Alpha-2C adrenergic receptor

Adrenoceptor alpha 2C

PDB rendering based on 1hll.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1hll, 1ho9, 1hod, 1hof

Identifiers

Symbols

ADRA2C ; ADRA2L2; ADRA2RL2; ADRARL2; ALPHA2CAR

External IDs

OMIM: 104250 MGI: 87936 HomoloGene: 20170 IUPHAR: 27 ChEMBL: 1916 GeneCards: ADRA2C Gene

Gene ontology
Molecular function	• alpha2-adrenergic receptor activity • protein binding • alpha-2A adrenergic receptor binding • protein homodimerization activity • protein heterodimerization activity • epinephrine binding
Cellular component	• cytoplasm • endosome • plasma membrane • integral component of plasma membrane • axon terminus
Biological process	• energy reserve metabolic process • G-protein coupled receptor signaling pathway • negative regulation of adenylate cyclase activity • cell-cell signaling • female pregnancy • blood coagulation • negative regulation of norepinephrine secretion • platelet activation • activation of protein kinase B activity • negative regulation of epinephrine secretion • epidermal growth factor-activated receptor transactivation by G-protein coupled receptor signaling pathway • small molecule metabolic process • positive regulation of neuron differentiation • positive regulation of vasoconstriction • regulation of insulin secretion • regulation of sensory perception of pain • negative regulation of insulin secretion involved in cellular response to glucose stimulus • negative regulation of uterine smooth muscle contraction • adenylate cyclase-inhibiting adrenergic receptor signaling pathway • activation of MAPK activity by adrenergic receptor signaling pathway
Sources: Amigo / QuickGO

Orthologs

Species

Human

Mouse

152

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 4:
3.77 – 3.77 Mb

Chr 5:
35.28 – 35.28 Mb

PubMed search

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.^[1]

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.^[1]

Ligands

Agonists

(R)-3-Nitrobiphenyline (also weak antagonist at α_2A and α_2B)^[2]

Antagonists

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

References

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. doi:10.1021/jm061487a. PMID 17630725.
↑ 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. doi:10.1111/j.1474-8673.2005.00342.x. PMID 16176444.
↑ 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. doi:10.1038/sj.bjp.0707005. PMC 2189732. PMID 17220913.
↑ 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. doi:10.1124/jpet.106.105981. PMID 16873606.
↑ 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. doi:10.1016/j.bmcl.2008.08.055. PMID 18799310.

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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. doi:10.1074/jbc.274.16.11253. PMID 10196213.
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. doi:10.1074/jbc.274.19.13462. PMID 10224112.
Hein L, Altman JD, Kobilka BK (2000). "Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission". Nature 402 (6758): 181–4. doi:10.1038/46040. PMID 10647009.
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. doi:10.1074/jbc.M000796200. PMID 10801795.
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. doi:10.1034/j.1399-0004.2000.580106.x. PMID 10945659.
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. doi:10.1056/NEJMoa020803. PMID 12374873.
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. doi:10.1152/ajpheart.00268.2003. PMID 12946937.
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. doi:10.1073/pnas.0405074101. PMC 516511. PMID 15319474.
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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) 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) GHB receptor 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)

Other	Calcium-sensing receptor GABA B (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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