Skip to main content
SpringerLink
Log in

A3 Adenosine Receptor: Pharmacology and Role in Disease

  • Chapter
  • First Online:
Adenosine Receptors in Health and Disease

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 193))

Abstract

The study of the A3 adenosine receptor (A3AR) represents a rapidly growing and intense area of research in the adenosine field. The present chapter will provide an overview of the expression patterns, molecular pharmacology and functional role of this A3AR subtype under pathophysiological conditions. Through studies utilizing selective A3AR agonists and antagonists, or A3AR knockout mice, it is now clear that this receptor plays a critical role in the modulation of ischemic diseases as well as in inflammatory and autoimmune pathologies. Therefore, the potential therapeutic use of agonists and antagonists will also be described. The discussion will principally address the use of such compounds in the treatment of brain and heart ischemia, asthma, sepsis and glaucoma. The final part concentrates on the molecular basis of A3ARs in autoimmune diseases such as rheumatoid arthritis, and includes a description of clinical trials with the selective agonist CF101. Based on this chapter, it is evident that continued research to discover agonists and antagonists for the A3AR subtype is warranted.

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 389.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 499.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 549.99
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

Δψ:

Mitocondrial membrane potential

A1ARA1 :

Adenosine receptor

A2AARA2A :

Adenosine receptor

A2BARA2B :

Adenosine receptor

\({\mathrm{{A}_{3}AR}}^{-/-}\) :

Functional deletions of the A3AR

A3ARA3 :

Adenosine receptor

AC:

Adenylyl cyclase

ACR:

American College of Rheumatology

ADA:

Adenosine deaminase

\({\mathrm{ADA}}^{-/-}\) :

Adenosine deaminase deficient

AIA:

Adjuvant-induced arthritis

AICAR:

Aminoimidazole carboxamide ribonucleotide

AR:

Adenosine receptor

Ca2 + :

Calcium

cAMP:

Cyclic adenosine monophosphate

CHO − hA3 :

Chinese hamster ovary cells transfected with human A3AR

Cl − IB − MECA:

2-Chloro-N 6-(3-iodobenzyl)-N-methyl-5′-carbamoyladenosine

CNS:

Central nervous system

ConA:

Concanavalin A

COPD:

Chronic obstructive pulmonary disease

COX:

Cyclooxygenase

CP-532,903:

N 6-(2,5-Dichlorobenzyl)-3-aminoadenosine-5-N-methylcarboxamide

DAG:

1,2-Diacylglycerol

DMARDs:

Disease-modifying antirheumatic drugs

DPCPX:

8-Cyclopentyl-1,3-dipropylxanthine

ERK1/2:

Extracellular signal-regulated kinases

GPCR:

G-protein-coupled receptor

GRKs:

G-protein-coupled receptor kinases

GSK-3β:

Glycogen synthase kinase

HIF-1α:

Hypoxia-inducible factor 1α

IB − MECA:

N 6-(3-Iodobenzyl)-adenosine-5′-N-methylcarboxamide

IκB:

Inhibitor of κB

IKK:

IκB kinase

IL:

Interleukin

IPC:

Ischemic preconditioning

IP3 :

Inositol triphosphate

JNK:

Jun N-terminal kinase

KATP :

ATP-sensitive potassium

KO:

Knockout

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MBP:

Myelin basic protein

MEK:

Mitogen-activated protein kinase kinase

Mito:

Mitochondrial

MTX:

Methotrexate

mPTP:

Mitochondrial permeability transition pore

MRS 1191:

3-Ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-( ± )-dihydropyridine-3,5-dicarboxylate

MRS 1523:

5-Propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate

NF-kB:

Nuclear factor kappa B

NOS:

Nitric oxide synthase

OGD:

Oxygen and glucose deprivation

p38:

Stress-activated protein kinase with molecular weight 38 kDa

PBMC:

Peripheral blood mononuclear cells

PI3K:

Phosphoinositide 3-kinase

PKA:

Protein kinase A

PKB/Akt:

Protein kinase B

PKC:

Protein kinase C

PLC:

Phospholipase C

PLD:

Phospholipase D

PTX:

Pertussis toxin

RA:

Rheumatoid arthritis

RBL:

Rat basophilic leukemia

STAT3:

Signal transducer and activator of transcription 3

t 1 / 2 :

Half-life

TNF-α:

Tumor necrosis factor alpha

References

  • Abbracchio MP, Brambilla R, Ceruti S, Kim HO, von Lubitz DK, Jacobson KA, Cattabeni F (1995) G protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain. Mol Pharmacol 48:1038–1045

    CAS  PubMed  Google Scholar 

  • Abbracchio MP, Rainaldi G, Giammarioli AM, Ceruti S, Brambilla R, Cattabeni F, Barbieri D, Franceschi C, Jacobson KA, Malorni W (1997) The A3 adenosine receptor mediates cell spreading, reorganization of actin cytoskeleton, and distribution of Bcl-XL: studies in human astroglioma cells. Biochem Biophys Res Commun 241:297–304

