CAC1D_HUMAN
ID CAC1D_HUMAN Reviewed; 2161 AA.
AC Q01668; B0FYA3; Q13916; Q13931; Q71UT1; Q9UDC3;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 213.
DE RecName: Full=Voltage-dependent L-type calcium channel subunit alpha-1D;
DE AltName: Full=Calcium channel, L type, alpha-1 polypeptide, isoform 2;
DE AltName: Full=Voltage-gated calcium channel subunit alpha Cav1.3;
GN Name=CACNA1D; Synonyms=CACH3, CACN4, CACNL1A2, CCHL1A2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM NEURONAL-TYPE).
RC TISSUE=Neuroblastoma;
RX PubMed=1309651; DOI=10.1016/0896-6273(92)90109-q;
RA Williams M.E., Feldman D.H., McCue A.F., Brenner R., Velicelebi G.,
RA Ellis S.B., Harpold M.M.;
RT "Structure and functional expression of alpha 1, alpha 2, and beta subunits
RT of a novel human neuronal calcium channel subtype.";
RL Neuron 8:71-84(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BETA-CELL-TYPE).
RC TISSUE=Pancreatic islet;
RX PubMed=1309948; DOI=10.1073/pnas.89.2.584;
RA Seino S., Chen L., Seino M., Blondel O., Takeda J., Johnson J.H.,
RA Bell G.I.;
RT "Cloning of the alpha 1 subunit of a voltage-dependent calcium channel
RT expressed in pancreatic beta cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:584-588(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM BETA-CELL-TYPE), AND VARIANT
RP MET-1 INS.
RX PubMed=7557998; DOI=10.1006/geno.1995.1048;
RA Yamada Y., Masuda K., Li Q., Ihara Y., Kubota A., Miura T., Nakamura K.,
RA Fujii Y., Seino S., Seino Y.;
RT "The structures of the human calcium channel alpha 1 subunit (CACNL1A2) and
RT beta subunit (CACNLB3) genes.";
RL Genomics 27:312-319(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION, SUBUNIT, SUBCELLULAR
RP LOCATION, AND ALTERNATIVE SPLICING (ISOFORM 4).
RC TISSUE=Pancreas;
RX PubMed=18482979; DOI=10.1074/jbc.m802254200;
RA Singh A., Gebhart M., Fritsch R., Sinnegger-Brauns M.J., Poggiani C.,
RA Hoda J.C., Engel J., Romanin C., Striessnig J., Koschak A.;
RT "Modulation of voltage- and Ca2+-dependent gating of CaV1.3 L-type calcium
RT channels by alternative splicing of a C-terminal regulatory domain.";
RL J. Biol. Chem. 283:20733-20744(2008).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-125.
RX PubMed=9894156; DOI=10.1038/emm.1998.36;
RA Kim H.-L., Chang Y.J., Lee S.M., Hong Y.-S.;
RT "Genomic structure of the regulatory region of the voltage-gated calcium
RT channel alpha 1D.";
RL Exp. Mol. Med. 30:246-251(1998).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 747-1039, AND TISSUE SPECIFICITY.
RC TISSUE=Lung carcinoma;
RX PubMed=1335101; DOI=10.1016/s0025-6196(12)61144-6;
RA Oguro-Okano M., Griesmann G.E., Wieben E.D., Slaymaker S.J., Snutch T.P.,
RA Lennon V.A.;
RT "Molecular diversity of neuronal-type calcium channels identified in small
RT cell lung carcinoma.";
RL Mayo Clin. Proc. 67:1150-1159(1992).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 502-510 IN COMPLEX WITH HLA.
RX PubMed=21280120; DOI=10.1002/pro.559;
RA Loll B., Ruckert C., Hee C.S., Saenger W., Uchanska-Ziegler B., Ziegler A.;
RT "Loss of recognition by cross-reactive T cells and its relation to a C-
RT terminus-induced conformational reorientation of an HLA-B*2705-bound
RT peptide.";
RL Protein Sci. 20:278-290(2011).
RN [9]
RP VARIANT SANDD GLY-403 INS, AND CHARACTERIZATION OF VARIANT SANDD GLY-403
RP INS.
RX PubMed=21131953; DOI=10.1038/nn.2694;
RA Baig S.M., Koschak A., Lieb A., Gebhart M., Dafinger C., Nurnberg G.,
RA Ali A., Ahmad I., Sinnegger-Brauns M.J., Brandt N., Engel J., Mangoni M.E.,
RA Farooq M., Khan H.U., Nurnberg P., Striessnig J., Bolz H.J.;
RT "Loss of Ca(v)1.3 (CACNA1D) function in a human channelopathy with
RT bradycardia and congenital deafness.";
RL Nat. Neurosci. 14:77-84(2011).
