ID ADA2A_HUMAN Reviewed; 465 AA. AC P08913; B0LPF6; Q2I8G2; Q2XN99; Q86TH8; Q9BZK1; DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot. DT 11-DEC-2019, sequence version 4. DT 02-SEP-2026, entry version 243. DE RecName: Full=Alpha-2A adrenergic receptor {ECO:0000303|PubMed:10948191}; DE AltName: Full=Alpha-2 adrenergic receptor subtype C10; DE AltName: Full=Alpha-2A adrenoreceptor; DE Short=Alpha-2A adrenoceptor; DE Short=Alpha-2AAR; GN Name=ADRA2A {ECO:0000312|HGNC:HGNC:281}; Synonyms=ADRA2R, ADRAR; 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 [GENOMIC DNA], AND FUNCTION. RX PubMed=2568356; DOI=10.1016/s0021-9258(18)80130-2; RA Fraser C.M., Arakawa S., McCombie W.R., Venter J.C.; RT "Cloning, sequence analysis, and permanent expression of a human alpha 2- RT adrenergic receptor in Chinese hamster ovary cells. Evidence for RT independent pathways of receptor coupling to adenylate cyclase attenuation RT and activation."; RL J. Biol. Chem. 264:11754-11761(1989). RN [2] RP SEQUENCE REVISION TO 333-365, AND FUNCTION. RX PubMed=2170371; DOI=10.1016/s0021-9258(17)44904-0; RA Guyer C.A., Horstman D.A., Wilson A.L., Clark J.D., Kragoe E.J. Jr., RA Limbird L.E.; RT "Cloning, sequencing, and expression of the gene encoding the porcine alpha RT 2-adrenergic receptor. Allosteric modulation by Na+, H+, and amiloride RT analogs."; RL J. Biol. Chem. 265:17307-17317(1990). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=16567612; DOI=10.1073/pnas.0601345103; RA Small K.M., Brown K.M., Seman C.A., Theiss C.T., Liggett S.B.; RT "Complex haplotypes derived from noncoding polymorphisms of the intronless RT alpha-2A-adrenergic gene diversify receptor expression."; RL Proc. Natl. Acad. Sci. U.S.A. 103:5472-5477(2006). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Mao Z.-M., Tang K., Li B.-M., Jing N.-H.; RT "Cloning and expression of human alpha-2A adrenergic receptor in SY5Y RT cells."; RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Castellano M., Giacche' M., Rossi F., Rivadossi F., Perani C., Beschi M., RA Agabiti Rosei E.; RT "A search for genetic variability in the human alpha-2 adrenergic receptor RT on chromosome 10."; RL Submitted (AUG-2000) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Liu L., Yuan L.; RT "Human alpha-2A adrenergic receptor gene and the genotype of -1296 RT nucleotide and motionsickness."; RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LYS-266. RG SeattleSNPs variation discovery resource; RL Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=PNS, and Testis; 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 [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 7-465, AND PARTIAL PROTEIN SEQUENCE. RC TISSUE=Platelet; RX PubMed=2823383; DOI=10.1126/science.2823383; RA Kobilka B.K., Matsui H., Kobilka T.S., Yang-Feng T.L., Francke U., RA Caron M.G., Lefkowitz R.J., Regan J.W.; RT "Cloning, sequencing, and expression of the gene coding for the human RT platelet alpha 2-adrenergic receptor."; RL Science 238:650-656(1987). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-465, AND VARIANT LYS-266. RX PubMed=10948191; DOI=10.1074/jbc.m004550200; RA Small K.M., Forbes S.L., Brown K.M., Liggett S.B.; RT "An Asn to Lys polymorphism in the third intracellular loop of the human RT alpha 2A-adrenergic receptor imparts enhanced agonist-promoted Gi RT coupling."; RL J. Biol. Chem. 275:38518-38523(2000). RN [13] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 92-224. 