    Article  CAS  PubMed  Google Scholar 

  • Abbracchio MP, Cimurri A, Ceruti S, Cattabeni F, Falzano L, Giammarioli AM, Jacobson KA, Trincavelli L, Martini C, Malorni W, Fiorentini C (2001) The A3 adenosine receptor induces cytoskeleton rearrangement in human astrocytoma cells via a specific action on Rho proteins. Ann New York Acad Sci 939:63–73

    Article  CAS  Google Scholar 

  • Ali H, Cunha-Melo JR, Saul WF, Beaven MA (1990) Activation of phospholipase C via adenosine receptors provides synergistic signals for secretion in antigen-stimulated RBL-2H3 cells. Evidence for a novel adenosine receptor. J Biol Chem 265:745–753

    CAS  Google Scholar 

  • Ansari HR, Nadeem A, Tilley SL, Mustafa SJ (2007) Involvement of COX-1 in A3 adenosine receptor-mediated contraction through endothelium in mice aorta. Am J Physiol Heart Circ Physiol 293:H3448–H3455

    Article  CAS  PubMed  Google Scholar 

  • Appel E, Kazimirsky G, Ashkenazi E, Kim SG, Jacobson KA, Brodie C (2001) Roles of BCL-2 and caspase 3 in the adenosine A3 receptor-induced apoptosis. J Mol Neurosci 17:285–292

    Article  CAS  PubMed  Google Scholar 

  • Armstrong S, Ganote CE (1994) Adenosine receptor specificity in preconditioning of isolated rabbit cardiomyocytes: evidence of A3 receptor involvement. Cardiovasc Res 28:1049–1056

    Article  CAS  PubMed  Google Scholar 

  • Ashton KJ, Nilsson U, Willems L, Holmgren K, Headrick JP (2003) Effects of aging and ischemia on adenosine receptor transcription in mouse myocardium. Biochem Biophys Res Commun 312:367–372

    Article  CAS  PubMed  Google Scholar 

  • 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 29:73–79

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Auchampach JA, Jin X, Wan TC, Caughey GH, Linden J (1997b) Canine mast cell adenosine receptors: cloning and expression of the A3 receptor and evidence that degranulation is mediated by the A2B receptor. Mol Pharmacol 52:846–860

    CAS  PubMed  Google Scholar 

  • Auchampach JA, Ge Z-D, Wan TC, Moore J, Gross GJ (2003) A3 adenosine receptor agonist IB-MECA reduces myocardial ischemia-reperfusion injury in dogs. Am J Physiol Heart Circ Physiol 285:H607–H613

    CAS  PubMed  Google Scholar 

  • Auchampach JA, Jin X, Moore J, Wan TC, Kreckler LM, Ge ZD, Narayanan J, Whalley E, Kiesman W, Ticho B, Smits G, Gross GJ (2004) Comparison of three different A1 adenosine receptor antagonists on infarct size and multiple cycle ischemic preconditioning in anesthetized dogs. J Pharmacol Exp Ther 308:846–856

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Baggott JE, Morgan SL, Sams WM, Linden J (1999) Urinary adenosine and aminoimidazolecarboxamide excretion in methotrexate-treated patients with psoriasis. Arch Dermatol 135:813–817

    Article  CAS  PubMed  Google Scholar 

  • Baharav E, Bar-Yehuda S, Madi L, Silberman D, Rath-Wolfson L, Halpren M, Ochaion A, Weinberger A, Fishman P (2005) Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models. J Rheumatol 32:469–476

    CAS  PubMed  Google Scholar 

  • Baraldi PG, Tabrizi MA, Gessi S, Borea PA (2008) Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility. Chem Rev 108:238–263

    Article  CAS  PubMed  Google Scholar 

  • Bar-Yehuda S, Silverman MH, Kerns WD, Ochaion A, Cohen S, Fishman P (2007) The anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis. Expert Opin Investig Drugs 16:1601–1613

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bouma MG, Jeuhomme TMMA, Boyle DL, Dentener MA,Voitenok NN, van den Wildenberg FAJM, Buurman WA (1997) Adenosine inhibits neutrophil degranulation in activated human whole blood. J Immunol 158:5400–5408

    CAS  PubMed  Google Scholar 

  • Brand A, Vissiennon Z, Eschke D, Nieber K (2001) Adenosine A1 and A3 receptors mediate inhibition of synaptic transmission in rat cortical neurons. Neuropharmacology 40:85–95

    Google Scholar 

  • Brandon CI, Vandenplas M, Dookwah H, Murray TF (2006) Cloning and pharmacological characterization of the equine adenosine A3 receptor. J Vet Pharmacol Ther 29:255–263

    Article  CAS  PubMed  Google Scholar 

  • Broussas M, Cornillet-Lefebvre P, Potron G, Nguyen P (1999) Inhibition of fMLP-triggered respiratory burst of human monocytes by adenosine: involvement of A3 adenosine receptor. J Leukoc Biol 66:495–501

    CAS  PubMed  Google Scholar 

  • Broussas M, Cornillet-Lefebvre P, Potron G, Nguyen P (2002) Adenosine inhibits tissue factor expression by LPS-stimulated human monocytes: involvement of the A3 adenosine receptor. Thromb Haemost 88:123–130

