Skip to main content
SpringerLink
Log in

Pharmacology and Molecular Biology of A3 Adenosine Receptors

  • Chapter
  • First Online:
A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics

  • 1047 Accesses

Abstract

Adenosine is an important metabolite and a building block for many biologically relevant molecules. Most abundantly, it contributes the purine base adenine and a ribose to ATP which as an energy-providing compound occurs in millimolar concentrations in every cell. Such high concentrations of ATP are the basis for functionally significant levels of adenosine to occur in all cells and in the extracellular space. Adenosine concentrations vary widely in tissues and body fluids as it is formed both intra- and extracellularly, it undergoes metabolism by adenosine deaminase and adenosine kinase, and may be transported through the plasma membrane with equilibrative and concentrative types of transporter proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CCPA:

2-Chloro-N 6-cyclopentyladenosine

Cl-IB-MECA:

2-Chloro-N 6-3-iodobenzyladenosine-5′-N-methyluronamide

HEMADO:

2-Hexyn-1-yl-N 6-methyladenosine

NECA:

Adenosine-5′-N-ethyluronamide

R-PIA:

R-N 6-(2-phenylisopropyl) adenosine

References

  • Atkinson MR, Townsend-Nicholson A, Nicholl JK, Sutherland GR, Schofield PR (1997) Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene. Neurosci Res 29(1):73–79

    Article  CAS  PubMed  Google Scholar 

  • Auchampach JA, Rizvi A, Qiu Y, Tang X-L, Maldonado C, Teschner S, Bolli R (1997) Selective activation of A3 adenosine receptors with N6-(3-iodobenzyl)adenosine-5’-N-methyluronamide protects against myocardial stunning and infarction without hemodynamic changes in conscious rabbits. Circ Res 80(6):800–809

    CAS  PubMed  Google Scholar 

  • Avila MY, Stone RA, Civan MM (2002) Knockout of A3 adenosine receptors reduces mouse intraocular pressure. Invest Ophthalmol Vis Sci 43(9):3021–3026

    PubMed  Google Scholar 

  • Baraldi PG, Tabrizi MA, Fruttarolo F, Bovero A, Avitabile B, Preti D, Romagnoli R, Merighi S, Gessi S, Varani K, Borea PA (2003) Recent developments in the field of A3 adenosine receptor antagonists. Drug Dev Res 58(4):315–329

    Article  CAS  Google Scholar 

  • Black RS Jr, Guo Y, Ge Z-D, Murphree S, Prabhu SD, Jones WK, Bolli R, Auchampach JA (2002) Gene dosage-dependent effects of cardiac-specific overexpression of the A3 adenosine receptor. Circ Res 91(2):165–172

    Article  CAS  PubMed  Google Scholar 

  • Blay J, White TD, Hoskin DW (1997) The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 57(13):2602–2605

    CAS  PubMed  Google Scholar 

  • Bruns RF (1980) Adenosine receptor activation in human fibroblasts: nucleoside agonists and antagonists. Can J Physiol Pharmacol 58(6):673–691

    CAS  PubMed  Google Scholar 

  • Cerniway RJ, Yang Z, Jacobson MA, Linden J, Matherne GP (2001) Targeted deletion of A3 adenosine receptors improves tolerance to ischemia-reperfusion injury in mouse myocardium. Am J Physiol 281(4):H1751–H1758

    CAS  Google Scholar 

  • Deussen A (2000) Metabolic flux rates of adenosine in the heart. Naunyn Schmiedebergs Arch Pharmacol 362(4–5):351–363

    Article  CAS  PubMed  Google Scholar 

  • Dixon AK, Gubitz AK, Sirinathsinghji DJS, Richardson PJ, Freeman TC (1996) Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 118(6):1461–1468

    CAS  PubMed  Google Scholar 

  • Dougherty C, Barucha J, Schofield PR, Jacobson KA, Liang BT (1998) Cardiac myocytes rendered ischemia resistant by expressing the human adenosine A1 or A3 receptor. FASEB J 12(15):1785–1792

    CAS  PubMed  Google Scholar 

  • Drury AN, Szent-Györgyi A (1929) The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 68(3):213–237

    CAS  PubMed  Google Scholar 

  • Englert M, Quitterer U, Klotz K-N (2002) Effector coupling of stably transfected human A3 adenosine receptors in CHO cells. Biochem Pharmacol 64(1):69–73