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). RN [14] RP MUTAGENESIS OF PHE-427. RX PubMed=1678390; DOI=10.1016/s0021-9258(18)98642-4; RA Suryanarayana S., Daunt D.A., von Zastrow M., Kobilka B.K.; RT "A point mutation in the seventh hydrophobic domain of the alpha 2 RT adrenergic receptor increases its affinity for a family of beta receptor RT antagonists."; RL J. Biol. Chem. 266:15488-15492(1991). RN [15] RP MUTAGENESIS OF ASPARTIC ACID AND SERINE RESIDUES. RX PubMed=1678850; DOI=10.1016/s0026-895x(25)12922-2; RA Wang C.-D., Buck M.A., Fraser C.M.; RT "Site-directed mutagenesis of alpha 2a-adrenergic receptors: Identification RT of amino acids involved in ligand binding and receptor activation by RT agonists."; RL Mol. Pharmacol. 40:168-179(1991). RN [16] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=23105096; DOI=10.1074/jbc.m112.410936; RA Li C., Fan Y., Lan T.H., Lambert N.A., Wu G.; RT "Rab26 modulates the cell surface transport of alpha2-adrenergic receptors RT from the Golgi."; RL J. Biol. Chem. 287:42784-42794(2012). RN [17] {ECO:0007744|PDB:1HLL, ECO:0007744|PDB:1HO9, ECO:0007744|PDB:1HOD, ECO:0007744|PDB:1HOF} RP STRUCTURE BY NMR OF 133-164, AND PROBABLE MEMBRANE TOPOLOGY. RX PubMed=11888275; DOI=10.1021/bi015811+; RA Chung D.A., Zuiderweg E.R.P., Fowler C.B., Soyer O.S., Mosberg H.I., RA Neubig R.R.; RT "NMR structure of the second intracellular loop of the alpha 2A adrenergic RT receptor: evidence for a novel cytoplasmic helix."; RL Biochemistry 41:3596-3604(2002). RN [18] {ECO:0007744|PDB:7EJ0, ECO:0007744|PDB:7EJ8, ECO:0007744|PDB:7EJA, ECO:0007744|PDB:7EJK} RP STRUCTURE BY ELECTRON MICROSCOPY (3.00 ANGSTROMS) IN COMPLEX WITH G RP PROTEINS AND NORADRENALINE, DISULFIDE BONDS, SUBCELLULAR LOCATION, RP FUNCTION, AND MUTAGENESIS OF ASP-128; SER-215; TYR-409; PHE-427 AND RP TYR-431. RX PubMed=35245122; DOI=10.1126/sciadv.abj5347; RA Xu J., Cao S., Hubner H., Weikert D., Chen G., Lu Q., Yuan D., Gmeiner P., RA Liu Z., Du Y.; RT "Structural insights into ligand recognition, activation, and signaling of RT the alpha2A adrenergic receptor."; RL Sci. Adv. 8:eabj5347-eabj5347(2022). RN [19] RP VARIANT FPLD8 PHE-68, CHARACTERIZATION OF VARIANT FPLD8 PHE-68, INVOLVEMENT RP IN FPLD8, AND FUNCTION. RX PubMed=27376152; DOI=10.1172/jci.insight.86870; RA Garg A., Sankella S., Xing C., Agarwal A.K.; RT "Whole-exome sequencing identifies ADRA2A mutation in atypical familial RT partial lipodystrophy."; RL JCI Insight 1:0-0(2016). CC -!- FUNCTION: Alpha-2 adrenergic receptors are G protein-coupled receptors CC for catecholamines that activate the G(i/o) protein pathway, thereby CC promoting adenylyl cyclase inhibition, ERK1/2 stimulation, and voltage- CC gated calcium channels suppression (PubMed:2170371, PubMed:23105096, CC PubMed:2568356, PubMed:35245122, PubMed:27376152). Control a variety of CC physiological processes, such as regulation of blood pressure, CC lipolysis and insulin release (PubMed:2568356, PubMed:27376152). ADRA2A CC and ADRA2C mediates the presynaptic feedback inhibition of CC neurotransmitter release from noradrenergic nerve terminals in CC sympathetic and central nervous systems. ADRA2A inhibits transmitter CC release at high stimulation frequencies, whereas ADRA2C modulates CC neurotransmission at lower levels of nerve activity (By similarity). CC The rank order of potency for agonists of ADRA2A is oxymetazoline > CC clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > CC p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, CC the rank order is yohimbine > phentolamine = mianserine > CC chlorpromazine = spiperone = prazosin > propanolol > alprenolol = CC pindolol (PubMed:2170371, PubMed:2568356). CC {ECO:0000250|UniProtKB:Q01338, ECO:0000269|PubMed:2170371, CC ECO:0000269|PubMed:23105096, ECO:0000269|PubMed:2568356, CC ECO:0000269|PubMed:27376152, ECO:0000269|PubMed:35245122}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23105096}; CC Multi-pass membrane protein {ECO:0000269|PubMed:35245122}. CC -!