    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 Heart Circ Physiol 281:H1751–H1758

    CAS  PubMed  Google Scholar 

  • Chan ES, Cronstein BN (2002) Molecular action of methotrexate in inflammatory diseases. Arthritis Res 4:266–273

    Article  PubMed  Google Scholar 

  • Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, Zinkernagel A, Nizet V, Insel PA, Junger WG (2006a) ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314:1792–1795

    Article  CAS  PubMed  Google Scholar 

  • Chen GJ, Harvey BK, Shen H, Chou J, Victor A, Wang Y (2006b) Activation of adenosine A3 receptors reduces ischemic brain injury in rodents. J Neurosci Res 84:1848–1855

    Article  CAS  PubMed  Google Scholar 

  • Chung H, Jung JY, Cho SD, Hong KA, Kim HJ, Shin DH, Kim H, Kim HO, Shin DH, Lee HW, Jeong LS, Kong G (2006) The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor-positive and estrogen receptor-negative human breast cancers. Mol Cancer Ther 5:685–692

    Article  CAS  PubMed  Google Scholar 

  • Cohen MV, Downey JM (2008) Adenosine: trigger and mediator of cardioprotection. Basic Res Cardiol 103(3):203–215

    Article  CAS  PubMed  Google Scholar 

  • Cordoro KM, Feldman SR (2007) TNF-alpha inhibitors in dermatology. Skin Ther Lett 12:4–6

    CAS  Google Scholar 

  • Cronstein BN (1994) Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol 76:5–13

    CAS  PubMed  Google Scholar 

  • Cross HR, Murphy E, Black RG, Auchampach J, Steenbergen C (2002) Overexpression of A3 adenosine receptors decreases heart rate, preserves energetics, and protects ischemic hearts. Am J Physiol Heart Circ Physiol 283:H1562–H1568

    CAS  PubMed  Google Scholar 

  • Danese S, Pagano N, Angelucci E, Stefanelli T, Repici A, Omodei P, Daperno M, Malesci A (2007) Tumor necrosis factor-alpha monoclonal antibodies for Crohn’s disease: tipping the balance. Curr Med Chem 14:1489–1497

    Article  CAS  PubMed  Google Scholar 

  • Daré E, Schulte G, Karovic O, Hammarberg C, Fredholm BB (2007) Modulation of glial cell functions by adenosine receptors. Physiol Behav 92(1–2):15–20

    Article  PubMed  CAS  Google Scholar 

  • Dawson VL, Dawson TM (2000) Neuronal ischaemic preconditioning. Trends Pharmacol Sci 21:423–424

    Article  CAS  PubMed  Google Scholar 

  • Desai SB, Furst DE (2006) Problems encountered during anti-tumour necrosis factor therapy. Best Pract Res Clin Rheumatol 20:757–590

    Article  CAS  PubMed  Google Scholar 

  • Dickenson JM, Reeder S, Rees B, Alexander S, Kendall D (2003) Functional expression of adenosine A2A and A3 receptors in the mouse dendritic cell line XS-106. Eur J Pharmacol 474:43–51

    Article  CAS  PubMed  Google Scholar 

  • Di Iorio P, Kleywegt S, Ciccarelli R, Traversa U, Andrew CM, Crocker CE, Werstiuk ES, Rathbone MP (2002) Mechanisms of apoptosis induced by purine nucleosides in astrocytes. Glia 38:179–190

    Article  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 118:1461–1468

    CAS  PubMed  Google Scholar 

  • Dunwiddie TV, Diao L, Kim HO, Jiang J-L, Jacobson KA (1997) Activation of hippocampal adenosine A3 receptors produces a desensitization of A1 receptor-mediated responses in rat hippocampus. J Neurosci 17:607–614

    CAS  PubMed  Google Scholar 

  • Ezeamuzie CI, Philips E (1999) Adenosine A3 receptors on human eosinophils mediate inhibition of degranulation and superoxide anion release. Br J Pharmacol 127:188–194

    Article  CAS  PubMed  Google Scholar 

  • Fedorova IM, Jacobson MA, Basile A, Jacobson KA (2003) Behavioral characterization of mice lacking the A3 adenosine receptor: sensitivity to hypoxic neurodegeneration. Cell Mol Neurobiol 23:431–447

    Article  CAS  PubMed  Google Scholar 

  • Feoktistov I, Biaggioni I (1995) Adenosine A2B receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. J Clin Invest 96:1979–1986

    CAS  Google Scholar 

  • Ferguson G, Watterson KR, Palmer TM (2000) Subtype-specific kinetics of inhibitory adenosine receptor internalization are determined by sensitivity to phosphorylation by G protein-coupled receptor kinases. Mol Pharmacol 57:546–552

    CAS  PubMed  Google Scholar 

  • Fishman P, Bar-Yehuda S, Madi L, Cohn I (2002a) A3 adenosine receptor as a target for cancer therapy. Anticancer Drug 13:1–8

    Article  Google Scholar 

  • Fishman P, Madi L, Bar-Yehuda S, Barer F, Del Valle, Khalili K (2002b) Evidence for involvement of Wnt signalling pathway in IB-MECA mediated suppression of melanoma cells. Oncogene 21:4060–4064