    Article  Google Scholar 

  • Fossetta J, Jackson J, Deno G, Fan X, Du XK, Bober L, Soudé-Bermejo A, de Bouteiller O, Caux C, Lunn C, Lundell D, Palmer RK (2003) Pharmacological analysis of calcium responses mediated by the human A3 adenosine receptor in monocyte-derived dendritic cells and recombinant cells. Mol Pharmacol 63(2):342–350

    Article  CAS  PubMed  Google Scholar 

  • Fozard JR, Pfannkuche HJ, Schuurman H-J (1996) Mast cell degranulation following adenosine A3 receptor activation in rats. Eur J Pharmacol 298(3):293–297

    Article  CAS  PubMed  Google Scholar 

  • Fredholm BB, Arslan G, Halldner L, Kull B, Schulte G, Wasserman W (2000) Structure and function of adenosine receptors and their genes. Naunyn Schmiedebergs Arch Pharmacol 362(4–5):364–374

    Article  CAS  PubMed  Google Scholar 

  • Fredholm BB, IJzerman AP, Jacobson KA, Klotz K-N, Linden J (2001a) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53(4):1–26

    Google Scholar 

  • Fredholm BB, Irenius E, Kull B, Schulte G (2001b) Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 61(4):443–448

    Article  CAS  PubMed  Google Scholar 

  • Freissmuth M, Selzer E, Schütz W (1991) Interactions of purified bovine brain A1-adenosine receptors with G-proteins. Reciprocal modulation of agonist and antagonist binding. Biochem J 275(Pt 3):651–656

    CAS  PubMed  Google Scholar 

  • Gessi S, Cattabriga E, Avitabile A, Gafa R, Lanza G, Cavazzini L, Bianchi N, Gambari R, Feo C, Liboni A, Gullini S, Leung E, Mac Lennan S, Borea PA (2004) Elevated expression of A3 adenosine receptors in human colorectal cancer is reflected in peripheral blood cells. Clin Cancer Res 10(17):5895–5901

    Article  CAS  PubMed  Google Scholar 

  • Gessi S, Merighi S, Varani K, Leung E, Mac Lennan S, Borea PA (2008) The A3 adenosine receptor: An enigmatic player in cell biology. Pharmacol Ther 117(1):123–140

    Article  CAS  PubMed  Google Scholar 

  • Graham S, Combes P, Crumiere M, Klotz K-N, Dickenson JM (2001) Regulation of p42/p44 mitogen-activated protein kinase by the human adenosine A3 receptor in transfected CHO cells. Eur J Pharmacol 420(1):19–26

    Article  CAS  PubMed  Google Scholar 

  • Harrison GJ, Cerniway RJ, Peart J, Berr SS, Ashton K, Regan S, Matherne GP, Headrick JP (2002) Effects of A3 adenosine receptor activation and gene knock-out in ischemic-reperfusion mouse heart. Cardiovasc Res 53(1):147–155

    Article  CAS  PubMed  Google Scholar 

  • Hill RJ, Oleynek JJ, Hoth CF, Kiron MAR, Weng W, Wester RT, Tracey WR, Knight DR, Buchholz RA, Kennedy SP (1997) Cloning, expression and pharmacological characterization of rabbit adenosine A1 and A3 receptors. J Pharmacol Exp Ther 280(1):122–128

    CAS  PubMed  Google Scholar 

  • Jiang J, van Rhee AM, Chang L, Patchornik A, Ji X, Evans P, Melman N, Jacobson KA (1997) Structure–activity relationships of 4-(phenylethynyl)-6-phenyl-1, 4-dihydropyridines as highly selective A3 adenosine receptor antagonists. J Med Chem 40(16):2596–2608

    Article  CAS  PubMed  Google Scholar 

  • Kim HO, Ji X, Olah ME, Stiles GL, Jacobson KA (1994) 2-Substitution of N6-benzyladenosine-5′-uronamides enhances selectivity for A3 adenosine receptors. J Med Chem 37(21):3614–3621

    Article  CAS  PubMed  Google Scholar 

  • Klotz K-N (2000) Adenosine receptors and their ligands. Naunyn Schmiedebergs Arch Pharmacol 362(4–5):382–391