- DISEASE: Lipodystrophy, familial partial, 8 (FPLD8) [MIM:620679]: An CC autosomal dominant form of partial lipodystrophy, a disorder CC characterized by abnormal subcutaneous fat distribution. FPLD8 patients CC show selective loss of subcutaneous adipose tissue from the limbs, CC beginning around 13 to 15 years of age, and abnormal accumulation of CC subcutaneous adipose tissue in the dorsal neck and face, as well as in CC the posterior thoracic and abdominal regions. The disorder is CC associated with metabolic abnormalities, including diabetes mellitus CC and hyperlipidemia. {ECO:0000269|PubMed:27376152}. Note=The disease may CC be caused by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the G protein-coupled receptor 1 family. CC Adrenergic receptor subfamily. ADRA2A sub-subfamily. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC -!- CAUTION: It is uncertain whether Met-1 or Met-16 is the initiator. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA51664.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAA51664.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAA51665.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAA51665.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAG00447.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH35047.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH50414.4; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAK26743.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAK51162.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAZ73101.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=ABB72683.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=ABY87535.1; Type=Erroneous initiation; Note=Truncated N-terminus.; 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; M23533; AAA51665.1; ALT_SEQ; Genomic_DNA. DR EMBL; DQ149926; AAZ73101.1; ALT_INIT; Genomic_DNA. DR EMBL; AF284095; AAK26743.1; ALT_INIT; mRNA. DR EMBL; AF262016; AAG00447.2; ALT_INIT; Genomic_DNA. DR EMBL; AY032736; AAK51162.1; ALT_INIT; Genomic_DNA. DR EMBL; DQ285607; ABB72683.1; ALT_INIT; Genomic_DNA. DR EMBL; EU332846; ABY87535.1; ALT_INIT; Genomic_DNA. DR EMBL; AL158163; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC035047; AAH35047.1; ALT_INIT; mRNA. DR EMBL; BC050414; AAH50414.4; ALT_INIT; mRNA. DR EMBL; M18415; AAA51664.1; ALT_SEQ; Genomic_DNA. DR EMBL; AF281308; AAF91441.1; -; Genomic_DNA. DR EMBL; AF316894; AAK01634.1; -; Genomic_DNA. DR CCDS; CCDS7569.2; -. DR PIR; A34169; A34169. DR RefSeq; NP_000672.3; NM_000681.4. DR PDB; 1HLL; NMR; -; A=133-164. DR PDB; 1HO9; NMR; -; A=133-164. DR PDB; 1HOD; NMR; -; A=133-164. DR PDB; 1HOF; NMR; -; A=133-164. DR PDB; 6K42; EM; 4.10 A; R=37-44. DR PDB; 6KUX; X-ray; 2.70 A; A=35-460. DR PDB; 6KUY; X-ray; 3.20 A; A=35-460. DR PDB; 7EJ0; EM; 3.20 A; R=1-465. DR PDB; 7EJ8; EM; 3.00 A; R=1-465. DR PDB; 7EJA; EM; 3.60 A; R=1-465. DR PDB; 7EJK; EM; 3.40 A; R=1-465. DR PDB; 7W6P; EM; 3.47 A; R=1-465. DR PDB; 7W7E; EM; 3.40 A; R=1-465. DR PDB; 9CBL; EM; 2.80 A; R=35-460. DR PDB; 9CBM; EM; 3.20 A; R=35-460. DR PDB; 9IQR; EM; 3.40 A; B=38-456. DR PDB; 9PLN; EM; 2.80 A; R=2-465. DR PDB; 9PLO; EM; 2.74 