||
| LSAMMSLFTV | STFEGWPQLL | YKAIDSNAED | VGPIYNNRVE | MAIFFIIYII | ||||
| LIAFFMMNIF | VGFVIVTFQE | QGETEYKNCE | LDKNQRQCVQ | YALKARPLRC | ||||
| YIPKNPYQYQ | VWYIVTSSYF | EYLMFALIML | NTICLGMQHY | NQSEQMNHIS | ||||
| DILNVAFTII | FTLEMILKLM | AFKARGYFGD | PWNVFDFLIV | IGSIIDVILS | ||||
| EIDTFLASSG | GLYCLGGGCG | NVDPDESARI | SSAFFRLFRV | MRLIKLLSRA | ||||
| EGVRTLLWTF | IKSFQALPYV | ALLIVMLFFI | YAVIGMQMFG | KIALVDGTQI | ||||
| NRNNNFQTFP | QAVLLLFRCA | TGEAWQEILL | ACSYGKLCDP | ESDYAPGEEY | ||||
| TCGTNFAYYY | FISFYMLCAF | LVINLFVAVI | MDNFDYLTRD | WSILGPHHLD | ||||
| EFKAIWAEYD | PEAKGRIKHL | DVVTLLRRIQ | PPLGFGKFCP | HRVACKRLVG | ||||
| MNMPLNSDGT | VTFNATLFAL | VRTALKIKTE | GNFEQANEEL | RAIIKKIWKR | ||||
| TSMKLLDQVI | PPIGDDEVTV | GKFYATFLIQ | EHFRKFMKRQ | EEYYGYRPKK | ||||
| DIVQIQAGLR | TIEEEAAPEI | CRTVSGDLAA | EEELERAMVE | AAMEEGIFRR | ||||
| TGGLFGQVDN | FLERTNSLPP | VMANQRPLQF | AEIEMEEMES | PVFLEDFPQD | ||||
| PRTNPLARAN | TNNANANVAY | GNSNHSNSHV | FSSVHYEREF | PEETETPATR | ||||
| GRALGQPCRV | LGPHSKPCVE | MLKGLLTQRA | MPRGQAPPAP | CQCPRVESSM | ||||
| PEDRKSSTPG | SLHEETPHSR | STRENTSRCS | APATALLIQK | ALVRGGLGTL | ||||
| AADANFIMAT | GQALADACQM | EPEEVEIMAT | ELLKGREAPE | GMASSLGCLN | ||||
| LGSSLGSLDQ | HQGSQETLIP | PRL |
Funkcija[uredi | uredi izvor]
Ovaj gen kodira jednu od pet podjedinica sporo inaktivirajućeg L-tipa napon-zavisnog kalcijskog kanala u ćelijama skeletnih mišića. Mutacije ovog gena su povezane sa osjetljivošću na hipokalemijsku periodičnu paralizu, tireotoksičnu periodičnu paralizu i malignu hipertermiju.[5]
Cav1.1 je naponski ovisni kalcijski kanal koji se nalazi u mišićnim poprečnim tubulama. U skeletnim mišićima se povezuje sa rijanodinski mreceptorom RyR1 sarkoplazmatskog retikuluma putem mehaničke veze. On osjeća promjenu napona uzrokovanu potencijalom krajnje ploče od nervne stimulacije i propagiranu natrijskim kanalima kao akcijski potencijal do T-tubula. Ranije se smatralo da kada se mišić depolarizuje, otvara se kalcijski kanal, omogućavajući kalciju i aktivirajući RyR1, koji posreduje mnogo veće oslobađanje kalcija iz sarkoplazmatskog retikuluma. Ovo je prvi dio procesa spoj ekscitacija-kontrakcija, koji na kraju uzrokuje kontrakciju mišića. Unos kalcija kroz Cav1.1 nije potreban u skeletnim mišićima, kao što je to u srčanom mišiću; Cav1.1 prolazi kroz konformacijsku promjenu koja alosterno aktivira RyR1.[6]
Klinički značaj[uredi | uredi izvor]
U hipokalemijskoj periodičnoj paralizi (HOKPP), senzori napona u domenima 2 i 4 Cav1.1 su mutirani (gubitak funkcije), smanjujući dostupnost kanala da osjeti depolarizaciju , te stoga ne može tako efikasno aktivirati rijanodinski receptor. Kao rezultat toga, mišić se ne može dobro kontrahirati i pacijent je paraliziran. Stanje je hipokalemijsko jer će niska koncentracija vanćelijskih iona kalija uzrokovati bržu repolarizaciju mišića u potencijal mirovanja, tako da se bilo kakva provodljivost kalcija koja se pojavi ne može održati. Postaje teže doći do praga na kojem se mišić može kontrahirati, a čak i ako se to postigne onda je skloniji opuštanju. Zbog toga bi se ozbiljnost smanjila ako bi se održavale koncentracije kalijevih iona. Nasuprot tome, hiperkalemijska periodična paraliza odnosi se na mutacije pojačanja funkcije u natrijskim kanalima koje održavaju depolarizaciju mišića i stoga su pogoršane "visokim" koncentracijama kalijevih iona.[7]
Za dijagnostiku maligne hipertermije, Evropska Grupa zha malignu hipertermiju prihvata dvije mutacije u CACNA1S.[8]
Blokatori[uredi | uredi izvor]
Cav1.1 je blokiran putem dihidropiridina.
