ADA2C_HUMAN
ID ADA2C_HUMAN Reviewed; 462 AA.
AC P18825; P35369; Q9HB49;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
DT 11-FEB-2002, sequence version 2.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Alpha-2C adrenergic receptor;
DE AltName: Full=Alpha-2 adrenergic receptor subtype C4;
DE AltName: Full=Alpha-2C adrenoreceptor;
DE Short=Alpha-2C adrenoceptor;
DE Short=Alpha-2CAR;
GN Name=ADRA2C; Synonyms=ADRA2L2, ADRA2RL2;
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].
RC TISSUE=Kidney;
RX PubMed=2842764; DOI=10.1073/pnas.85.17.6301;
RA Regan J.W., Kobilka T.S., Yang-Feng T.L., Caron M.G., Lefkowitz R.J.,
RA Kobilka B.K.;
RT "Cloning and expression of a human kidney cDNA for an alpha 2-adrenergic
RT receptor subtype.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:6301-6305(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Brain;
RX PubMed=9371698; DOI=10.1042/bj3280431;
RA Schaak S., Devedjian J.C., Cayla C., Sender Y., Paris H.;
RT "Molecular cloning, sequencing and functional study of the promoter region
RT of the human alpha2C4-adrenergic receptor gene.";
RL Biochem. J. 328:431-438(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Yano K., Takeda M., Sugimoto E., Sagai H.;
RT "Molecular cloning and expression of a novel human alpha2C-adrenerginc
RT receptor, alpha2CII, gene.";
RL Submitted (OCT-1992) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT 322-GLY--PRO-325 DEL.
RX PubMed=10801795; DOI=10.1074/jbc.m000796200;
RA Small K.M., Forbes S.L., Rahman F.F., Bridges K.M., Liggett S.B.;
RT "A four amino acid deletion polymorphism in the third intracellular loop of
RT the human alpha 2C-adrenergic receptor confers impaired coupling to
RT multiple effectors.";
RL J. Biol. Chem. 275:23059-23064(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT 322-GLY--PRO-325 DEL.
RX PubMed=15319474; DOI=10.1073/pnas.0405074101;
RA Small K.M., Mialet-Perez J., Seman C.A., Theiss C.T., Brown K.M.,
RA Liggett S.B.;
RT "Polymorphisms of cardiac presynaptic alpha2C adrenergic receptors: Diverse
RT intragenic variability with haplotype-specific functional effects.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:13020-13025(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT 322-GLY--PRO-325 DEL.
RA Kopatz S.A., Aronstam R.S., Sharma S.V.;
RT "Isolation of complete coding sequence for adrenergic receptor alpha 2C
RT (ADRA2C).";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 95-223.
RX PubMed=1849485; DOI=10.1016/0014-5793(91)80301-i;
RA Chhajlani V., Rangel N., Uhlen S., Wikberg J.E.S.;
RT "Identification of an additional gene belonging to the alpha 2 adrenergic
RT receptor family in the human genome by PCR.";
RL FEBS Lett. 280:241-244(1991).
CC -!- FUNCTION: Alpha-2 adrenergic receptors mediate the catecholamine-
CC induced inhibition of adenylate cyclase through the action of G
CC proteins.
CC -!- INTERACTION:
CC P18825; Q8N4L8: CCDC24; NbExp=3; IntAct=EBI-12015266, EBI-1104933;
CC P18825; Q9Y6H1: CHCHD2; NbExp=3; IntAct=EBI-12015266, EBI-2321769;
CC P18825; Q9Y2B0: CNPY2; NbExp=3; IntAct=EBI-12015266, EBI-1054195;
CC P18825; O14964: HGS; NbExp=3; IntAct=EBI-12015266, EBI-740220;
CC P18825; Q2WGJ6: KLHL38; NbExp=3; IntAct=EBI-12015266, EBI-6426443;
CC P18825; O76011: KRT34; NbExp=3; IntAct=EBI-12015266, EBI-1047093;
CC P18825; Q99750: MDFI; NbExp=3; IntAct=EBI-12015266, EBI-724076;
CC P18825; O14770-4: MEIS2; NbExp=3; IntAct=EBI-12015266, EBI-8025850;
CC P18825; Q13064: MKRN3; NbExp=3; IntAct=EBI-12015266, EBI-2340269;
CC P18825; Q7Z4N8: P4HA3; NbExp=3; IntAct=EBI-12015266, EBI-10181968;
CC P18825; Q9NZC7-5: WWOX; NbExp=3; IntAct=EBI-12015266, EBI-12040603;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- POLYMORPHISM: The Del322-325 variant has a significant loss of
CC function. It is approximately 10 times more frequent in African-
CC Americans compared with Caucasians (allele frequencies 0.381 versus
CC 0.040). {ECO:0000269|PubMed:10801795}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC Adrenergic receptor subfamily. ADRA2C sub-subfamily.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA35513.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=AAC78723.1; Type=Frameshift; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; J03853; AAA35513.1; ALT_FRAME; mRNA.