    Article  CAS  PubMed  Google Scholar 

  • Fishman P, Bar-Yehuda S, Ardon E, Rath-Wolfson L, Barrer F, Ochaion A, Madi L (2003) Targeting the A3 adenosine receptor for cancer therapy: inhibition of prostate carcinoma cell growth by A3AR agonist. Anticancer Res 23:2077–2083

    CAS  PubMed  Google Scholar 

  • Fishman P, Bar-Yehuda S, Ohana G, Barer F, Ochaion A, Erlanger A, Madi L (2004) An agonist to the A2 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3β and NF-kB. Oncogene 23:2465–2471

    Article  CAS  PubMed  Google Scholar 

  • Fishman P, Bar-Yehuda S, Madi L, Rath-Wolfson L, Ochaion A, Cohen S, Baharav E (2006) The PI3K-NF-kappaB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant-induced arthritis. Arthritis Res Ther 8:R33

    Article  PubMed  CAS  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 63:342–350

    Article  CAS  PubMed  Google Scholar 

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

    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–Schmiedeberg’s Arch Pharmacol 362:364–374

    Article  CAS  Google Scholar 

  • Gao Z, Li BS, Day YJ, Linden J (2001) A3 adenosine receptor activation triggers phosphorylation of protein kinase B and protects rat basophilic leukemia 2H3 mast cells from apoptosis. Mol Pharmacol 59:76–82

    CAS  PubMed  Google Scholar 

  • Ge Z-D, Peart JN, Kreckler LM, Wan TC, Jacobson MA, Gross GJ, Auchampach JA (2006) Cl-IB-MECA [2-Chloro-N 6-(3-iodobenzyl)adenosine-5′-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor. J Pharm Exp Ther 319:1200–1210

    Article  CAS  Google Scholar 

  • Germack R, Dickenson JM (2004) Characterization of ERK 1/2 signalling pathways induced by adenosine receptor subtype in newborn rat cardiomyocytes. Br J Pharmacol 141:329–339

    Article  CAS  PubMed  Google Scholar 

  • Germack R, Dickenson JM (2005) Adenosine triggers preconditioning through MEK/ERK1/2 signalling pathway during hypoxia/reoxygenation in neonatal rat cardiomyocytes. J Mol Cell Cardiol 39:429–442

    Article  CAS  PubMed  Google Scholar 

  • Gessi S, Varani K, Merighi S, Morelli A, Ferrari D, Leung E, Baraldi PG, Spalluto G, Borea PA (2001) Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat T cells. Br J Pharmacol 134:116–126

    Article  CAS  PubMed  Google Scholar 

  • Gessi S, Varani K, Merighi S, Cattabriga E, Iannotta V, Leung E, Baraldi PG, Borea PA (2002) A3 adenosine receptors in human neutrophils and promyelocytic HL60 cells: a pharmacological and biochemical study. Mol Pharmacol 61:415–424

    Article  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 (2004a) Elevated expression of A3 adenosine receptors in human colorectal cancer is reflected in peripheral blood cells. Clin Cancer Res 10:5895–5901

    Article  CAS  PubMed  Google Scholar 

  • Gessi S, Varani K, Merighi S, Cattabriga E, Avitabile A, Gavioli R, Fortini C, Klotz KN, Leung E, MacLennan S, Borea PA (2004b) Expression of A3 adenosine receptors in human lymphocytes: up-regulation in T cell activation. Mol Pharmacol 65:711–719

    Article  CAS  PubMed  Google Scholar 

  • Gessi S, Merighi S, Varani K, Cattabriga E, Benini A, Mirandola P, Leung E, Mac Lennan S, Feo C, Baraldi S, Borea PA (2007) Adenosine receptors in colon carcinoma tissues and colon tumoral cell lines: focus on the A3 adenosine subtype. J Cell Physiol 211:826–836

    Article  CAS  PubMed  Google Scholar 

  • Guo Y, Bolli R, Bao W, Wu WJ, Black RG, Murphree SS, Salvatore CA, Jacobson MA, Auchampach JA (2001) Targeted deletion of the A3 adenosine receptor confers resistance to myocardial ischemic injury and does not prevent early preconditioning. J Mol Cell Cardiol 33:825–830

    Article  CAS  PubMed  Google Scholar 

  • Guzman J, Yu JG, Suntres Z, Bozarov A, Cooke H, Javed N, Auer H, Palatini J, Hassanain HH, Cardounel AJ, Javed A, Grants I, Wunderlich JE, Christofi FL (2006) ADOA3R as a therapeutic target in experimental colitis: proof by validated high-density oligonucleotide microarray analysis. Inflamm Bowel Dis 12:766–789

    Article  PubMed  Google Scholar 

  • Hammarberg C, Schulte G, Fredholm BB (2003) Evidence for functional adenosine A3 receptors in microglia cells. J Neurochem 86:1051–1054

    Article  CAS  PubMed  Google Scholar 

  • Hammarberg C, Fredholm BB, Schulte G (2004) Adenosine A3 receptor-mediated regulation of p38 and extracellular-regulated kinase ERK1/2 via phosphatidylinositol-3′-kinase. Biochem Pharmacol 67:129–134