RN [10]
RP VARIANT GLY-749.
RX PubMed=22495309; DOI=10.1038/nature10989;
RA O'Roak B.J., Vives L., Girirajan S., Karakoc E., Krumm N., Coe B.P.,
RA Levy R., Ko A., Lee C., Smith J.D., Turner E.H., Stanaway I.B., Vernot B.,
RA Malig M., Baker C., Reilly B., Akey J.M., Borenstein E., Rieder M.J.,
RA Nickerson D.A., Bernier R., Shendure J., Eichler E.E.;
RT "Sporadic autism exomes reveal a highly interconnected protein network of
RT de novo mutations.";
RL Nature 485:246-250(2012).
RN [11]
RP VARIANT ARG-407.
RX PubMed=22542183; DOI=10.1016/j.neuron.2012.04.009;
RA Iossifov I., Ronemus M., Levy D., Wang Z., Hakker I., Rosenbaum J.,
RA Yamrom B., Lee Y.H., Narzisi G., Leotta A., Kendall J., Grabowska E.,
RA Ma B., Marks S., Rodgers L., Stepansky A., Troge J., Andrews P.,
RA Bekritsky M., Pradhan K., Ghiban E., Kramer M., Parla J., Demeter R.,
RA Fulton L.L., Fulton R.S., Magrini V.J., Ye K., Darnell J.C., Darnell R.B.,
RA Mardis E.R., Wilson R.K., Schatz M.C., McCombie W.R., Wigler M.;
RT "De novo gene disruptions in children on the autistic spectrum.";
RL Neuron 74:285-299(2012).
RN [12]
RP VARIANTS PASNA ASP-403 AND MET-750, AND CHARACTERIZATION OF VARIANTS PASNA
RP ASP-403 AND MET-750.
RX PubMed=23913001; DOI=10.1038/ng.2695;
RA Scholl U.I., Goh G., Stoelting G., de Oliveira R.C., Choi M., Overton J.D.,
RA Fonseca A.L., Korah R., Starker L.F., Kunstman J.W., Prasad M.L.,
RA Hartung E.A., Mauras N., Benson M.R., Brady T., Shapiro J.R., Loring E.,
RA Nelson-Williams C., Libutti S.K., Mane S., Hellman P., Westin G.,
RA Aakerstroem G., Bjoerklund P., Carling T., Fahlke C., Hidalgo P.,
RA Lifton R.P.;
RT "Somatic and germline CACNA1D calcium channel mutations in aldosterone-
RT producing adenomas and primary aldosteronism.";
RL Nat. Genet. 45:1050-1054(2013).
RN [13]
RP INVOLVEMENT IN AUTISM SPECTRUM DISORSERS, FUNCTION, AND CHARACTERIZATION OF
RP VARIANTS ARG-407 AND GLY-749.
RX PubMed=25620733; DOI=10.1016/j.biopsych.2014.11.020;
RA Pinggera A., Lieb A., Benedetti B., Lampert M., Monteleone S., Liedl K.R.,
RA Tuluc P., Striessnig J.;
RT "CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-
RT type calcium channels.";
RL Biol. Psychiatry 77:816-822(2015).
RN [14]
RP INVOLVEMENT IN AUTISM SPECTRUM DISORSERS, FUNCTION, VARIANT LEU-401, AND
RP CHARACTERIZATION OF VARIANT LEU-401.
RX PubMed=28472301; DOI=10.1093/hmg/ddx175;
RA Pinggera A., Mackenroth L., Rump A., Schallner J., Beleggia F., Wollnik B.,
RA Striessnig J.;
RT "New gain-of-function mutation shows CACNA1D as recurrently mutated gene in
RT autism spectrum disorders and epilepsy.";
RL Hum. Mol. Genet. 26:2923-2932(2017).
CC -!- FUNCTION: Voltage-sensitive calcium channels (VSCC) mediate the entry
CC of calcium ions into excitable cells and are also involved in a variety
CC of calcium-dependent processes, including muscle contraction, hormone
CC or neurotransmitter release, gene expression, cell motility, cell
CC division and cell death. The isoform alpha-1D gives rise to L-type
CC calcium currents. Long-lasting (L-type) calcium channels belong to the
CC 'high-voltage activated' (HVA) group. They are blocked by
CC dihydropyridines (DHP), phenylalkylamines, and by benzothiazepines.
CC {ECO:0000269|PubMed:18482979, ECO:0000269|PubMed:25620733,
CC ECO:0000269|PubMed:28472301}.