    Article  CAS  PubMed  Google Scholar 

  • Klotz K-N, Falgner N, Kachler S, Lambertucci C, Vittori S, Volpini R, Cristalli G (2007) [3H]HEMADO— a novel tritiated agonist selective for the human adenosine A3 receptor. Eur J Pharmacol 556(1–3):14–18

    Article  CAS  PubMed  Google Scholar 

  • Klotz K-N, Hessling J, Hegler J, Owman C, Kull B, Fredholm BB, Lohse MJ (1998) Comparative pharmacology of human adenosine receptor subtypes – Characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 357(1):1–9

    Article  CAS  PubMed  Google Scholar 

  • Kohno Y, Ji X, Mawhorter SD, Koshiba M, Jacobson KA (1996) Activation of A3 adenosine receptors on human eosinophils elevartes intracellular calcium. Blood 88(9):3569–3574

    CAS  PubMed  Google Scholar 

  • Lee HT, Ota-Setlik A, Xu H, D’Agati VD, Jacobson MA, Emala CW (2003) A3 adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure. Am J Physiol 284(2):F267–F273

    CAS  Google Scholar 

  • Liang BT, Jacobson KA (1998) A physiological role of the adenosine A3 receptor: sustained cardioprotection. Proc Natl Acad Sci U S A 95(12):6995–6999

    Article  CAS  PubMed  Google Scholar 

  • Linden J, Taylor HE, Robeva AS, Tucker AL, Stehle JH, Rivkees SA, Fink JS, Reppert SM (1993) Molecular cloning and functional expression of a sheep A3 adenosine receptor with widespread tissue distribution. Mol Pharmacol 44(3):524–532

    CAS  PubMed  Google Scholar 

  • Londos C, Cooper DMF, Wolff J (1980) Subclasses of external adenosine receptors. Proc Natl Acad Sci U S A 77(5):2551–2554

    Article  CAS  PubMed  Google Scholar 

  • Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Baraldi PG, Borea PA (2007a) Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of Bad in glioblastoma cells. Mol Pharmacol 72(1):162–172

    Article  CAS  PubMed  Google Scholar 

  • Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Simioni C, Leung E, Mac Lennan S, Baraldi PG, Borea PA (2007b) Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1a, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol Pharmacol 72(2):395–406

    Article  CAS  PubMed  Google Scholar 

  • Meyerhof W, Müller-Brechlin R, Richter D (1991) Molecular cloning of a novel putative G-protein coupled receptor expressed during spermiogenesis. FEBS Lett 284(2):155–160

    Article  CAS  PubMed  Google Scholar 

  • Molina-Arcas M, Trigueros-Motos L, Casado FJ, Pastor-Anglada M (2008) Physiological and pharmacological roles of nucleoside transporter proteins. Nucleosides Nucleotids Nucleic Acids 27(6):769–778

    Article  CAS  Google Scholar 

  • Müller CE (2003) Medicinal chemistry of adenosine A3 receptor ligands. Curr Topics Med Chem 3(4):445–462

    Article  Google Scholar 

  • Murrison EM, Goodson SJ, Edbrooke MR, Harris CA (1996) Cloning and characterisation of the human adenoisne A3 receptor gene. FEBS Lett 384(3):243–246

    Article  CAS  PubMed  Google Scholar 

  • Pierce KD, Furlong TJ, Selbie L-A, Shine J (1992) Molecular cloning and expression of an adenosine A2b receptor from human brain. Biochem Biophys Res Commun 187(1):86–93

    Article  CAS  PubMed  Google Scholar 

  • Priego E-M, von Frijtag Drabbe Kuenzel J, IJzerman AP, Camarasa M-J, Pérez-Pérez M-J (2002) Pyrido[2, 1-f]purine-2, 4-dione derivatives as a novel class of highly potent human A3 adenosine receptor antagonists. J Med Chem 45(16):3337–3344

    Article  CAS  PubMed  Google Scholar 

  • Ryzhov S, McCaleb JL, Goldstein AE, Biaggioni I (2007) Role of adenosine receptors in the regulation of angiogenic factos and neovascularization in hypoxia. J Pharmacol Exp Ther 320(2):565–572