    Article  CAS  PubMed  Google Scholar 

  • Hansen RA, Gartlehner G, Powell GE, Sandler RS (2007) Serious adverse events with infliximab: analysis of spontaneously reported adverse events. Clin Gastroenterol Hepatol 5:729–735

    Article  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-reperfused mouse heart. Cardiovasc Res 53:147–155

    Article  CAS  PubMed  Google Scholar 

  • Haskó G, Szabó C, Németh ZH, Kvetan V, Pastores SM, Vizi ES (1996) Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. J Immunol 157:4634–4640

    PubMed  Google Scholar 

  • Haskó G, Nemeth ZH, Vizi ES, Salzman AL, Szabo C (1998) An agonist of adenosine A3 receptors decreases interleukin-12 and interferon-gamma production and prevents lethality in endotoxemic mice. Eur J Pharmacol 358:261–268

    Article  PubMed  Google Scholar 

  • Haskó G, Pacher P, Vizi ES, Illes P (2005) Adenosine receptor signalling in the brain immune system. Trends Pharmacol Sci 26:511–516

    Article  PubMed  CAS  Google Scholar 

  • Headrick JP, Peart J (2005) A3 adenosine receptor-mediated protection of the ischemic heart. Vasc Pharmacol 42:271–279

    Article  CAS  Google Scholar 

  • Hentschel S, Lewerenz A, Nieber K (2003) Activation of A3 receptors by endogenous adenosine inhibits synaptic transmission during hypoxia in rat cortical neurons. Restor Neurol Neurosci 21:55–63

    CAS  PubMed  Google Scholar 

  • Hofer S, Ivarsson L, Stoitzner P, Auffinger M, Rainer C, Romani N, Heufler C (2003) Adenosine slows migration of dendritic cells but does not affect other aspects of dendritic cell maturation. J Invest Dermatol 121:300–307

    Article  CAS  PubMed  Google Scholar 

  • Inoue Y, Chen Y, Hirsh MI, Yip L, Junger WG (2008) A3 and P2Y2 receptors control the recruitment of neutrophils to the lungs in a mouse model of sepsis. Shock 30:173–177

    Article  PubMed  Google Scholar 

  • Ishida T, Yarimizu K, Gute DC, Korthuis RJ (1997) Mechanisms of ischemic preconditioning. Shock 8:86–94

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Gao Z-G (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Nikodijevic O, Shi D, Gallo-Rodriguez C, Olah ME, Stiles GL, Daly JW (1993) A role for central A3-adenosine receptors: mediation of behavioural depressant effects. FEBS Lett 336:57–60

    Article  CAS  PubMed  Google Scholar 

  • Jenner TL, Rose’meyer RB (2006) Adenosine A3 receptor mediated coronary vasodilation in the rat heart: changes that occur with maturation. Mech Ageing Dev 127:264–273

    Article  CAS  PubMed  Google Scholar 

  • Ji X-D, von Lubitz D, Olah ME, Stiles GL, Jacobson KA (1994) Species differences in ligand affinity at central A3-adenosine receptors. Drug Dev Res 33:51–59

    Article  CAS  Google Scholar 

  • Jordan JE, Thourani VH, Auchampach JA, Robinson JA, Wang N-P, Vinten-Johansen J (1999) A3 adenosine receptor activation attenuates neutrophil function and neutrophil-mediated reperfusion injury. Am J Physiol 277:H1895–H1905

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Kohno Y, Sei Y, Koshiba M, Kim HO, Jacobson KA (1996b) Induction of apoptosis in HL-60 human promyelocytic leukemia cells by adenosine A3 receptor agonists. Biochem Biophys Res Comm 219:904–910

    Article  CAS  PubMed  Google Scholar 

  • Laghi Pasini F, Capecchi PL, Di Perri T (1997) Adenosine plasma levels after low dose methotrexate administration. J Rheumatol 24:2492–2493

    CAS  PubMed  Google Scholar 

  • la Sala A, Gadina M, Kelsall BL (2005) G(i)-protein-dependent inhibition of IL-12 production is mediated by activation of the phosphatidylinositol 3-kinase–protein 3 kinase B/Akt pathway and JNK. J Immunol 175:2994–2999

    PubMed  Google Scholar 

  • Laudadio MA, Psarropoulou C (2004) The A3 adenosine receptor agonist 2-CL-IB-MECA facilitates epileptiform discharges in the CA3 area of immature rat hippocampal slices. Epilepsy Res 59:83–94

    Article  CAS  PubMed  Google Scholar 

  • Lee HT, Emala CW (2000) Protective effects of renal ischemic preconditioning and adenosine pre-treatment: role of A1 and A3 receptors. Am J Physiol Renal Physiol 278:F380–F387

    CAS  PubMed  Google Scholar 

  • Lee JE, Bokoch G, Liang B (2001) A novel cardioprotective role of RhoA: new signaling mechanism for adenosine. FASEB J 15:1886–1894

    Article  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 Renal Physiol 284:F267–F273