CC -!- SUBUNIT: Voltage-dependent calcium channels are multisubunit complexes,
CC consisting of alpha-1, alpha-2, beta and delta subunits in a 1:1:1:1
CC ratio. The channel activity is directed by the pore-forming and
CC voltage-sensitive alpha-1 subunit. In many cases, this subunit is
CC sufficient to generate voltage-sensitive calcium channel activity. The
CC auxiliary subunits beta and alpha-2/delta linked by a disulfide bridge
CC regulate the channel activity. Channel activity is further modulated,
CC depending on the presence of specific delta subunit isoforms. Interacts
CC (via IQ domain) with CABP1 and CABP4 in a calcium independent manner
CC (By similarity). Interacts with RIMBP2 (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC Q01668; Q9BYB0-1: SHANK3; NbExp=2; IntAct=EBI-9207771, EBI-20939234;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:18482979}; Multi-
CC pass membrane protein {ECO:0000269|PubMed:18482979}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Comment=Additional isoforms seem to exist.;
CC Name=Neuronal-type;
CC IsoId=Q01668-1; Sequence=Displayed;
CC Name=Beta-cell-type;
CC IsoId=Q01668-2; Sequence=VSP_000913, VSP_000914;
CC Name=4; Synonyms=Ca(V)1.3(42A);
CC IsoId=Q01668-4; Sequence=VSP_047921, VSP_047922;
CC Name=3;
CC IsoId=Q01668-3; Sequence=VSP_046743, VSP_046744;
CC -!- TISSUE SPECIFICITY: Expressed in pancreatic islets and in brain, where
CC it has been seen in cerebral cortex, hippocampus, basal ganglia,
CC habenula and thalamus. Expressed in the small cell lung carcinoma cell
CC line SCC-9. No expression in skeletal muscle.
CC {ECO:0000269|PubMed:1335101}.
CC -!- DOMAIN: Each of the four internal repeats contains five hydrophobic
CC transmembrane segments (S1, S2, S3, S5, S6) and one positively charged
CC transmembrane segment (S4). S4 segments probably represent the voltage-
CC sensor and are characterized by a series of positively charged amino
CC acids at every third position.
CC -!- POLYMORPHISM: A change from seven to eight ATG trinucleotide repeats,
CC resulting in an additional N-terminal methionine, has been found in a
CC patient with non-insulin-dependent diabetes mellitus (NIDDM).
CC {ECO:0000269|PubMed:7557998}.
CC -!- DISEASE: Sinoatrial node dysfunction and deafness (SANDD) [MIM:614896]:
CC A disease characterized by congenital severe to profound deafness
CC without vestibular dysfunction, associated with episodic syncope due to
CC intermittent pronounced bradycardia. {ECO:0000269|PubMed:21131953}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Primary aldosteronism, seizures, and neurologic abnormalities
CC (PASNA) [MIM:615474]: A disorder characterized by hypertension,
CC hypokalemia, and high aldosterone levels with low plasma renin activity
CC and an elevated aldosterone/renin ratio. Other features include
CC generalized seizures, cerebral palsy, spasticity, intellectual
CC disability, and developmental delay. {ECO:0000269|PubMed:23913001}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Note=Gain of function variations affecting the gene
CC represented in this entry may be associated with susceptibility to
CC autism spetrum disorders. {ECO:0000269|PubMed:22495309,
CC ECO:0000269|PubMed:22542183, ECO:0000269|PubMed:25620733,
CC ECO:0000269|PubMed:28472301}.
CC -!- MISCELLANEOUS: [Isoform 4]: Expressed at 5% to 15% of isoform Neuronal-
CC type in brain tissues, increased current density. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the calcium channel alpha-1 subunit (TC
CC 1.A.1.11) family. CACNA1D subfamily. {ECO:0000305}.
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DR EMBL; M76558; AAA58402.1; -; mRNA.
DR EMBL; M83566; AAA35629.1; -; mRNA.
DR EMBL; D43747; BAA07804.1; -; Genomic_DNA.
DR EMBL; EU363339; ABY66526.1; -; mRNA.
DR EMBL; AC005905; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC012467; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC024149; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC132810; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF055575; AAD08651.1; -; Genomic_DNA.
DR CCDS; CCDS2872.1; -. [Q01668-2]
DR CCDS; CCDS46848.1; -. [Q01668-1]
DR CCDS; CCDS46849.1; -. [Q01668-3]
DR PIR; JH0564; JH0564.
DR RefSeq; NP_000711.1; NM_000720.3. [Q01668-2]
DR RefSeq; NP_001122311.1; NM_001128839.2. [Q01668-3]
DR RefSeq; NP_001122312.1; NM_001128840.2. [Q01668-1]
DR PDB; 3LV3; X-ray; 1.94 A; C=502-510.