    Article  CAS  PubMed  Google Scholar 

  • Salvatore CA, Jacobson MA, Taylor HE, Linden J, Johnson RG (1993) Molecular cloning and characterization of the human A3 adenosine receptor. Proc Natil Acad Sci U S A 90(21):10365–10369

    Article  CAS  Google Scholar 

  • Sattin A, Rall TW (1970) The effect of adenosine and adenine nucleotides on the cyclic adenosine 3’, 5’-phosphate content of guinea pig cerebral cortex slices. Mol Pharmacol 6(1):13–23

    CAS  PubMed  Google Scholar 

  • Schulte G, Fredholm BB (2000) Human adenosine A1, A2A, A2B, and A3 receptors expressed in Chinese hamster ovary cells all mediate the phosphorylation of extracellular-regulated kinase 1/2. Mol Pharmacol 58(3):477–482

    CAS  PubMed  Google Scholar 

  • Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, Ohta A, Thiel M (2004) Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 22:657–682

    Article  CAS  PubMed  Google Scholar 

  • Talukder MAH, Morrison RR, Jacobson MA, Jacobson KA, Ledent C, Mustafa SJ (2002) Targeted deletion of adenosine A3 receptors augments adenosine-induced coronary flow in isolated mouse heart. Am J Physiol 282(6):H2183–H2189

    CAS  Google Scholar 

  • Tilley SL, Wagoner VA, Salvatore CA, Jacobson MA, Koller BH (2000) Adenosine and inosine increase cutaneous vasopermeability by activating A3 receptors on mast cells. J Clin Invest 105(3):361–367

    Article  CAS  PubMed  Google Scholar 

  • van Calker D, Müller M, Hamprecht B (1979) Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J Neurochem 33(5):999–1005

    Article  PubMed  Google Scholar 

  • van der Hoeven D, Wan TC, Auchampach JA (2008) Activation of the A3 adenosine receptor suppresses superoxide production and chemotaxis of mouse bone marrow neutrophils. Mol Pharmacol 74(3):685–696

    Article  PubMed  Google Scholar 

  • Volpini R, Costanzi S, Lambertucci C, Taffi S, Vittori S, Klotz K-N, Cristalli G (2002) N6-alkyl-2-alkynyl derivatives of adenosine as potent and selective agonists at the human adenosine A3 receptor and a starting point for searching A2B ligands. J Med Chem 45(15):3271–3279

    Article  CAS  PubMed  Google Scholar 

  • Volpini R, Costanzi S, Lambertucci C, Vittori S, Klotz K-N, Lorenzen A, Cristalli G (2001) Introduction of alkynyl chains on C-8 of adenosine led to very selective antagonists of the A3 adenosine receptors. Bioorg Med Chem Lett 11(14):1931–1934

    Google Scholar 

  • von Lubitz DKJE, Lin RCS, Popik P, Carter MF, Jacobson KA (1994) Adenosne A3 receptor stimulation and cerebral ischemia. Eur J Pharmacol 263(1–2):59–67

    Google Scholar 

  • Zhao Z, Francis C, Ravid K (1999) Characterization of the mouse A3 adenosine receptor gene: exon/intron organization and promoter activity. Genomics 57(1):152–155

    Article  CAS  PubMed  Google Scholar 

  • Zhao Z, Makaritsis K, Francis CE, Gavras H, Ravid K (2000) A role for the A3 adenosine receptor in determining tissue levels of cAMP and blood pressure: studies on knock-out mice. Biochim Biophys Acta 1500(3):280–290

    CAS  PubMed  Google Scholar 

  • Zhou Q-Y, Li C, Olah ME, Johnson RA, Stiles GL, Civelli O (1992) Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc Natl Acad Sci U S A 89(16):7432–7436

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann H (2000) Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 362(4–5):299–309

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Str. 9, D-97078, Würzburg, Germany

    Karl-Norbert Klotz

Authors
  1. Karl-Norbert Klotz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karl-Norbert Klotz .

Editor information

Editors and Affiliations

  1. Ist. Farmacologia, Universita Ferrara, Via Fossato di Mortara 64 B, Ferrara, 44100, Italy

    Pier Andrea Borea

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Klotz, KN. (2010). Pharmacology and Molecular Biology of A3 Adenosine Receptors. In: Borea, P. (eds) A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3144-0_3

Download citation

Publish with us

Policies and ethics

Search

Navigation