    CAS  PubMed  Google Scholar 

  • Lee HT, Kim M, Joo JD, Gallos G, Chen JF, Emala CW (2006a) A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis. Am J Physiol Regul Integr Comp Physiol 291:R959–R969

    CAS  PubMed  Google Scholar 

  • Lee JY, Jhun BS, Oh YT, Lee JH, Choe W, Baik HH, Ha J, Yoon K-S, Kim SS, Kang I (2006b) Activation of adenosine A3 receptor suppresses lipopolysaccaride-induced TNF-α production through inhibition of PI-3-kinase/Akt and NF-kB activation in murine BV2 microglial cells. Neurosci Lett 396:1–6

    Article  CAS  PubMed  Google Scholar 

  • Levy O, Coughlin M, Cronstein BN, Roy RM, Desai A, Wessels MR (2006) The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J Immunol 177:1956–1966

    CAS  PubMed  Google Scholar 

  • Lewerenz A, Hentschel S, Vissiennon Z, Michael S, Nieber K (2003) A3 receptors in cortical neurons: pharmacological aspects and neuroprotection during hypoxia. Drug Dev Res 58:420–427

    Article  CAS  Google Scholar 

  • Linden J (1994) Cloned adenosine A3 receptors: pharmacological properties, species differences and receptor functions. Trends Pharmacol Sci 15:298–306

    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 44:524–532

    CAS  PubMed  Google Scholar 

  • Liu GS, Richards SC, Olsson RA, Mullane K, Walsh RS, Downey JM (1994) Evidence that the adenosine A3 receptor may mediate the protection afforded by preconditioning in the isolated rabbit heart. Cardiovasc Res 28:1057–1061

    Article  CAS  PubMed  Google Scholar 

  • Lopes LV, Rebola N, Costenla AR, Halldner L, Jacobson MA, Oliveira CR, Richardson PJ, Fredholm BB, Ribeiro JA, Cunha RA (2003) Adenosine A3 receptors in the rat hippocampus: lack of interaction with A1 receptors. Drug Dev Res 58:428–438

    Article  CAS  Google Scholar 

  • Mabley J, Soriano F, Pacher P, Haskó G, Marton A, Wallace R, Salzman A, Szabo C (2003) The adenosine A3 receptor agonist, N 6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide, is protective in two murine models of colitis. Eur J Pharmacol 466:323–329

    Article  CAS  PubMed  Google Scholar 

  • Maddock HL, Mocanu MM, Yellon DM (2002) Adenosine A3 receptor activation protects the myocardium from reperfusion/reoxygenation injury. Am J Physiol Heart Circ Physiol 283:H1307–H1313

    CAS  PubMed  Google Scholar 

  • Maddock HL, Gardner NM, Khandoudi N, Bril A, Broadley KJ (2003) Protection from myocardial stunning by ischaemia and hypoxia with the adenosine A3 receptor agonist, IB-MECA. Eur J Pharmacol 477:235–245

    Article  CAS  PubMed  Google Scholar 

  • Mader R, Keystone E (2007) Optimizing treatment with biologics. J Rheumatol 80:16–24

    CAS  Google Scholar 

  • Madi L, Bar-Yehuda S, Barer F, Ardon E, Ochaion A, Fishman P (2003) A3 adenosine receptor activation in melanoma cells: association between receptor fate and tumor growth inhibition. J Biol Chem 278:42121–42130

    Article  CAS  PubMed  Google Scholar 

  • Madi L, Ochaion A, Rath-Wolfson L, Bar-Yehuda S, Erlanfer A, Ohana G, Harish A, Merimski O, Barer F, Fishman P (2004) The A3 adenosine receptor is highly expressed in tumor versus normal cells: potential target for tumor growth inhibition. Clin Cancer Res 10:4472–4479

    Article  CAS  PubMed  Google Scholar 

  • Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar MA, Browne KF, Eisenberg PR, Bolli R, Casas AC, Molina-Viamonte V, Orlandi C, Blevins R, Gibbons RJ, Califf RM, Granger CB (1999) Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction Study of ADenosine (AMISTAD) trial. J Am Coll Cardiol 34(6):1711–1720

    Article  CAS  PubMed  Google Scholar 

  • Martin L, Pingle SC, Hallam DM, Rybak LP, Ramkumar V (2006) Activation of the adenosine A3 receptor in RAW 264.7 cells inhibits lipopolysaccharide-stimulated tumor necrosis factor-α release by reducing calcium-dependent activation of nuclear factor-kB and extracellular signal-regulated kinase 1/2. J Pharmacol Exp Ther 316:71–78

    Article  CAS  PubMed  Google Scholar 

  • Matot I, Weiniger CF, Zeira E, Galun E, Joshi BV, Jacobson KA (2006) A3 adenosine receptors and mitogen-activated protein kinases in lung injury following in vivo reperfusion. Crit Care 10:R65

    Article  PubMed  Google Scholar 

  • McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, Hill RA, Jones A, Mujica Mota R, Walley T (2007) Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation. Health Technol Assess 11:1–158