DR EMBL; U72648; AAC78723.1; ALT_FRAME; Genomic_DNA.
DR EMBL; D13538; BAA02737.1; -; Genomic_DNA.
DR EMBL; AF280399; AAG28076.1; -; Genomic_DNA.
DR EMBL; AF280400; AAG28077.1; -; Genomic_DNA.
DR EMBL; AY605898; AAT02221.1; -; Genomic_DNA.
DR EMBL; AY455666; AAR18071.1; -; Genomic_DNA.
DR EMBL; X59684; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS47004.1; -.
DR PIR; A31237; A31237.
DR RefSeq; NP_000674.2; NM_000683.3.
DR PDB; 6KUW; X-ray; 2.80 A; A/B=29-241, A/B=372-458.
DR PDBsum; 6KUW; -.
DR AlphaFoldDB; P18825; -.
DR SMR; P18825; -.
DR BioGRID; 106661; 16.
DR IntAct; P18825; 12.
DR STRING; 9606.ENSP00000386069; -.
DR BindingDB; P18825; -.
DR ChEMBL; CHEMBL1916; -.
DR DrugBank; DB08838; Agmatine.
DR DrugBank; DB00543; Amoxapine.
DR DrugBank; DB00182; Amphetamine.
DR DrugBank; DB00714; Apomorphine.
DR DrugBank; DB09229; Aranidipine.
DR DrugBank; DB01238; Aripiprazole.
DR DrugBank; DB14185; Aripiprazole lauroxil.
DR DrugBank; DB06216; Asenapine.
DR DrugBank; DB00217; Bethanidine.
DR DrugBank; DB09128; Brexpiprazole.
DR DrugBank; DB00484; Brimonidine.
DR DrugBank; DB01200; Bromocriptine.
DR DrugBank; DB00248; Cabergoline.
DR DrugBank; DB01136; Carvedilol.
DR DrugBank; DB04846; Celiprolol.
DR DrugBank; DB00477; Chlorpromazine.
DR DrugBank; DB09202; Cirazoline.
DR DrugBank; DB00575; Clonidine.
DR DrugBank; DB00363; Clozapine.
DR DrugBank; DB01151; Desipramine.
DR DrugBank; DB01576; Dextroamphetamine.
DR DrugBank; DB11273; Dihydroergocornine.
DR DrugBank; DB13345; Dihydroergocristine.
DR DrugBank; DB00320; Dihydroergotamine.
DR DrugBank; DB11278; DL-Methylephedrine.
DR DrugBank; DB09167; Dosulepin.
DR DrugBank; DB04855; Dronedarone.
DR DrugBank; DB06262; Droxidopa.
DR DrugBank; DB01363; Ephedra sinica root.
DR DrugBank; DB05492; Epicept NP-1.
DR DrugBank; DB01049; Ergoloid mesylate.
DR DrugBank; DB00696; Ergotamine.
DR DrugBank; DB01175; Escitalopram.
DR DrugBank; DB06678; Esmirtazapine.
DR DrugBank; DB09194; Etoperidone.
DR DrugBank; DB00800; Fenoldopam.
DR DrugBank; DB00502; Haloperidol.
DR DrugBank; DB04946; Iloperidone.
DR DrugBank; DB11577; Indigotindisulfonic acid.
DR DrugBank; DB06707; Levonordefrin.
DR DrugBank; DB00589; Lisuride.
DR DrugBank; DB09195; Lorpiprazole.
DR DrugBank; DB00408; Loxapine.
DR DrugBank; DB08815; Lurasidone.
DR DrugBank; DB00934; Maprotiline.
DR DrugBank; DB01365; Mephentermine.
DR DrugBank; DB01577; Metamfetamine.
DR DrugBank; DB01403; Methotrimeprazine.
DR DrugBank; DB06148; Mianserin.
DR DrugBank; DB09205; Moxisylyte.
DR DrugBank; DB00368; Norepinephrine.
DR DrugBank; DB00540; Nortriptyline.
DR DrugBank; DB06229; Ocaperidone.