DR PDBsum; 3LV3; -.
DR AlphaFoldDB; Q01668; -.
DR SMR; Q01668; -.
DR BioGRID; 107230; 10.
DR DIP; DIP-48998N; -.
DR IntAct; Q01668; 4.
DR STRING; 9606.ENSP00000288139; -.
DR BindingDB; Q01668; -.
DR ChEMBL; CHEMBL4138; -.
DR DrugBank; DB01118; Amiodarone.
DR DrugBank; DB09229; Aranidipine.
DR DrugBank; DB09231; Benidipine.
DR DrugBank; DB13746; Bioallethrin.
DR DrugBank; DB11148; Butamben.
DR DrugBank; DB11093; Calcium citrate.
DR DrugBank; DB11348; Calcium Phosphate.
DR DrugBank; DB14481; Calcium phosphate dihydrate.
DR DrugBank; DB09232; Cilnidipine.
DR DrugBank; DB00568; Cinnarizine.
DR DrugBank; DB04920; Clevidipine.
DR DrugBank; DB04855; Dronedarone.
DR DrugBank; DB06751; Drotaverine.
DR DrugBank; DB00228; Enflurane.
DR DrugBank; DB00153; Ergocalciferol.
DR DrugBank; DB00898; Ethanol.
DR DrugBank; DB01023; Felodipine.
DR DrugBank; DB13961; Fish oil.
DR DrugBank; DB00270; Isradipine.
DR DrugBank; DB09236; Lacidipine.
DR DrugBank; DB09237; Levamlodipine.
DR DrugBank; DB00825; Levomenthol.
DR DrugBank; DB00653; Magnesium sulfate.
DR DrugBank; DB09238; Manidipine.
DR DrugBank; DB01388; Mibefradil.
DR DrugBank; DB01110; Miconazole.
DR DrugBank; DB00622; Nicardipine.
DR DrugBank; DB01115; Nifedipine.
DR DrugBank; DB06712; Nilvadipine.
DR DrugBank; DB00393; Nimodipine.
DR DrugBank; DB00401; Nisoldipine.
DR DrugBank; DB01054; Nitrendipine.
DR DrugBank; DB00252; Phenytoin.
DR DrugBank; DB00243; Ranolazine.
DR DrugBank; DB00421; Spironolactone.
DR DrugBank; DB00273; Topiramate.
DR DrugBank; DB09089; Trimebutine.
DR DrugCentral; Q01668; -.
DR GuidetoPHARMACOLOGY; 530; -.
DR TCDB; 1.A.1.11.31; the voltage-gated ion channel (vic) superfamily.
DR GlyGen; Q01668; 4 sites, 1 O-linked glycan (1 site).
DR iPTMnet; Q01668; -.
DR PhosphoSitePlus; Q01668; -.
DR BioMuta; CACNA1D; -.
DR DMDM; 116241275; -.
DR MassIVE; Q01668; -.
DR PaxDb; Q01668; -.
DR PeptideAtlas; Q01668; -.
DR PRIDE; Q01668; -.
DR ProteomicsDB; 2547; -.
DR ProteomicsDB; 57981; -. [Q01668-1]
DR ProteomicsDB; 57982; -. [Q01668-2]
DR ABCD; Q01668; 2 sequenced antibodies.
DR Antibodypedia; 4062; 323 antibodies from 32 providers.
DR DNASU; 776; -.
DR Ensembl; ENST00000288139.11; ENSP00000288139.3; ENSG00000157388.20. [Q01668-2]
DR Ensembl; ENST00000350061.11; ENSP00000288133.5; ENSG00000157388.20. [Q01668-1]
DR Ensembl; ENST00000422281.7; ENSP00000409174.2; ENSG00000157388.20. [Q01668-3]
DR GeneID; 776; -.
DR KEGG; hsa:776; -.
DR MANE-Select; ENST00000350061.11; ENSP00000288133.5; NM_001128840.3; NP_001122312.1.
DR UCSC; uc003dgu.6; human. [Q01668-1]
DR CTD; 776; -.
DR DisGeNET; 776; -.
DR GeneCards; CACNA1D; -.
DR HGNC; HGNC:1391; CACNA1D.
DR HPA; ENSG00000157388; Tissue enhanced (brain).
DR MalaCards; CACNA1D; -.
DR MIM; 114206; gene.
DR MIM; 614896; phenotype.
DR MIM; 615474; phenotype.
DR neXtProt; NX_Q01668; -.
DR OpenTargets; ENSG00000157388; -.