    CAS  Google Scholar 

  • McWhinney CD, Dudley MW, Bowlin TL, Peet NP, Schook L, Bradshaw M, De M, Borcheerding DR, Edwards CK (1996) Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-α. Eur J Pharmacol 310:209–216

    Article  CAS  PubMed  Google Scholar 

  • Merighi S, Varani K, Gessi S, Cattabriga E, Iannotta V, Ulouglu C, Leung E, Borea PA (2001) Pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375. Br J Pharmacol 134:1215–1226

    Article  CAS  PubMed  Google Scholar 

  • Merighi S, Mirandola P, Varani K, Gessi S, Leung E, Baraldi PG, Tabrizi MA, Borea PA (2003) A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol Ther 100:31–48

    Article  CAS  PubMed  Google Scholar 

  • Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Borea PA (2005a) A3 adenosine receptor activation inhibits cell proliferation via phosphatidylinositol 3-kinase/Akt-dependent inhibition of the extracellular signal-regulated kinase 1/2 phosphorylation in A375 human melanoma cells. J Biol Chem 280:19516–19526

    Article  CAS  PubMed  Google Scholar 

  • Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, MacLennan S, Baraldi PG, Borea PA (2005b) A3 adenosine receptors modulate hypoxia-inducible factor-1alpha expression in human A375 melanoma cells. Neoplasia 10:894–903

    Article  CAS  Google Scholar 

  • Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Borea PA (2006) Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells. Biochem Pharmacol 72:19–31

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    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 rat spermiogenesis. FEBS Lett 284:155–160

    Article  CAS  PubMed  Google Scholar 

  • Mitchell CH, Peterson-Yantorno K, Carre DA, McGlinn AM, Coca-Prados M, Stone RA, Civan MM (1999) A3 adenosine receptors regulate Cl − channels of nonpigmented ciliary epithelial cell. Am J Physiol 276:C659–C666

    CAS  PubMed  Google Scholar 

  • Montesinos MC, Desai A, Delano D, Chen JF, Fink JS, Jacobson MA, Cronstein BN (2003) Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68. Arthritis Rheum 48:240–247

    Article  CAS  PubMed  Google Scholar 

  • Mozzicato S, Joshi BV, Jacobson A, Liang BT (2004) Role of direct RhoA-phospholipase D1 interaction in mediating adenosine-induced protection from cardiac ischemia. FASEB J 18:406–408

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    CAS  PubMed  Google Scholar 

  • Ochaion A, Bar-Yehuda S, Cohn S, Del Valle L, Perez-Liz G, Madi L, Barer F, Farbstein M, Fishman-Furman S, Reitblat T, Reitblat A, Amital H, Levi Y, Molad Y, Mader R, Tishler M, Langevitz P, Zabutti A, Fishman P (2006) Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A3 adenosine receptor expression. Arthritis Res Ther 8:R169

    Article  PubMed  CAS  Google Scholar 

  • Ochaion A, Bar-Yehuda S, Cohen S, Amital H, Jacobson KA, Joshi BV, Gao ZG, Barer F, Patoka R, Del Valle L, Perez-Liz G, Fishman P (2008) The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF-κB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats. Biochem Pharmacol 76:482–494.

    Article  CAS  PubMed  Google Scholar 

  • Okamura T, Kurogi Y, Hashimoto K, Nishikawa H, Nagao Y (2004) Facile synthesis of fused 1,2,4-triazolo[1,5-c]pyrimidine derivatives as human adenosine A3 receptor ligands. Bioorg Med Chem Lett 14:3775–3779

    Article  CAS  PubMed  Google Scholar 

  • Olah ME, Gallo-Rodriguez C, Jacobson KA, Stiles GL (1994) [125I]AB-MECA, a high affinity radioligand for the rat A3 adenosine receptor. Mol Pharmacol 45:978–982

    CAS  PubMed  Google Scholar 

  • Palmer TM, Stiles GL (2000) Identification of threonine residues controlling the agonist-dependent phosphorylation and desensitization of the rat A3 adenosine receptor. Mol Pharmacol 57:539–545

    CAS  PubMed  Google Scholar 

  • Palmer TM, Benovic JL, Stiles GL (1995a) Agonist-dependent phosphorylation and desensitization of the rat A3 adenosine receptor. J Biol Chem 270:29607–29613

    Article  CAS  PubMed  Google Scholar 

  • Palmer TM, Gettys TW, Stiles GL (1995b) Differential interaction with and regulation of multiple G-proteins by the rat A3 adenosine receptor. J Biol Chem 270:16895–16902

    Article  CAS  PubMed  Google Scholar 

  • Palmer TM, Benovic JL, Stiles GL (1996) Molecular basis for subtype-specific desensitization of inhibitory adenosine receptors. Analysis of a chimeric A1 − A3 adenosine receptor. J Biol Chem 271:15272–15278

    Article  CAS  PubMed  Google Scholar 

  • Palmer TM, Harris CA, Coote J, Stiles GL (1997) Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor. Mol Pharmacol 52:632–640

    CAS  PubMed  Google Scholar 

  • Panther E, Idzko M, Herouy Y, Rheinen H, Geboicke-Haerter PJ, Mrowietz U, Dichmann S, Norgauer J (2001) Expression and function of adenosine receptors in human dendritic cells. FASEB J 15:1963–1970