DR DrugBank; DB05461; OPC-28326.
DR DrugBank; DB00935; Oxymetazoline.
DR DrugBank; DB01267; Paliperidone.
DR DrugBank; DB00715; Paroxetine.
DR DrugBank; DB01186; Pergolide.
DR DrugBank; DB00925; Phenoxybenzamine.
DR DrugBank; DB00397; Phenylpropanolamine.
DR DrugBank; DB06153; Pizotifen.
DR DrugBank; DB00433; Prochlorperazine.
DR DrugBank; DB01069; Promethazine.
DR DrugBank; DB01224; Quetiapine.
DR DrugBank; DB11124; Racepinephrine.
DR DrugBank; DB00734; Risperidone.
DR DrugBank; DB00268; Ropinirole.
DR DrugBank; DB09304; Setiptiline.
DR DrugBank; DB06764; Tetryzoline.
DR DrugBank; DB13025; Tiapride.
DR DrugBank; DB00697; Tizanidine.
DR DrugBank; DB00797; Tolazoline.
DR DrugBank; DB00193; Tramadol.
DR DrugBank; DB11477; Xylazine.
DR DrugBank; DB06694; Xylometazoline.
DR DrugBank; DB01392; Yohimbine.
DR DrugBank; DB00246; Ziprasidone.
DR DrugCentral; P18825; -.
DR GuidetoPHARMACOLOGY; 27; -.
DR GlyGen; P18825; 2 sites.
DR iPTMnet; P18825; -.
DR PhosphoSitePlus; P18825; -.
DR BioMuta; ADRA2C; -.
DR DMDM; 20141211; -.
DR jPOST; P18825; -.
DR MassIVE; P18825; -.
DR PaxDb; P18825; -.
DR PeptideAtlas; P18825; -.
DR PRIDE; P18825; -.
DR ProteomicsDB; 53608; -.
DR ABCD; P18825; 1 sequenced antibody.
DR Antibodypedia; 21167; 524 antibodies from 33 providers.
DR DNASU; 152; -.
DR Ensembl; ENST00000330055.7; ENSP00000386069.2; ENSG00000184160.8.
DR GeneID; 152; -.
DR KEGG; hsa:152; -.
DR MANE-Select; ENST00000330055.7; ENSP00000386069.2; NM_000683.4; NP_000674.2.
DR CTD; 152; -.
DR DisGeNET; 152; -.
DR GeneCards; ADRA2C; -.
DR HGNC; HGNC:283; ADRA2C.
DR HPA; ENSG00000184160; Tissue enhanced (cervix, endometrium).
DR MIM; 104250; gene.
DR neXtProt; NX_P18825; -.
DR OpenTargets; ENSG00000184160; -.
DR PharmGKB; PA37; -.
DR VEuPathDB; HostDB:ENSG00000184160; -.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT00940000161707; -.
DR HOGENOM; CLU_009579_11_1_1; -.
DR InParanoid; P18825; -.
DR OMA; TQLAIWG; -.
DR OrthoDB; 737211at2759; -.
DR PhylomeDB; P18825; -.
DR TreeFam; TF316350; -.
DR PathwayCommons; P18825; -.
DR Reactome; R-HSA-390696; Adrenoceptors.
DR Reactome; R-HSA-392023; Adrenaline signalling through Alpha-2 adrenergic receptor.
DR Reactome; R-HSA-400042; Adrenaline,noradrenaline inhibits insulin secretion.
DR Reactome; R-HSA-418594; G alpha (i) signalling events.
DR Reactome; R-HSA-418597; G alpha (z) signalling events.
DR Reactome; R-HSA-5683826; Surfactant metabolism.
DR SignaLink; P18825; -.
DR SIGNOR; P18825; -.
DR BioGRID-ORCS; 152; 11 hits in 1073 CRISPR screens.
DR GeneWiki; Alpha-2C_adrenergic_receptor; -.
DR GenomeRNAi; 152; -.
DR Pharos; P18825; Tclin.
DR PRO; PR:P18825; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P18825; protein.
DR Bgee; ENSG00000184160; Expressed in decidua and 166 other tissues.
DR ExpressionAtlas; P18825; baseline and differential.
DR Genevisible; P18825; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005768; C:endosome; TAS:ProtInc.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0031694; F:alpha-2A adrenergic receptor binding; IPI:BHF-UCL.
DR GO; GO:0004938; F:alpha2-adrenergic receptor activity; IDA:BHF-UCL.
DR GO; GO:0051379; F:epinephrine binding; IDA:BHF-UCL.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL.
