CA2D3_HUMAN
ID CA2D3_HUMAN Reviewed; 1091 AA.
AC Q8IZS8; B2RPL6; Q9NY16; Q9NY18;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=Voltage-dependent calcium channel subunit alpha-2/delta-3;
DE AltName: Full=Voltage-gated calcium channel subunit alpha-2/delta-3;
DE Contains:
DE RecName: Full=Voltage-dependent calcium channel subunit alpha-2-3;
DE Contains:
DE RecName: Full=Voltage-dependent calcium channel subunit delta-3;
DE Flags: Precursor;
GN Name=CACNA2D3;
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] (ISOFORMS 2 AND 3).
RC TISSUE=Brain;
RX PubMed=11245980; DOI=10.1016/s0378-1119(00)00600-4;
RA Hanke S., Bugert P., Chudek J., Kovacs G.;
RT "Cloning a calcium channel alpha2delta-3 subunit gene from a putative tumor
RT suppressor gene region at chromosome 3p21.1 in conventional renal cell
RT carcinoma.";
RL Gene 264:69-75(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=12181424; DOI=10.1124/mol.62.3.485;
RA Qin N., Yagel S., Momplaisir M.-L., Codd E.E., D'Andrea M.R.;
RT "Molecular cloning and characterization of the human voltage-gated calcium
RT channel alpha(2)delta-4 subunit.";
RL Mol. Pharmacol. 62:485-496(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=11687876; DOI=10.1007/s00232-001-0072-7;
RA Gong H.C., Hang J., Kohler W., Li L., Su T.-Z.;
RT "Tissue-specific expression and gabapentin-binding properties of calcium
RT channel alpha2delta subunit subtypes.";
RL J. Membr. Biol. 184:35-43(2001).
CC -!- FUNCTION: The alpha-2/delta subunit of voltage-dependent calcium
CC channels regulates calcium current density and activation/inactivation
CC kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-
CC type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR
CC CACNA1D) but not T-type (CACNA1G) (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Dimer formed of alpha-2-2 and delta-2 chains; disulfide-
CC linked. Voltage-dependent calcium channels are multisubunit complexes,
CC consisting of alpha-1 (CACNA1), alpha-2 (CACNA2D), beta (CACNB) and
CC delta (CACNA2D) subunits in a 1:1:1:1 ratio (By similarity).
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I
CC membrane protein {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q8IZS8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IZS8-2; Sequence=VSP_028064;
CC Name=3;
CC IsoId=Q8IZS8-3; Sequence=VSP_028064, VSP_028065, VSP_028066,
CC VSP_028067;
CC -!- TISSUE SPECIFICITY: Only detected in brain. Not present in lung,
CC testis, aorta, spleen, jejunum, ventricular muscle and kidney (at
CC protein level). According to PubMed:11687876, it is brain-specific,
CC while according to PubMed:11245980, it is widely expressed.
CC {ECO:0000269|PubMed:11687876}.
CC -!- DOMAIN: The MIDAS-like motif in the VWFA domain binds divalent metal
CC cations and is required to promote trafficking of the alpha-1 (CACNA1)
CC subunit to the plasma membrane by an integrin-like switch.
CC {ECO:0000250}.
CC -!- PTM: N-glycosylated. {ECO:0000250}.
CC -!- PTM: May be proteolytically processed into subunits alpha-2-3 and
CC delta-3 that are disulfide-linked. It is however unclear whether such
CC cleavage really takes place in vivo and has a functional role (By
CC similarity). {ECO:0000250}.
CC -!- MISCELLANEOUS: In contrast to CACNA2D1 and CACNA2D2, it does not bind
CC gabapentin, an antiepileptic drug.
CC -!- SIMILARITY: Belongs to the calcium channel subunit alpha-2/delta
CC family. {ECO:0000305}.
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DR EMBL; AJ272268; CAB75962.1; -; mRNA.
DR EMBL; AJ272213; CAB75878.1; -; mRNA.
DR EMBL; AF516696; AAN06673.1; -; mRNA.
DR EMBL; BC137502; AAI37503.1; -; mRNA.
DR EMBL; BC137505; AAI37506.1; -; mRNA.
DR CCDS; CCDS54598.1; -. [Q8IZS8-1]
DR RefSeq; NP_060868.2; NM_018398.2. [Q8IZS8-1]
DR AlphaFoldDB; Q8IZS8; -.
DR SMR; Q8IZS8; -.
DR BioGRID; 120911; 14.
DR IntAct; Q8IZS8; 1.
DR STRING; 9606.ENSP00000419101; -.
DR ChEMBL; CHEMBL2363032; -.
DR DrugBank; DB00381; Amlodipine.
DR DrugBank; DB13746; Bioallethrin.
