Alpha-2C adrenergic receptor

ADRA2C

Identifiers

ADRA2C, ADRA2L2, ADRA2RL2, ADRARL2, ALPHA2CAR, adrenoceptor alpha 2C

External IDs

MGI: 87936 HomoloGene: 20170 GeneCards: ADRA2C

Gene ontology
Molecular function	• G-protein coupled receptor activity • epinephrine binding • protein homodimerization activity • signal transducer activity • adrenergic receptor activity • protein binding • alpha-2A adrenergic receptor binding • alpha2-adrenergic receptor activity • protein heterodimerization activity
Cellular component	• cytoplasm • axon terminus • integral component of membrane • endosome • membrane • plasma membrane • integral component of plasma membrane • axon
Biological process	• G-protein coupled receptor signaling pathway • activation of protein kinase B activity • negative regulation of epinephrine secretion • regulation of sensory perception of pain • regulation of smooth muscle contraction • regulation of insulin secretion • epidermal growth factor-activated receptor transactivation by G-protein coupled receptor signaling pathway • female pregnancy • cell-cell signaling • negative regulation of norepinephrine secretion • negative regulation of uterine smooth muscle contraction • activation of MAPK activity by adrenergic receptor signaling pathway • adenylate cyclase-activating adrenergic receptor signaling pathway • regulation of vasoconstriction • positive regulation of neuron differentiation • positive regulation of vasoconstriction • signal transduction • platelet activation
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

Entrez


152


11553

Ensembl


ENSG00000184160


ENSMUSG00000045318

UniProt


P18825


Q01337

RefSeq (mRNA)


NM_000683


NM_007418

RefSeq (protein)


NP_000674


NP_031444

Location (UCSC)

Chr 4: 3.77 – 3.77 Mb

Chr 5: 35.28 – 35.28 Mb

PubMed search

^[1]

^[2]

Wikidata

View/Edit Human

View/Edit Mouse

The alpha-2C adrenergic receptor (α_2C adrenoceptor), also known as ADRA2C, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.^[3]

Receptor

Alpha-2-adrenergic receptors include 3 highly homologous subtypes: alpha_2A, alpha_2B, and alpha_2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. Studies in mice revealed that both the alpha_2A and alpha_2C subtypes were required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons; the alpha_2A subtype inhibited transmitter release at high stimulation frequencies, whereas the alpha_2C subtype modulated neurotransmission at lower levels of nerve activity.

Gene

This gene encodes the alpha2C subtype, which contains no introns in either its coding or untranslated sequences.^[3]

Ligands

Agonists

(R)-3-Nitrobiphenyline (also weak antagonist at α_2A and α_2B)^[4]

Antagonists

BMY 7378 (also α_1D antagonist)^[5]
JP-1302: selective over α2A, α2B, α2C^[6]
spiroxatrine
yohimbine derivatives 9 and 10: >43 fold selectivity over α2A, α2B and α1 subtypes^[7]
N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide^[8]
Risperidone

References

↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
1 2 "Entrez Gene: ADRA2C adrenergic, alpha-2C-, receptor".
↑ Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, Ghelfi F, Giannella M, Paris H, Piergentili A, Quaglia W, Schaak S, Vesprini C, Pigini M (August 2007). "Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and alpha2C-subtype selective agonist". Journal of Medicinal Chemistry. 50 (16): 3964–8. PMID 17630725. doi:10.1021/jm061487a.
↑ Cleary L, Murad K, Bexis S, Docherty JR (2005). "The alpha (1D)-adrenoceptor antagonist BMY 7378 is also an alpha (2C)-adrenoceptor antagonist". Auton Autacoid Pharmacol. 25 (4): 135–41. PMID 16176444. doi:10.1111/j.1474-8673.2005.00342.x.
↑ Sallinen J, Höglund I, Engström M, Lehtimäki J, Virtanen R, Sirviö J, Wurster S, Savola JM, Haapalinna A (2007). "Pharmacological characterization and CNS effects of a novel highly selective alpha2C-adrenoceptor antagonist JP-1302". Br. J. Pharmacol. 150 (4): 391–402. PMC 2189732 . PMID 17220913. doi:10.1038/sj.bjp.0707005.
↑ Bavadekar SA, Ma G, Mustafa SM, Moore BM, Miller DD, Feller DR (November 2006). "Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands". J. Pharmacol. Exp. Ther. 319 (2): 739–48. PMID 16873606. doi:10.1124/jpet.106.105981.
↑ Patel SD, Habeski WM, Min H, Zhang J, Roof R, Snyder B, Bora G, Campbell B, Li C, Hidayetoglu D, Johnson DS, Chaudhry A, Charlton ME, Kablaoui NM (2008). "Identification and SAR around N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide, a selective alpha2C adrenergic receptor antagonist". Bioorg. Med. Chem. Lett. 18 (20): 5689–93. PMID 18799310. doi:10.1016/j.bmcl.2008.08.055.