DR Orphanet; 85142; NON RARE IN EUROPE: Aldosterone-producing adenoma.
DR Orphanet; 369929; Primary hyperaldosteronism-seizures-neurological abnormalities syndrome.
DR Orphanet; 324321; Sinoatrial node dysfunction and deafness.
DR PharmGKB; PA84; -.
DR VEuPathDB; HostDB:ENSG00000157388; -.
DR eggNOG; KOG2301; Eukaryota.
DR GeneTree; ENSGT00940000154839; -.
DR HOGENOM; CLU_000540_0_1_1; -.
DR InParanoid; Q01668; -.
DR OMA; YEIADAC; -.
DR OrthoDB; 172471at2759; -.
DR PhylomeDB; Q01668; -.
DR TreeFam; TF312805; -.
DR PathwayCommons; Q01668; -.
DR Reactome; R-HSA-400042; Adrenaline,noradrenaline inhibits insulin secretion.
DR Reactome; R-HSA-419037; NCAM1 interactions.
DR Reactome; R-HSA-422356; Regulation of insulin secretion.
DR Reactome; R-HSA-9662360; Sensory processing of sound by inner hair cells of the cochlea.
DR SignaLink; Q01668; -.
DR SIGNOR; Q01668; -.
DR BioGRID-ORCS; 776; 14 hits in 1077 CRISPR screens.
DR ChiTaRS; CACNA1D; human.
DR GeneWiki; Cav1.3; -.
DR GenomeRNAi; 776; -.
DR Pharos; Q01668; Tclin.
DR PRO; PR:Q01668; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q01668; protein.
DR Bgee; ENSG00000157388; Expressed in buccal mucosa cell and 148 other tissues.
DR ExpressionAtlas; Q01668; baseline and differential.
DR Genevisible; Q01668; HS.
DR GO; GO:1990454; C:L-type voltage-gated calcium channel complex; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; ISS:BHF-UCL.
DR GO; GO:0005891; C:voltage-gated calcium channel complex; IDA:UniProtKB.
DR GO; GO:0030018; C:Z disc; ISS:BHF-UCL.
DR GO; GO:0051393; F:alpha-actinin binding; IPI:BHF-UCL.
DR GO; GO:0030506; F:ankyrin binding; ISS:BHF-UCL.
DR GO; GO:0005262; F:calcium channel activity; IMP:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005245; F:voltage-gated calcium channel activity; IDA:UniProtKB.
DR GO; GO:0086007; F:voltage-gated calcium channel activity involved in cardiac muscle cell action potential; IC:BHF-UCL.
DR GO; GO:0086059; F:voltage-gated calcium channel activity involved SA node cell action potential; IMP:BHF-UCL.
DR GO; GO:0007188; P:adenylate cyclase-modulating G protein-coupled receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0070509; P:calcium ion import; IDA:BHF-UCL.
DR GO; GO:0098703; P:calcium ion import across plasma membrane; IBA:GO_Central.
DR GO; GO:0070588; P:calcium ion transmembrane transport; ISS:BHF-UCL.
DR GO; GO:0006816; P:calcium ion transport; IDA:UniProtKB.
DR GO; GO:0086002; P:cardiac muscle cell action potential involved in contraction; IMP:BHF-UCL.
DR GO; GO:0086012; P:membrane depolarization during cardiac muscle cell action potential; IC:BHF-UCL.
DR GO; GO:0086046; P:membrane depolarization during SA node cell action potential; IMP:BHF-UCL.
DR GO; GO:0045762; P:positive regulation of adenylate cyclase activity; ISS:UniProtKB.
DR GO; GO:0051928; P:positive regulation of calcium ion transport; IDA:BHF-UCL.
DR GO; GO:0060372; P:regulation of atrial cardiac muscle cell membrane repolarization; ISS:BHF-UCL.
DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IMP:BHF-UCL.
DR GO; GO:1901379; P:regulation of potassium ion transmembrane transport; ISS:BHF-UCL.
DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; ISS:BHF-UCL.
DR GO; GO:0007605; P:sensory perception of sound; IMP:BHF-UCL.
DR Gene3D; 1.20.120.350; -; 4.
DR InterPro; IPR031688; CAC1F_C.
DR InterPro; IPR031649; GPHH_dom.
DR InterPro; IPR005821; Ion_trans_dom.
DR InterPro; IPR005452; LVDCC_a1dsu.
DR InterPro; IPR014873; VDCC_a1su_IQ.
DR InterPro; IPR005446; VDCC_L_a1su.
DR InterPro; IPR002077; VDCCAlpha1.
DR InterPro; IPR027359; Volt_channel_dom_sf.