Također pogledajte[uredi | uredi izvor]
Reference[uredi | uredi izvor]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000081248 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026407 - 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 c "Entrez Gene: CACNA1S calcium channel, voltage-dependent, L type, alpha 1S subunit".
- ^ Proenza C, O'Brien J, Nakai J, Mukherjee S, Allen PD, Beam KG (februar 2002). "Identification of a region of RyR1 that participates in allosteric coupling with the alpha(1S) (Ca(V)1.1) II-III loop". J. Biol. Chem. 277 (8): 6530–5. doi:10.1074/jbc.M106471200. PMID 11726651.
- ^ Jurkat-Rott K, Lehmann-Horn F (august 2005). "Muscle channelopathies and critical points in functional and genetic studies". J. Clin. Invest. 115 (8): 2000–9. doi:10.1172/JCI25525. PMC 1180551. PMID 16075040.
- ^ "European Malignant Hyperthermia Group: Mutations in RYR1". Arhivirano s originala, 21. 3. 2016. Pristupljeno 14. 5. 2015.
Dopunska literatura[uredi | uredi izvor]
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- Elbaz A, Vale-Santos J, Jurkat-Rott K, Lapie P, Ophoff RA, Bady B, Links TP, Piussan C, Vila A, Monnier N (1995). "Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families". Am. J. Hum. Genet. 56 (2): 374–80. PMC 1801148. PMID 7847370.
- Boerman RH, Ophoff RA, Links TP, van Eijk R, Sandkuijl LA, Elbaz A, Vale-Santos JE, Wintzen AR, van Deutekom JC, Isles DE (1995). "Mutation in DHP receptor alpha 1 subunit (CACLN1A3) gene in a Dutch family with hypokalaemic periodic paralysis". J. Med. Genet. 32 (1): 44–7. doi:10.1136/jmg.32.1.44. PMC 1050178. PMID 7897626.
- Gregg RG, Couch F, Hogan K, Powers PA (1993). "Assignment of the human gene for the alpha 1 subunit of the skeletal muscle DHP-sensitive Ca2+ channel (CACNL1A3) to chromosome 1q31-q32". Genomics. 15 (1): 107–12. doi:10.1006/geno.1993.1017. PMID 7916735.
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- Ptácek LJ, Tawil R, Griggs RC, Engel AG, Layzer RB, Kwieciński H, McManis PG, Santiago L, Moore M, Fouad G (1994). "Dihydropyridine receptor mutations cause hypokalemic periodic paralysis". Cell. 77 (6): 863–8. doi:10.1016/0092-8674(94)90135-X. PMID 8004673. S2CID 13538157.
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- Iles DE, Segers B, Olde Weghuis D, Suijkerbuijk R, Mikala G, Schwartz A, Wieringa B (1994). "Refined localization of the alpha 1-subunit of the skeletal muscle L-type voltage-dependent calcium channel (CACNL1A3) to human chromosome 1q32 by in situ hybridization". Genomics. 19 (3): 561–3. doi:10.1006/geno.1994.1106. PMID 8188298.
- O'Brien RO, Taske NL, Hansbro PM, Matthaei KI, Hogan SP, Denborough MA, Foster PS (1995). "Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia". J. Med. Genet. 32 (11): 913–4. doi:10.1136/jmg.32.11.913. PMC 1051750. PMID 8592342.
- Hogan K, Gregg RG, Powers PA (1996). "The structure of the gene encoding the human skeletal muscle alpha 1 subunit of the dihydropyridine-sensitive L-type calcium channel (CACNL1A3)". Genomics. 31 (3): 392–4. doi:10.1006/geno.1996.0066. PMID 8838325.
- Robinson RL, Monnier N, Wolz W, Jung M, Reis A, Nuernberg G, Curran JL, Monsieurs K, Stieglitz P, Heytens L, Fricker R, van Broeckhoven C, Deufel T, Hopkins PM, Lunardi J, Mueller CR (1997). "A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees". Hum. Mol. Genet. 6 (6): 953–61. doi:10.1093/hmg/6.6.953. PMID 9175745.
- Monnier N, Procaccio V, Stieglitz P, Lunardi J (1997). "Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle". Am. J. Hum. Genet. 60 (6): 1316–25. doi:10.1086/515454. PMC 1716149. PMID 9199552.
- Meyers MB, Puri TS, Chien AJ, Gao T, Hsu PH, Hosey MM, Fishman GI (1998). "Sorcin associates with the pore-forming subunit of voltage-dependent L-type Ca2+ channels". J. Biol. Chem. 273 (30): 18930–5. doi:10.1074/jbc.273.30.18930. PMID 9668070.
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- Protasi F, Paolini C, Nakai J, Beam KG, Franzini-Armstrong C, Allen PD (2002). "Multiple regions of RyR1 mediate functional and structural interactions with alpha(1S)-dihydropyridine receptors in skeletal muscle". Biophys. J. 83 (6): 3230–44. Bibcode:2002BpJ....83.3230P. doi:10.1016/S0006-3495(02)75325-3. PMC 1302400. PMID 12496092.
- Carsana A, Fortunato G, De Sarno C, Brancadoro V, Salvatore F (2003). "Identification of new polymorphisms in the CACNA1S gene". Clin. Chem. Lab. Med. 41 (1): 20–2. doi:10.1515/CCLM.2003.004. PMID 12636044. S2CID 20811090.
Vanjski linkovi[uredi | uredi izvor]
- GeneReviews/NCBI/NIH/UW entry on Malignant Hyperthermia Susceptibility
- CACNA1S protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.