A; R=2-465. DR PDB; 9PQD; EM; 3.29 A; R=2-465. DR AlphaFoldDB; P08913; -. DR BMRB; P08913; -. DR EMDB; EMD-31147; -. DR EMDB; EMD-31156; -. DR EMDB; EMD-31157; -. DR EMDB; EMD-31162; -. DR EMDB; EMD-32331; -. DR EMDB; EMD-32342; -. DR EMDB; EMD-45425; -. DR EMDB; EMD-45426; -. DR EMDB; EMD-60793; -. DR EMDB; EMD-71718; -. DR EMDB; EMD-71719; -. DR EMDB; EMD-71783; -. DR SMR; P08913; -. DR BioGRID; 106659; 10. DR CORUM; P08913; -. DR DIP; DIP-61452N; -. DR FunCoup; P08913; 833. DR IntAct; P08913; 10. DR NDEx; IQUERY-CP-ADRA2A; 5 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000280155; -. DR BindingDB; P08913; -. DR ChEMBL; CHEMBL1867; -. DR DrugBank; DB03468; 1,2,3,4-Tetrahydro-Isoquinoline-7-Sulfonic Acid Amide. DR DrugBank; DB01472; 4-Methoxyamphetamine. DR DrugBank; DB08550; 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline. DR DrugBank; DB00321; Amitriptyline. DR DrugBank; DB00543; Amoxapine. DR DrugBank; DB00182; Amphetamine. DR DrugBank; DB00714; Apomorphine. DR DrugBank; DB00964; Apraclonidine. DR DrugBank; DB09229; Aranidipine. DR DrugBank; DB01238; Aripiprazole. DR DrugBank; DB14185; Aripiprazole lauroxil. DR DrugBank; DB06216; Asenapine. DR DrugBank; DB00865; Benzphetamine. DR DrugBank; DB00217; Bethanidine. 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; DB00633; Dexmedetomidine. DR DrugBank; DB01576; Dextroamphetamine. DR DrugBank; DB11273; Dihydroergocornine. DR DrugBank; DB13345; Dihydroergocristine. DR DrugBank; DB00320; Dihydroergotamine. DR DrugBank; DB00449; Dipivefrin. 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; DB00751; Epinastine. DR DrugBank; DB00668; Epinephrine. 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; DB06623; Flupirtine. DR DrugBank; DB00629; Guanabenz. DR DrugBank; DB01018; Guanfacine. DR DrugBank; DB00502; Haloperidol. DR DrugBank; DB04946; Iloperidone. DR DrugBank; DB11577; Indigotindisulfonic acid. DR DrugBank; DB00555; Lamotrigine. DR DrugBank; DB06707; Levonordefrin. DR DrugBank; DB00589; Lisuride. DR DrugBank; DB04948; Lofexidine. DR DrugBank; DB09195; Lorpiprazole. DR DrugBank; DB00408; Loxapine. DR DrugBank; DB08815; Lurasidone. DR DrugBank; DB00934; Maprotiline. DR DrugBank; DB20960; Mazapertine. DR DrugBank; DB11428; Medetomidine. DR DrugBank; DB01365; Mephentermine. DR DrugBank; DB01577; Metamfetamine. DR DrugBank; DB01403; Methotrimeprazine. DR DrugBank; DB00968; Methyldopa. DR DrugBank; DB21271; Mezilamine. DR DrugBank; DB06148; Mianserin. DR DrugBank; DB24348; Milsaperidone. DR DrugBank; DB00370; Mirtazapine. DR DrugBank; DB09205; Moxisylyte. DR DrugBank; DB09242; Moxonidine. DR DrugBank; DB06711; Naphazoline. DR DrugBank; DB01149; Nefazodone. DR DrugBank; DB00368; Norepinephrine. DR DrugBank; DB00540; Nortriptyline. DR DrugBank; DB06229; Ocaperidone. DR DrugBank; DB00935; Oxymetazoline. DR DrugBank; DB01267; Paliperidone. DR DrugBank; DB00715; Paroxetine. DR DrugBank; DB01186; Pergolide. DR DrugBank; DB01608; Periciazine. DR DrugBank; DB00925; Phenoxybenzamine. DR DrugBank; DB00692; Phentolamine. DR DrugBank; DB00397; Phenylpropanolamine. DR DrugBank; DB09286; Pipamperone. DR DrugBank; DB09244; Pirlindole. DR DrugBank; DB06153; Pizotifen. DR DrugBank; DB00413; Pramipexole. DR DrugBank; DB00457; Prazosin. DR DrugBank; DB00433; Prochlorperazine. DR DrugBank; DB01069; Promethazine. DR DrugBank; DB00852; Pseudoephedrine. DR DrugBank; DB01224; Quetiapine. DR DrugBank; DB11124; Racepinephrine. DR DrugBank; DB11738; Rilmenidine. 