DR Pfam; PF08763; Ca_chan_IQ; 1.
DR Pfam; PF16885; CAC1F_C; 2.
DR Pfam; PF16905; GPHH; 1.
DR Pfam; PF00520; Ion_trans; 4.
DR PRINTS; PR00167; CACHANNEL.
DR PRINTS; PR01630; LVDCCALPHA1.
DR PRINTS; PR01636; LVDCCALPHA1D.
DR SMART; SM01062; Ca_chan_IQ; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Calcium channel;
KW Calcium transport; Deafness; Disease variant; Disulfide bond; Epilepsy;
KW Glycoprotein; Ion channel; Ion transport; Membrane; Metal-binding;
KW Phosphoprotein; Reference proteome; Repeat; Transmembrane;
KW Transmembrane helix; Transport; Triplet repeat expansion;
KW Voltage-gated channel.
FT CHAIN 1..2161
FT /note="Voltage-dependent L-type calcium channel subunit
FT alpha-1D"
FT /id="PRO_0000053933"
FT TOPO_DOM 1..126
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 127..145
FT /note="Helical; Name=S1 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 146..163
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 164..183
FT /note="Helical; Name=S2 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 184..195
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 196..214
FT /note="Helical; Name=S3 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 215..235
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 236..254
FT /note="Helical; Name=S4 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 255..273
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 274..293
FT /note="Helical; Name=S5 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 294..381
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 382..406
FT /note="Helical; Name=S6 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 407..523
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 524..543
FT /note="Helical; Name=S1 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 544..558
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 559..577
FT /note="Helical; Name=S2 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 578..585
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 586..604
FT /note="Helical; Name=S3 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 605..614
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 615..633
FT /note="Helical; Name=S4 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 634..652
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 653..673
FT /note="Helical; Name=S5 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 674..727
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 728..752
FT /note="Helical; Name=S6 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 753..886
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 887..905
FT /note="Helical; Name=S1 of repeat III"
FT /evidence="ECO:0000255"
FT TOPO_DOM 906..921
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 922..941
FT /note="Helical; Name=S2 of repeat III"
FT /evidence="ECO:0000255"
FT TOPO_DOM 942..953
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 954..972
FT /note="Helical; Name=S3 of repeat III"
FT /evidence="ECO:0000255"
FT TOPO_DOM 973..978
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 979..998
FT /note="Helical; Name=S4 of repeat III"
FT /evidence="ECO:0000255"
FT TOPO_DOM 999..1017
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 1018..1037
FT /note="Helical; Name=S5 of repeat III"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1038..1127
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 1128..1148
FT /note="Helical; Name=S6 of repeat III"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1149..1205
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 1206..1224
FT /note="Helical; Name=S1 of repeat IV"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1225..1239
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 1240..1259
FT /note="Helical; Name=S2 of repeat IV"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1260..1266
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 1267..1288
FT /note="Helical; Name=S3 of repeat IV"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1289..1313
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 1314..1333
FT /note="Helical; Name=S4 of repeat IV"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1334..1352