DR DrugBank; DB11148; Butamben.
DR DrugBank; DB00228; Enflurane.
DR DrugBank; DB00153; Ergocalciferol.
DR DrugBank; DB06712; Nilvadipine.
DR DrugBank; DB00421; Spironolactone.
DR TCDB; 8.A.18.3.1; the ca(2+) channel auxiliary subunit Alpha2Delta types 1-4 (cca-Alpha2Delta) family.
DR GlyGen; Q8IZS8; 5 sites.
DR iPTMnet; Q8IZS8; -.
DR PhosphoSitePlus; Q8IZS8; -.
DR BioMuta; CACNA2D3; -.
DR DMDM; 74723683; -.
DR MassIVE; Q8IZS8; -.
DR PaxDb; Q8IZS8; -.
DR PeptideAtlas; Q8IZS8; -.
DR PRIDE; Q8IZS8; -.
DR ProteomicsDB; 71421; -. [Q8IZS8-1]
DR ProteomicsDB; 71422; -. [Q8IZS8-2]
DR ProteomicsDB; 71423; -. [Q8IZS8-3]
DR Antibodypedia; 31444; 117 antibodies from 21 providers.
DR DNASU; 55799; -.
DR Ensembl; ENST00000288197.9; ENSP00000288197.5; ENSG00000157445.15. [Q8IZS8-1]
DR Ensembl; ENST00000415676.6; ENSP00000389506.2; ENSG00000157445.15. [Q8IZS8-1]
DR Ensembl; ENST00000471363.5; ENSP00000418228.1; ENSG00000157445.15. [Q8IZS8-3]
DR Ensembl; ENST00000474759.6; ENSP00000419101.1; ENSG00000157445.15. [Q8IZS8-1]
DR Ensembl; ENST00000490478.5; ENSP00000417279.1; ENSG00000157445.15. [Q8IZS8-2]
DR Ensembl; ENST00000620722.4; ENSP00000478969.1; ENSG00000157445.15. [Q8IZS8-3]
DR GeneID; 55799; -.
DR KEGG; hsa:55799; -.
DR MANE-Select; ENST00000474759.6; ENSP00000419101.1; NM_018398.3; NP_060868.2.
DR UCSC; uc003dhf.3; human. [Q8IZS8-1]
DR CTD; 55799; -.
DR DisGeNET; 55799; -.
DR GeneCards; CACNA2D3; -.
DR HGNC; HGNC:15460; CACNA2D3.
DR HPA; ENSG00000157445; Tissue enhanced (brain, skeletal muscle, tongue).
DR MIM; 606399; gene.
DR neXtProt; NX_Q8IZS8; -.
DR OpenTargets; ENSG00000157445; -.
DR PharmGKB; PA26013; -.
DR VEuPathDB; HostDB:ENSG00000157445; -.
DR eggNOG; KOG2353; Eukaryota.
DR GeneTree; ENSGT00940000155766; -.
DR HOGENOM; CLU_004660_1_1_1; -.
DR InParanoid; Q8IZS8; -.
DR OMA; RTMQVPC; -.
DR OrthoDB; 69856at2759; -.
DR PhylomeDB; Q8IZS8; -.
DR TreeFam; TF315824; -.
DR PathwayCommons; Q8IZS8; -.
DR Reactome; R-HSA-112308; Presynaptic depolarization and calcium channel opening.
DR SignaLink; Q8IZS8; -.
DR SIGNOR; Q8IZS8; -.
DR BioGRID-ORCS; 55799; 7 hits in 1061 CRISPR screens.
DR ChiTaRS; CACNA2D3; human.
DR GenomeRNAi; 55799; -.
DR Pharos; Q8IZS8; Tbio.
DR PRO; PR:Q8IZS8; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q8IZS8; protein.
DR Bgee; ENSG00000157445; Expressed in middle temporal gyrus and 135 other tissues.
DR ExpressionAtlas; Q8IZS8; baseline and differential.
DR Genevisible; Q8IZS8; HS.
DR GO; GO:0005891; C:voltage-gated calcium channel complex; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005245; F:voltage-gated calcium channel activity; IBA:GO_Central.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.410; -; 1.
DR InterPro; IPR013680; VDCC_a2/dsu.
DR InterPro; IPR013608; VWA_N.
DR InterPro; IPR002035; VWF_A.
DR InterPro; IPR036465; vWFA_dom_sf.
DR Pfam; PF08473; VGCC_alpha2; 1.
DR Pfam; PF13768; VWA_3; 1.
DR Pfam; PF08399; VWA_N; 1.
DR SMART; SM00327; VWA; 1.
DR SUPFAM; SSF53300; SSF53300; 1.