DR GO; GO:0032148; P:activation of protein kinase B activity; IDA:BHF-UCL.
DR GO; GO:0071880; P:adenylate cyclase-activating adrenergic receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0071875; P:adrenergic receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0032811; P:negative regulation of epinephrine secretion; NAS:BHF-UCL.
DR GO; GO:0010700; P:negative regulation of norepinephrine secretion; TAS:BHF-UCL.
DR GO; GO:0030168; P:platelet activation; IEA:InterPro.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; IDA:BHF-UCL.
DR GO; GO:0035624; P:receptor transactivation; IDA:BHF-UCL.
DR GO; GO:0006940; P:regulation of smooth muscle contraction; IEA:InterPro.
DR GO; GO:0019229; P:regulation of vasoconstriction; IEA:InterPro.
DR InterPro; IPR002233; ADR_fam.
DR InterPro; IPR000735; ADRA2C_rcpt.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR PANTHER; PTHR24248:SF25; PTHR24248:SF25; 1.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR01103; ADRENERGICR.
DR PRINTS; PR00560; ADRENRGCA2CR.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR SMART; SM01381; 7TM_GPCR_Srsx; 1.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Disulfide bond; G-protein coupled receptor;
KW Glycoprotein; Membrane; Receptor; Reference proteome; Transducer;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..462
FT /note="Alpha-2C adrenergic receptor"
FT /id="PRO_0000069105"
FT TOPO_DOM 1..51
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 52..76
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250"
FT TOPO_DOM 77..88
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 89..114
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250"
FT TOPO_DOM 115..124
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 125..147
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250"
FT TOPO_DOM 148..168
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 169..191
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250"
FT TOPO_DOM 192..207
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 208..231
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250"
FT TOPO_DOM 232..379
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 380..407
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250"
FT TOPO_DOM 408..420
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 421..441
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250"
FT TOPO_DOM 442..462
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT REGION 246..347
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 131
FT /note="Implicated in ligand binding"
FT /evidence="ECO:0000250"
FT SITE 214
FT /note="Implicated in catechol agonist binding and receptor
FT activation"
FT /evidence="ECO:0000250"
FT SITE 218
FT /note="Implicated in catechol agonist binding and receptor
FT activation"
FT /evidence="ECO:0000250"
FT CARBOHYD 19
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 33
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 124..202
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT VARIANT 322..325
FT /note="Missing"
FT /evidence="ECO:0000269|PubMed:10801795,
FT ECO:0000269|PubMed:15319474, ECO:0000269|Ref.6"
FT /id="VAR_012747"
FT CONFLICT 239
FT /note="L -> R (in Ref. 1 and 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 329
FT /note="E -> Q (in Ref. 1 and 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 401
FT /note="S -> I (in Ref. 1 and 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 446
FT /note="R -> P (in Ref. 1 and 2)"
FT /evidence="ECO:0000305"
FT HELIX 48..78
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 80..82
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 85..87
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 88..103
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 105..114
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 120..154
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 156..160
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 165..183
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 208..218
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 220..239
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 372..408
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 409..412
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 416..428
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 429..431
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 433..440
FT /evidence="ECO:0007829|PDB:6KUW"
FT HELIX 442..452
FT /evidence="ECO:0007829|PDB:6KUW"
SQ SEQUENCE 462 AA; 49522 MW; E1EF9CA21E7F6EDA CRC64;
MASPALAAAL AVAAAAGPNA SGAGERGSGG VANASGASWG PPRGQYSAGA VAGLAAVVGF
LIVFTVVGNV LVVIAVLTSR ALRAPQNLFL VSLASADILV ATLVMPFSLA NELMAYWYFG
QVWCGVYLAL DVLFCTSSIV HLCAISLDRY WSVTQAVEYN LKRTPRRVKA TIVAVWLISA
VISFPPLVSL YRQPDGAAYP QCGLNDETWY ILSSCIGSFF APCLIMGLVY ARIYRVAKLR
TRTLSEKRAP VGPDGASPTT ENGLGAAAGA GENGHCAPPP ADVEPDESSA AAERRRRRGA
LRRGGRRRAG AEGGAGGADG QGAGPGAAES GALTASRSPG PGGRLSRASS RSVEFFLSRR
RRARSSVCRR KVAQAREKRF TFVLAVVMGV FVLCWFPFFF SYSLYGICRE ACQVPGPLFK
FFFWIGYCNS SLNPVIYTVF NQDFRRSFKH ILFRRRRRGF RQ