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 1353..1372
FT /note="Helical; Name=S5 of repeat IV"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1373..1439
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 1440..1464
FT /note="Helical; Name=S6 of repeat IV"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1465..2161
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REPEAT 113..409
FT /note="I"
FT REPEAT 509..755
FT /note="II"
FT REPEAT 873..1155
FT /note="III"
FT REPEAT 1192..1467
FT /note="IV"
FT REGION 1..21
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 30..49
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 64..100
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 429..446
FT /note="Binding to the beta subunit"
FT /evidence="ECO:0000250"
FT REGION 449..482
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 766..850
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1075..1165
FT /note="Dihydropyridine binding"
FT /evidence="ECO:0000250"
FT REGION 1420..1486
FT /note="Dihydropyridine binding"
FT /evidence="ECO:0000250"
FT REGION 1432..1475
FT /note="Phenylalkylamine binding"
FT /evidence="ECO:0000250"
FT REGION 1659..1678
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1684..1804
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1872..1919
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2108..2152
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 35..49
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 462..482
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 766..788
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 803..822
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 823..838
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1697..1712
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1737..1766
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1782..1804
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1875..1908
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 364
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P07293"
FT BINDING 705
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P07293"
FT BINDING 1101
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P07293"
FT CARBOHYD 155
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 225
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 329
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 373..392
FT /note="MNDAMGFELPWVYFVSLVIF -> VNDAIGWEWPWVYFVSLIIL (in
FT isoform Beta-cell-type)"
FT /evidence="ECO:0000303|PubMed:1309948"
FT /id="VSP_000913"
FT VAR_SEQ 493
FT /note="C -> WCWWRRRGAAKAGPSGCRRWG (in isoform Beta-cell-
FT type)"
FT /evidence="ECO:0000303|PubMed:1309948"
FT /id="VSP_000914"
FT VAR_SEQ 1291..1305
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:18482979"
FT /id="VSP_046743"
FT VAR_SEQ 1642..1647
FT /note="AGLRTL -> MLERML (in isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_047921"
FT VAR_SEQ 1648..2161
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_047922"
FT VAR_SEQ 1803..1811
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:18482979"
FT /id="VSP_046744"
FT VARIANT 1
FT /note="M -> MM (in a NIDDM patient)"
FT /evidence="ECO:0000269|PubMed:7557998"
FT /id="VAR_001497"
FT VARIANT 401
FT /note="V -> L (probable disease-associated variant found in
FT a patient with autism spectrum disorder; gain of function;
FT increases channel activity; the mutant channel is activated
FT at less depolarized potentials with an increased current
FT density and impaired channel inactivation)"
FT /evidence="ECO:0000269|PubMed:28472301"
FT /id="VAR_079531"
FT VARIANT 403
FT /note="G -> D (in PASNA; the mutant channel is activated at
FT less depolarized potentials; results in increased current
FT density and impaired channel inactivation)"
FT /evidence="ECO:0000269|PubMed:23913001"
FT /id="VAR_070868"
FT VARIANT 403
FT /note="G -> GG (in SANDD; the mutant channels are unable to
FT conduct calcium ions currents and have abnormal voltage-
FT dependent gating)"
FT /evidence="ECO:0000269|PubMed:21131953"
FT /id="VAR_069170"
FT VARIANT 407
FT /note="G -> R (probable disease-associated variant found in