External links

Human ADRA2C genome location and ADRA2C gene details page in the UCSC Genome Browser.

Coupry I, Duzic E, Lanier SM (1992). "Factors determining the specificity of signal transduction by guanine nucleotide-binding protein-coupled receptors. II. Preferential coupling of the alpha 2C-adrenergic receptor to the guanine nucleotide-binding protein, Go". J. Biol. Chem. 267 (14): 9852–7. PMID 1349607.
Chhajlani V, Rangel N, Uhlén S, Wikberg JE (1991). "Identification of an additional gene belonging to the alpha 2 adrenergic receptor family in the human genome by PCR". FEBS Lett. 280 (2): 241–4. PMID 1849485. doi:10.1016/0014-5793(91)80301-I.
Regan JW, Kobilka TS, Yang-Feng TL, Caron MG, Lefkowitz RJ, Kobilka BK (1988). "Cloning and expression of a human kidney cDNA for an alpha 2-adrenergic receptor subtype". Proc. Natl. Acad. Sci. U.S.A. 85 (17): 6301–5. PMC 281957 . PMID 2842764. doi:10.1073/pnas.85.17.6301.
Eason MG, Liggett SB (1993). "Human alpha 2-adrenergic receptor subtype distribution: widespread and subtype-selective expression of alpha 2C10, alpha 2C4, and alpha 2C2 mRNA in multiple tissues". Mol. Pharmacol. 44 (1): 70–5. PMID 7688069.
Riess O, Thies U, Siedlaczck I, Potisek S, Graham R, Theilmann J, Grimm T, Epplen JT, Hayden MR (1994). "Precise mapping of the brain alpha 2-adrenergic receptor gene within chromosome 4p16". Genomics. 19 (2): 298–302. PMID 8188260. doi:10.1006/geno.1994.1061.
Klein U, Ramirez MT, Kobilka BK, von Zastrow M (1997). "A novel interaction between adrenergic receptors and the alpha-subunit of eukaryotic initiation factor 2B". J. Biol. Chem. 272 (31): 19099–102. PMID 9235896. doi:10.1074/jbc.272.31.19099.
Schaak S, Devedjian JC, Cayla C, Sender Y, Paris H (1998). "Molecular cloning, sequencing and functional study of the promoter region of the human alpha2C4-adrenergic receptor gene". Biochem. J. 328 (2): 431–8. PMC 1218938 . PMID 9371698.
DeGraff JL, Gagnon AW, Benovic JL, Orsini MJ (1999). "Role of arrestins in endocytosis and signaling of alpha2-adrenergic receptor subtypes". J. Biol. Chem. 274 (16): 11253–9. PMID 10196213. doi:10.1074/jbc.274.16.11253.
Prezeau L, Richman JG, Edwards SW, Limbird LE (1999). "The zeta isoform of 14-3-3 proteins interacts with the third intracellular loop of different alpha2-adrenergic receptor subtypes". J. Biol. Chem. 274 (19): 13462–9. PMID 10224112. doi:10.1074/jbc.274.19.13462.
Hein L, Altman JD, Kobilka BK (2000). "Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission". Nature. 402 (6758): 181–4. PMID 10647009. doi:10.1038/46040.
Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB (2000). "A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors". J. Biol. Chem. 275 (30): 23059–64. PMID 10801795. doi:10.1074/jbc.M000796200.
Comings DE, Gade-Andavolu R, Gonzalez N, Wu S, Muhleman D, Blake H, Chiu F, Wang E, Farwell K, Darakjy S, Baker R, Dietz G, Saucier G, MacMurray JP (2001). "Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder". Clin. Genet. 58 (1): 31–40. PMID 10945659. doi:10.1034/j.1399-0004.2000.580106.x.
Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB (2002). "Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure". N. Engl. J. Med. 347 (15): 1135–42. PMID 12374873. doi:10.1056/NEJMoa020803.
Chotani MA, Mitra S, Su BY, Flavahan S, Eid AH, Clark KR, Montague CR, Paris H, Handy DE, Flavahan NA (2004). "Regulation of alpha(2)-adrenoceptors in human vascular smooth muscle cells". Am. J. Physiol. Heart Circ. Physiol. 286 (1): H59–67. PMID 12946937. doi:10.1152/ajpheart.00268.2003.
Small KM, Mialet-Perez J, Seman CA, Theiss CT, Brown KM, Liggett SB (2004). "Polymorphisms of cardiac presynaptic alpha2C adrenergic receptors: Diverse intragenic variability with haplotype-specific functional effects". Proc. Natl. Acad. Sci. U.S.A. 101 (35): 13020–5. PMC 516511 . PMID 15319474. doi:10.1073/pnas.0405074101.
Chotani MA, Mitra S, Eid AH, Han SA, Flavahan NA (2005). "Distinct cAMP signaling pathways differentially regulate alpha2C-adrenoceptor expression: role in serum induction in human arteriolar smooth muscle cells". Am. J. Physiol. Heart Circ. Physiol. 288 (1): H69–76. PMID 15345481. doi:10.1152/ajpheart.01223.2003.
Belfer I, Buzas B, Hipp H, Phillips G, Taubman J, Lorincz I, Evans C, Lipsky RH, Enoch MA, Max MB, Goldman D (2005). "Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene". J. Hum. Genet. 50 (1): 12–20. PMID 15592690. doi:10.1007/s10038-004-0211-y.
Neumeister A, Charney DS, Belfer I, Geraci M, Holmes C, Sharabi Y, Alim T, Bonne O, Luckenbaugh DA, Manji H, Goldman D, Goldstein DS (2005). "Sympathoneural and adrenomedullary functional effects of alpha2C-adrenoreceptor gene polymorphism in healthy humans". Pharmacogenet. Genomics. 15 (3): 143–9. PMID 15861038. doi:10.1097/01213011-200503000-00002.
Neumeister A, Drevets WC, Belfer I, Luckenbaugh DA, Henry S, Bonne O, Herscovitch P, Goldman D, Charney DS (2006). "Effects of an alpha 2C-adrenoreceptor gene polymorphism on neural responses to facial expressions in depression". Neuropsychopharmacology. 31 (8): 1750–6. PMID 16407897. doi:10.1038/sj.npp.1301010.
Park JS, Zhang SY, Jo SH, Seo JB, Li L, Park KW, Oh BH, Park YB, Kim HS (2006). "Common adrenergic receptor polymorphisms as novel risk factors for vasospastic angina". Am. Heart J. 151 (4): 864–9. PMID 16569551. doi:10.1016/j.ahj.2005.06.009.