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; DB13064; Tramazoline. DR DrugBank; DB00656; Trazodone. DR DrugBank; DB00726; Trimipramine. DR DrugBank; DB11477; Xylazine. DR DrugBank; DB06694; Xylometazoline. DR DrugBank; DB01392; Yohimbine. DR DrugBank; DB00246; Ziprasidone. DR DrugBank; DB01624; Zuclopenthixol. DR DrugCentral; P08913; -. DR GuidetoPHARMACOLOGY; 25; -. DR TCDB; 9.A.14.3.16; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; P08913; 2 sites, No reported glycans. DR GlyGen; P08913; 3 sites, 1 O-linked glycan (1 site). DR iPTMnet; P08913; -. DR PhosphoSitePlus; P08913; -. DR SwissPalm; P08913; -. DR BioMuta; ADRA2A; -. DR DMDM; 1351829; -. DR jPOST; P08913; -. DR MassIVE; P08913; -. DR PaxDb; 9606-ENSP00000280155; -. DR PeptideAtlas; P08913; -. DR ProteomicsDB; 52176; -. DR Antibodypedia; 31769; 339 antibodies from 39 providers. DR DNASU; 150; -. DR Ensembl; ENST00000280155.4; ENSP00000280155.2; ENSG00000150594.7. DR GeneID; 150; -. DR KEGG; hsa:150; -. DR MANE-Select; ENST00000280155.4; ENSP00000280155.2; NM_000681.4; NP_000672.3. DR UCSC; uc001kzo.4; human. DR AGR; HGNC:281; -. DR ClinPGx; PA35; -. DR CTD; 150; -. DR DisGeNET; 150; -. DR GeneCards; ADRA2A; -. DR HGNC; HGNC:281; ADRA2A. DR HPA; ENSG00000150594; Tissue enhanced (adipose). DR MalaCards; ADRA2A; -. DR MIM; 104210; gene. DR MIM; 620679; phenotype. DR OpenTargets; ENSG00000150594; -. DR VEuPathDB; HostDB:ENSG00000150594; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT00940000161451; -. DR HOGENOM; CLU_009579_11_1_1; -. DR InParanoid; P08913; -. DR OMA; FFTYMLM; -. DR OrthoDB; 5975661at2759; -. DR PAN-GO; P08913; 3 GO annotations based on evolutionary models. DR PhylomeDB; P08913; -. DR PathwayCommons; P08913; -. 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; P08913; -. DR SIGNOR; P08913; -. DR Agora; ENSG00000150594; -. DR BioGRID-ORCS; 150; 9 hits in 1148 CRISPR screens. DR ChiTaRS; ADRA2A; human. DR EvolutionaryTrace; P08913; -. DR GeneWiki; Alpha-2A_adrenergic_receptor; -. DR GenomeRNAi; 150; -. DR Pharos; P08913; Tclin. DR PRO; PR:P08913; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; P08913; protein. DR Bgee; ENSG00000150594; Expressed in cortical plate and 158 other cell types or tissues. DR GO; GO:0043679; C:axon terminus; IEA:Ensembl. DR GO; GO:0016323; C:basolateral plasma membrane; TAS:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0098691; C:dopaminergic synapse; IEA:Ensembl. DR GO; GO:0098982; C:GABA-ergic synapse; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL. DR GO; GO:0098839; C:postsynaptic density membrane; IEA:Ensembl. DR GO; GO:0048787; C:presynaptic active zone membrane; IEA:Ensembl. DR GO; GO:0043235; C:signaling receptor complex; IDA:BHF-UCL. DR GO; GO:0031692; F:alpha-1B adrenergic receptor binding; ISS:BHF-UCL. DR GO; GO:0031696; F:alpha-2C 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:0032795; F:heterotrimeric G-protein binding; IDA:BHF-UCL. DR GO; GO:0051380; F:norepinephrine binding; IDA:BHF-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:BHF-UCL. DR GO; GO:0031996; F:thioesterase binding; IPI:BHF-UCL. DR GO; GO:0030036; P:actin cytoskeleton organization; TAS:ProtInc. DR GO; GO:0071880; P:adenylate cyclase-activating adrenergic receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:0071881; P:adenylate cyclase-inhibiting adrenergic receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0007193; P:adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:0071875; P:adrenergic receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0032870; P:cellular response to hormone stimulus; IGI:BHF-UCL. DR GO; GO:0006260; P:DNA replication; IEA:Ensembl. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0042593; P:glucose homeostasis; IMP:BHF-UCL. DR GO; GO:0050892; P:intestinal absorption; TAS:BHF-UCL. DR GO; GO:0051926; P:negative regulation of calcium ion transport; ISS:BHF-UCL. DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; IC:BHF-UCL. DR GO; GO:0032811; P:negative regulation of epinephrine secretion; NAS:BHF-UCL. DR GO; GO:0046676; P:negative regulation of insulin secretion; IMP:BHF-UCL. DR GO; GO:0061179; P:negative regulation of insulin secretion involved in cellular response to glucose stimulus; IMP:BHF-UCL. DR GO; GO:0050995; P:negative regulation of lipid catabolic process; IGI:BHF-UCL. DR GO; GO:0010700; P:negative regulation of norepinephrine secretion; ISS:UniProtKB. DR GO; GO:0070473; P:negative regulation of uterine smooth muscle contraction; IEA:Ensembl. DR GO; GO:0071882; P:phospholipase C-activating adrenergic receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0030168; P:platelet activation; IEA:InterPro. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; TAS:ProtInc. DR GO; GO:0001819; P:positive regulation of cytokine production; IDA:BHF-UCL. DR GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:BHF-UCL. DR GO; GO:0043268; P:positive regulation of potassium ion transport; ISS:BHF-UCL. DR GO; GO:0090303; P:positive regulation of wound healing; IMP:BHF-UCL. DR GO; GO:0099171; P:presynaptic modulation of chemical synaptic transmission; IEA:Ensembl. DR GO; GO:0007265; P:Ras protein signal transduction; TAS:ProtInc. DR GO; GO:0019229; P:regulation of vasoconstriction; IEA:InterPro. DR GO; GO:0097305; P:response to alcohol; IEA:Ensembl. DR GO; GO:0043278; P:response to morphine; IEA:Ensembl. DR GO; GO:0007266; P:Rho protein signal transduction; TAS:ProtInc. DR GO; GO:0050955; P:thermoception; IEA:Ensembl. DR GO; GO:0042311; P:vasodilation; IEA:Ensembl. DR CDD; cd15322; 7tmA_alpha2A_AR; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR002233; ADR_fam. DR InterPro; IPR001946; ADRA2A_rcpt. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR PANTHER; PTHR24248; ADRENERGIC RECEPTOR-RELATED G-PROTEIN COUPLED RECEPTOR; 1. DR PANTHER; PTHR24248:SF24; ALPHA-2A ADRENERGIC RECEPTOR; 1. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR01103; ADRENERGICR. DR PRINTS; PR00558; ADRENRGCA2AR. DR PRINTS; PR00237; GPCRRHODOPSN. DR SMART; SM01381; 7TM_GPCR_Srsx; 1. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. DR PDBsum; 1HLL; -. DR PDBsum; 1HO9; -. DR PDBsum; 1HOD; -. DR PDBsum; 1HOF; -. DR PDBsum; 6K42; -. DR PDBsum; 6KUX; -. DR PDBsum; 6KUY; -. DR PDBsum; 7EJ0; -. DR PDBsum; 7EJ8; -. DR PDBsum; 7EJA; -. DR PDBsum; 7EJK; -. DR PDBsum; 7W6P; -. DR PDBsum; 7W7E; -. DR PDBsum; 9CBL; -. DR PDBsum; 9CBM; -. DR PDBsum; 9IQR; -. DR PDBsum; 9PLN; -. DR PDBsum; 9PLO; -. DR PDBsum; 9PQD; -. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Direct protein sequencing; Disulfide bond; KW G protein-coupled receptor; Glycoprotein; Lipoprotein; Membrane; KW Methylation; Palmitate; Phosphoprotein; Proteomics identification; KW Receptor; Reference proteome; Transducer; Transmembrane; KW Transmembrane helix. FT CHAIN 1..465 FT /note="Alpha-2A adrenergic receptor" FT /id="PRO_0000069080" FT TOPO_DOM 1..47 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 48..71 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:35245122, FT ECO:0007744|PDB:7EJ0" FT TOPO_DOM 72..85 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 86..107 