FT a patient with autism spectrum disorder; gain of function;
FT increases channel activity; the mutant channel is activated
FT at less depolarized potentials with an increased current
FT density and impaired channel inactivation;
FT dbSNP:rs1163276899)"
FT /evidence="ECO:0000269|PubMed:22542183,
FT ECO:0000269|PubMed:25620733"
FT /id="VAR_079532"
FT VARIANT 749
FT /note="A -> G (probable disease-associated variant found in
FT a patient with autism spectrum disorder; gain of function;
FT increases channel activity; the mutant channel is activated
FT at less depolarized potentials with an increased current
FT density and impaired channel inactivation)"
FT /evidence="ECO:0000269|PubMed:22495309,
FT ECO:0000269|PubMed:25620733"
FT /id="VAR_079533"
FT VARIANT 750
FT /note="I -> M (in PASNA; the mutant channel is activated at
FT less depolarized potentials; results in increased current
FT density; dbSNP:rs41276445)"
FT /evidence="ECO:0000269|PubMed:23913001"
FT /id="VAR_070869"
FT VARIANT 2097
FT /note="D -> N (in dbSNP:rs41276455)"
FT /id="VAR_061103"
FT CONFLICT 576
FT /note="S -> T (in Ref. 3; BAA07804)"
FT /evidence="ECO:0000305"
FT CONFLICT 637
FT /note="S -> C (in Ref. 1; AAA58402)"
FT /evidence="ECO:0000305"
FT CONFLICT 650
FT /note="I -> S (in Ref. 1; AAA58402)"
FT /evidence="ECO:0000305"
FT CONFLICT 918
FT /note="I -> T (in Ref. 3; BAA07804)"
FT /evidence="ECO:0000305"
FT CONFLICT 960
FT /note="M -> I (in Ref. 3; BAA07804)"
FT /evidence="ECO:0000305"
FT CONFLICT 1289..1290
FT /note="Missing (in Ref. 3; BAA07804)"
FT /evidence="ECO:0000305"
FT CONFLICT 1346
FT /note="S -> F (in Ref. 1; AAA58402)"
FT /evidence="ECO:0000305"
FT CONFLICT 1433
FT /note="Y -> H (in Ref. 1; AAA58402)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 2161 AA; 245141 MW; 31B0ADFCDB30B575 CRC64;
MMMMMMMKKM QHQRQQQADH ANEANYARGT RLPLSGEGPT SQPNSSKQTV LSWQAAIDAA
RQAKAAQTMS TSAPPPVGSL SQRKRQQYAK SKKQGNSSNS RPARALFCLS LNNPIRRACI
SIVEWKPFDI FILLAIFANC VALAIYIPFP EDDSNSTNHN LEKVEYAFLI IFTVETFLKI
IAYGLLLHPN AYVRNGWNLL DFVIVIVGLF SVILEQLTKE TEGGNHSSGK SGGFDVKALR
AFRVLRPLRL VSGVPSLQVV LNSIIKAMVP LLHIALLVLF VIIIYAIIGL ELFIGKMHKT
CFFADSDIVA EEDPAPCAFS GNGRQCTANG TECRSGWVGP NGGITNFDNF AFAMLTVFQC
ITMEGWTDVL YWMNDAMGFE LPWVYFVSLV IFGSFFVLNL VLGVLSGEFS KEREKAKARG
DFQKLREKQQ LEEDLKGYLD WITQAEDIDP ENEEEGGEEG KRNTSMPTSE TESVNTENVS
GEGENRGCCG SLCQAISKSK LSRRWRRWNR FNRRRCRAAV KSVTFYWLVI VLVFLNTLTI
SSEHYNQPDW LTQIQDIANK VLLALFTCEM LVKMYSLGLQ AYFVSLFNRF DCFVVCGGIT
ETILVELEIM SPLGISVFRC VRLLRIFKVT RHWTSLSNLV ASLLNSMKSI ASLLLLLFLF
IIIFSLLGMQ LFGGKFNFDE TQTKRSTFDN FPQALLTVFQ ILTGEDWNAV MYDGIMAYGG
PSSSGMIVCI YFIILFICGN YILLNVFLAI AVDNLADAES LNTAQKEEAE EKERKKIARK
ESLENKKNNK PEVNQIANSD NKVTIDDYRE EDEDKDPYPP CDVPVGEEEE EEEEDEPEVP
AGPRPRRISE LNMKEKIAPI PEGSAFFILS KTNPIRVGCH KLINHHIFTN LILVFIMLSS
AALAAEDPIR SHSFRNTILG YFDYAFTAIF TVEILLKMTT FGAFLHKGAF CRNYFNLLDM
LVVGVSLVSF GIQSSAISVV KILRVLRVLR PLRAINRAKG LKHVVQCVFV AIRTIGNIMI
VTTLLQFMFA CIGVQLFKGK FYRCTDEAKS NPEECRGLFI LYKDGDVDSP VVRERIWQNS
DFNFDNVLSA MMALFTVSTF EGWPALLYKA IDSNGENIGP IYNHRVEISI FFIIYIIIVA
FFMMNIFVGF VIVTFQEQGE KEYKNCELDK NQRQCVEYAL KARPLRRYIP KNPYQYKFWY
VVNSSPFEYM MFVLIMLNTL CLAMQHYEQS KMFNDAMDIL NMVFTGVFTV EMVLKVIAFK
PKGYFSDAWN TFDSLIVIGS IIDVALSEAD PTESENVPVP TATPGNSEES NRISITFFRL
FRVMRLVKLL SRGEGIRTLL WTFIKSFQAL PYVALLIAML FFIYAVIGMQ MFGKVAMRDN
NQINRNNNFQ TFPQAVLLLF RCATGEAWQE IMLACLPGKL CDPESDYNPG EEYTCGSNFA
IVYFISFYML CAFLIINLFV AVIMDNFDYL TRDWSILGPH HLDEFKRIWS EYDPEAKGRI
KHLDVVTLLR RIQPPLGFGK LCPHRVACKR LVAMNMPLNS DGTVMFNATL FALVRTALKI
KTEGNLEQAN EELRAVIKKI WKKTSMKLLD QVVPPAGDDE VTVGKFYATF LIQDYFRKFK
KRKEQGLVGK YPAKNTTIAL QAGLRTLHDI GPEIRRAISC DLQDDEPEET KREEEDDVFK
RNGALLGNHV NHVNSDRRDS LQQTNTTHRP LHVQRPSIPP ASDTEKPLFP PAGNSVCHNH
HNHNSIGKQV PTSTNANLNN ANMSKAAHGK RPSIGNLEHV SENGHHSSHK HDREPQRRSS
VKRTRYYETY IRSDSGDEQL PTICREDPEI HGYFRDPHCL GEQEYFSSEE CYEDDSSPTW
SRQNYGYYSR YPGRNIDSER PRGYHHPQGF LEDDDSPVCY DSRRSPRRRL LPPTPASHRR
SSFNFECLRR QSSQEEVPSS PIFPHRTALP LHLMQQQIMA VAGLDSSKAQ KYSPSHSTRS
WATPPATPPY RDWTPCYTPL IQVEQSEALD QVNGSLPSLH RSSWYTDEPD ISYRTFTPAS
LTVPSSFRNK NSDKQRSADS LVEAVLISEG LGRYARDPKF VSATKHEIAD ACDLTIDEME
SAASTLLNGN VRPRANGDVG PLSHRQDYEL QDFGPGYSDE EPDPGRDEED LADEMICITT
L