PDB gallery

1hll: NMR STRUCTURE OF T3-I2, A 32 RESIDUE PEPTIDE FROM THE ALPHA-2A ADRENERGIC RECEPTOR

1ho9: BEST 20 NMR CONFORMERS OF D130I MUTANT T3-I2, A 32 RESIDUE PEPTIDE FROM THE ALPHA 2A ADRENERGIC RECEPTOR

1hod: NMR STRUCTURE OF D130I MUTANT T3-I2, A 32 RESIDUE PEPTIDE FROM THE ALPHA 2A ADRENERGIC RECEPTOR

1hof: NMR STRUCTURE OF T3-I2, A 32 RESIDUE PEPTIDE FROM THE ALPHA-2A ADRENERGIC RECEPTOR

Cell surface receptor: G protein–coupled receptors

Class A: Rhodopsin-like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3
Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)
Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)
Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine D1 D2 D3 D4 D5 GHB receptor Histamine H1 H2 H3 H4 Melatonin (1A 1B 1C) TAAR (1 2 3 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 1 2 FPRL1 OXE Prostaglandin DP (1 2), EP (1 2 3 4), FP Prostacyclin Thromboxane
Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Lactate Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Niacin (1 2) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide

B/W (1
2)
FF (1
2)
S
Y (1
2
4
5)
Neuromedin (B
U (1
2))
Neurotensin (1
2)

Other

Anaphylatoxin (C3a
C5a)
Angiotensin (1
2)
Apelin
Bombesin
- BRS3
- GRPR
- NMBR)
- Bradykinin (B1
- B2)
Chemokine
Cholecystokinin (A
B)
Endothelin
- A
- B
Formyl peptide (1
2
3)
FSH
Galanin (1
2
3)
Gonadotropin-releasing hormone (1
2)
Ghrelin
Kisspeptin
Luteinizing hormone/choriogonadotropin
MAS (1
1L
D
E
F
G
X1
X2
X3
X4)
Melanocortin (1
2
3
4
5)
MCHR (1
2)
Motilin
Opioid (Delta
Kappa
Mu
Nociceptin & Zeta, but not Sigma)
Orexin (1
2)
Oxytocin
Prokineticin (1
2)
Prolactin-releasing peptide
Relaxin (1
2
3
4)
Somatostatin (1
2
3
4
5)
Tachykinin (1
2
3)
Thyrotropin
Thyrotropin-releasing hormone
Urotensin-II
Vasopressin (1A
1B
2)

Miscellaneous

Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 77 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)
Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin-like

Adhesion	ADGRG (1 2 3 4 5 6 7)
Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)
Other	Brain-specific angiogenesis inhibitor (1 2 3) Cadherin (1 2 3) Calcitonin CALCRL CD97 Corticotropin-releasing hormone (1 2) EMR (1 2 3) Glucagon (GR GIPR GLP1R GLP2R) Growth-hormone-releasing hormone PACAPR1 GPR Latrophilin (1 2 3 ELTD1) Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic glutamate / pheromone

Taste	TAS1R (1 2 3) TAS2R (1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60 Vomeronasal receptor)
Other	Calcium-sensing receptor GABAB (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)

Class F: Frizzled / Smoothened

Frizzled	Frizzled (1 2 3 4 5 6 7 8 9 10)
Smoothened	Smoothened

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