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:35245122, FT ECO:0007744|PDB:7EJ0" FT TOPO_DOM 108..120 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 121..144 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:35245122, FT ECO:0007744|PDB:7EJ0" FT TOPO_DOM 145..167 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 168..181 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:35245122, FT ECO:0007744|PDB:7EJ0" FT TOPO_DOM 182..208 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 209..232 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:35245122, FT ECO:0007744|PDB:7EJ0" FT TOPO_DOM 233..388 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 389..413 FT /note="Helical; Name=6" FT /evidence="ECO:0000269|PubMed:35245122, FT ECO:0007744|PDB:7EJ0" FT TOPO_DOM 414..421 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 422..443 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:35245122, FT ECO:0007744|PDB:7EJ0" FT TOPO_DOM 444..465 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT REGION 242..368 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 313..330 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 128 FT /note="Implicated in norepinephrine binding" FT /evidence="ECO:0000269|PubMed:1678850, FT ECO:0000269|PubMed:35245122" FT SITE 215 FT /note="Implicated in catechol and norepinephrine agonist FT binding and receptor activation" FT /evidence="ECO:0000269|PubMed:1678850, FT ECO:0000269|PubMed:35245122" FT SITE 219 FT /note="Implicated in catechol agonist binding and receptor FT activation" FT /evidence="ECO:0000269|PubMed:1678850" FT SITE 409 FT /note="Implicated in norepinephrine binding and receptor FT activation" FT /evidence="ECO:0000269|PubMed:35245122" FT SITE 427 FT /note="Implicated in norepinephrine binding and receptor FT activation" FT /evidence="ECO:0000269|PubMed:35245122" FT SITE 431 FT /note="Implicated in norepinephrine binding and receptor FT activation" FT /evidence="ECO:0000269|PubMed:35245122" FT MOD_RES 346 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P22909" FT MOD_RES 368 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q01338" FT LIPID 457 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250" FT CARBOHYD 25 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 29 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 121..203 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521, FT ECO:0000269|PubMed:35245122, ECO:0007744|PDB:7EJ0" FT VARIANT 68 FT /note="L -> F (in FPLD8; uncertain significance; decreased FT function in adenylate cyclase-inhibiting adrenergic FT receptor signaling pathway; dbSNP:rs1224440739)" FT /evidence="ECO:0000269|PubMed:27376152" FT /id="VAR_089227" FT VARIANT 266 FT /note="N -> K (40% increase in agonist-promoted Gi FT coupling; dbSNP:rs1800035)" FT /evidence="ECO:0000269|PubMed:10948191, ECO:0000269|Ref.7" FT /id="VAR_014957" FT VARIANT 416 FT /note="C -> S (in dbSNP:rs35658213)" FT /id="VAR_055908" FT MUTAGEN 94 FT /note="D->N: No change in binding affinity. Eliminates FT guanine nucleotide-sensitive agonist binding." FT /evidence="ECO:0000269|PubMed:1678850" FT MUTAGEN 128 FT /note="D->A: Loss of receptor activation by FT norepinephrine." FT /evidence="ECO:0000269|PubMed:35245122" FT MUTAGEN 128 FT /note="D->N: No binding to yohimbine. Increase in adenylate FT cyclase activity." FT /evidence="ECO:0000269|PubMed:1678850" FT MUTAGEN 145 FT /note="D->N: Lower affinity for agonists. Eliminates FT guanine nucleotide-sensitive agonist binding." FT /evidence="ECO:0000269|PubMed:1678850" FT