DR PROSITE; PS50234; VWFA; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Calcium channel; Calcium transport;
KW Disulfide bond; Glycoprotein; Ion channel; Ion transport; Membrane;
KW Metal-binding; Phosphoprotein; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix; Transport; Voltage-gated channel.
FT SIGNAL 1..28
FT /evidence="ECO:0000255"
FT CHAIN 29..1091
FT /note="Voltage-dependent calcium channel subunit alpha-
FT 2/delta-3"
FT /id="PRO_0000304646"
FT CHAIN 29..?
FT /note="Voltage-dependent calcium channel subunit alpha-2-3"
FT /evidence="ECO:0000255"
FT /id="PRO_0000304647"
FT CHAIN ?..1091
FT /note="Voltage-dependent calcium channel subunit delta-3"
FT /evidence="ECO:0000255"
FT /id="PRO_0000304648"
FT TOPO_DOM 29..1068
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 1069..1089
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1090..1091
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 256..438
FT /note="VWFA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00219"
FT DOMAIN 452..549
FT /note="Cache"
FT MOTIF 262..266
FT /note="MIDAS-like motif"
FT BINDING 262
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /evidence="ECO:0000250"
FT BINDING 264
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /evidence="ECO:0000250"
FT BINDING 266
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /evidence="ECO:0000250"
FT MOD_RES 924
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q8CFG5"
FT CARBOHYD 166
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 309
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 553
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 632
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 793
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 412..1055
FT /note="Interchain (between alpha-2-3 and delta-3 chains)"
FT /evidence="ECO:0000250"
FT VAR_SEQ 1..94
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:11245980"
FT /id="VSP_028064"
FT VAR_SEQ 461..466
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:11245980"
FT /id="VSP_028065"
FT VAR_SEQ 595..619
FT /note="KRVLVMTNDYYYTDIKGTPFSLGVA -> FRCGAFQRSWEIFLPRECNHRRR
FT PA (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:11245980"
FT /id="VSP_028066"
FT VAR_SEQ 620..1091
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:11245980"
FT /id="VSP_028067"
SQ SEQUENCE 1091 AA; 123011 MW; 4E5E50BD38F05082 CRC64;
MAGPGSPRRA SRGASALLAA ALLYAALGDV VRSEQQIPLS VVKLWASAFG GEIKSIAAKY
SGSQLLQKKY KEYEKDVAIE EIDGLQLVKK LAKNMEEMFH KKSEAVRRLV EAAEEAHLKH
EFDADLQYEY FNAVLINERD KDGNFLELGK EFILAPNDHF NNLPVNISLS DVQVPTNMYN
KDPAIVNGVY WSESLNKVFV DNFDRDPSLI WQYFGSAKGF FRQYPGIKWE PDENGVIAFD
CRNRKWYIQA ATSPKDVVIL VDVSGSMKGL RLTIAKQTVS SILDTLGDDD FFNIIAYNEE
LHYVEPCLNG TLVQADRTNK EHFREHLDKL FAKGIGMLDI ALNEAFNILS DFNHTGQGSI
CSQAIMLITD GAVDTYDTIF AKYNWPDRKV RIFTYLIGRE AAFADNLKWM ACANKGFFTQ
ISTLADVQEN VMEYLHVLSR PKVIDQEHDV VWTEAYIDST LPQAQKLTDD QGPVLMTTVA
MPVFSKQNET RSKGILLGVV GTDVPVKELL KTIPKYKLGI HGYAFAITNN GYILTHPELR
LLYEEGKKRR KPNYSSVDLS EVEWEDRDDV LRNAMVNRKT GKFSMEVKKT VDKGKRVLVM
TNDYYYTDIK GTPFSLGVAL SRGHGKYFFR GNVTIEEGLH DLEHPDVSLA DEWSYCNTDL
HPEHRHLSQL EAIKLYLKGK EPLLQCDKEL IQEVLFDAVV SAPIEAYWTS LALNKSENSD
KGVEVAFLGT RTGLSRINLF VGAEQLTNQD FLKAGDKENI FNADHFPLWY RRAAEQIPGS
FVYSIPFSTG PVNKSNVVTA STSIQLLDER KSPVVAAVGI QMKLEFFQRK FWTASRQCAS
LDGKCSISCD DETVNCYLID NNGFILVSED YTQTGDFFGE IEGAVMNKLL TMGSFKRITL
YDYQAMCRAN KESSDGAHGL LDPYNAFLSA VKWIMTELVL FLVEFNLCSW WHSDMTAKAQ
KLKQTLEPCD TEYPAFVSER TIKETTGNIA CEDCSKSFVI QQIPSSNLFM VVVDSSCLCE
SVAPITMAPI EIRYNESLKC ERLKAQKIRR RPESCHGFHP EENARECGGA PSLQAQTVLL
LLPLLLMLFS R