MUTAGEN 215 FT /note="S->A: Lower affinity for agonists. No change in FT guanine nucleotide-sensitive agonist binding. Impaired FT receptor activation by norepinephrine." FT /evidence="ECO:0000269|PubMed:1678850, FT ECO:0000269|PubMed:35245122" FT MUTAGEN 219 FT /note="S->A: Lower affinity for agonists. Reduced guanine FT nucleotide-sensitive agonist binding." FT /evidence="ECO:0000269|PubMed:1678850" FT MUTAGEN 409 FT /note="Y->A: Impaired receptor activation by FT norepinephrine." FT /evidence="ECO:0000269|PubMed:35245122" FT MUTAGEN 427 FT /note="F->A: Impaired receptor activation by FT norepinephrine." FT /evidence="ECO:0000269|PubMed:35245122" FT MUTAGEN 427 FT /note="F->N: 350-fold reduced affinity for alpha-2 FT antagonist yohimbine, 3000-fold increase for FT beta-antagonist alprenolol." FT /evidence="ECO:0000269|PubMed:1678390" FT MUTAGEN 431 FT /note="Y->A: Impaired receptor activation by FT norepinephrine." FT /evidence="ECO:0000269|PubMed:35245122" FT CONFLICT 119 FT /note="A -> T (in Ref. 11; AAA51664)" FT /evidence="ECO:0000305" FT CONFLICT 139 FT /note="L -> P (in Ref. 13)" FT /evidence="ECO:0000305" FT CONFLICT 172 FT /note="V -> C (in Ref. 11; AAA51664)" FT /evidence="ECO:0000305" FT CONFLICT 383 FT /note="R -> L (in Ref. 11; AAA51664)" FT /evidence="ECO:0000305" FT STRAND 45..47 FT /evidence="ECO:0007829|PDB:7EJ8" FT HELIX 49..75 FT /evidence="ECO:0007829|PDB:6KUX" FT STRAND 76..78 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 82..84 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 85..99 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 102..110 FT /evidence="ECO:0007829|PDB:6KUX" FT STRAND 111..113 FT /evidence="ECO:0007829|PDB:7EJ8" FT HELIX 118..151 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 153..158 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 162..180 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 181..186 FT /evidence="ECO:0007829|PDB:9IQR" FT TURN 209..211 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 212..216 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 217..221 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 222..242 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 255..272 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 278..296 FT /evidence="ECO:0007829|PDB:6KUX" FT TURN 308..310 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 326..341 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 344..350 FT /evidence="ECO:0007829|PDB:6KUX" FT TURN 351..353 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 355..362 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 367..377 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 383..411 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 412..414 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 420..431 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 433..444 FT /evidence="ECO:0007829|PDB:6KUX" FT HELIX 446..457 FT /evidence="ECO:0007829|PDB:6KUX" SQ SEQUENCE 465 AA; 50647 MW; 585E576149BDB696 CRC64; MFRQEQPLAE GSFAPMGSLQ PDAGNASWNG TEAPGGGARA TPYSLQVTLT LVCLAGLLML LTVFGNVLVI IAVFTSRALK APQNLFLVSL ASADILVATL VIPFSLANEV MGYWYFGKAW CEIYLALDVL FCTSSIVHLC AISLDRYWSI TQAIEYNLKR TPRRIKAIII TVWVISAVIS FPPLISIEKK GGGGGPQPAE PRCEINDQKW YVISSCIGSF FAPCLIMILV YVRIYQIAKR RTRVPPSRRG PDAVAAPPGG TERRPNGLGP ERSAGPGGAE AEPLPTQLNG APGEPAPAGP RDTDALDLEE SSSSDHAERP PGPRRPERGP RGKGKARASQ VKPGDSLPRR GPGATGIGTP AAGPGEERVG AAKASRWRGR QNREKRFTFV LAVVIGVFVV CWFPFFFTYT LTAVGCSVPR TLFKFFFWFG YCNSSLNPVI YTIFNHDFRR AFKKILCRGD RKRIV //