    Article  CAS  PubMed  Google Scholar 

  • Park S-S, Zhao H, Jang Y, Mueller RA, Xu Z (2006) N 6-(3-Iodobenzyl)-adenosine-5′-N-methylcarboxamide confers cardioprotection at reperfusion by inhibiting mitochondrial permeability transition pore opening via glycogen synthase kinase 3β. J Pharm Exp Ther 318:124–131

    Article  CAS  Google Scholar 

  • Parsons M, Young L, Lee JE, Jacobson KA, Liang BT (2000) Distinct cardioprotective effects of adenosine mediated by differential coupling of receptor subtypes to phospholipases C and D. FASEB J 14:1423–1431

    Article  CAS  PubMed  Google Scholar 

  • Peart JN, Headrick JP (2007) Adenosinergic cardioprotection: multiple receptors, multiple pathways. Pharmacol Ther 114:208–221

    Article  CAS  PubMed  Google Scholar 

  • Philipp S, Yang XM, Cui L, Davis AM, Downey JM, Cohen MV (2006) Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2B receptor cascade. Cardiovasc Res 70:308–314

    Article  CAS  PubMed  Google Scholar 

  • Press NJ, Taylor RJ, Fullerton JD, Tranter P, McCarthy C, Keller TH, Brown L, Cheung R, Christie J, Haberthuer S, Hatto JD, Keenan M, Mercer MK, Press NE, Sahri H, Tuffnell AR, Tweed M, Fozard JR (2005) A new orally bioavailable dual adenosine A2B/A3 receptor antagonist with therapeutic potential. Bioorg Med Chem Lett 15:3081–3085

    Article  CAS  PubMed  Google Scholar 

  • Press NJ, Gessi S, Borea PA, Polosa R (2007) Therapeutic potential of adenosine receptor antagonists and agonists. Expert Opin Ther Patents 17:979–991

    Article  CAS  Google Scholar 

  • Pugliese AM, Latini S, Corradetti R, Pedata F (2003) Brief, repeated, oxygen-glucose deprivation episodes protect neurotransmission from a longer ischemic episode in the in vitro hippocampus: role of adenosine receptors. Br J Pharmacol 140(2):305–314

    Article  CAS  PubMed  Google Scholar 

  • Pugliese AM, Coppi E, Spalluto G, Corradetti R, Pedata F (2006) A3 adenosine receptor antagonists delay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitro. Br J Pharmacol 147(5):524–532

    Article  CAS  PubMed  Google Scholar 

  • Pugliese AM, Coppi E, Volpini R, Cristalli G, Corradetti R, Jeong LS, Jacobson KA, Pedata F (2007) Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen-glucose deprivation episodes of different duration. Biochem Pharmacol 74:768–779

    Article  CAS  PubMed  Google Scholar 

  • Ramkumar RV, Stiles GL, Beaven MA, Ali H (1993) The A3 adenosine receptor is the unique adenosine receptor which facilitates release of allergic mediators in mast cells. J Biol Chem 268:16887–16890

    CAS  PubMed  Google Scholar 

  • Rath-Wolfson L, Bar-Yehuda S, Madi L, Ochaion A, Cohen S, Zabutti A, Fishman P (2006) IB-MECA, an A3 adenosine receptor agonist prevents bone resorption in rats with adjuvant induced arthritis. Clin Exp Rheumatol 24:400–406

    CAS  PubMed  Google Scholar 

  • Reshkin SJ, Guerra L, Bagorda A, Debellis L, Cardone R, Li AH, Jacobson KA, Casavola V (2000) Activation of A3 adenosine receptor induces calcium entry and chloride secretion in A6 cells. J Membr Biol 178:103–113

    Article  CAS  PubMed  Google Scholar 

  • Rigopoulos D, Korfitis C, Gregoriou S, Katsambas AD (2008) Infliximab in dermatological treatment: beyond psoriasis. Expert Opin Biol Ther 8:123–133

    Article  CAS  PubMed  Google Scholar 

  • Rimmer J, Peake HL, Santos CMC, Lean M, Bardin P, Robson R, Haumann B, Loehrer F, Handel, ML (2007) Targeting adenosine receptors in the treatment of allergic rhinitis: a randomized, double-blind, placebo-controlled study. Clin Exp Allergy 37:8–14

    Article  CAS  PubMed  Google Scholar 

  • Rivkees SA (1994) Localization and characterization of adenosine receptor expression in rat testis. Endocrinology 135:2307–2313

    Article  CAS  PubMed  Google Scholar 

  • Rivo J, Zeira E, Galun E, Matot I (2004a) Activation of A3 adenosine receptor provides lung protection against ischemia-reperfusion injury associated with reduction in apoptosis. Am J Transplant 4:1941–1948

    Article  CAS  PubMed  Google Scholar 

  • Rivo J, Zeira E, Galun E, Matot I (2004b) Activation of A3 adenosine receptors attenuates lung injury after in vivo reperfusion. Anesthesiology 101:1153–1159

    Article  CAS  PubMed  Google Scholar 

  • Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW, AMISTAD-II Investigators (2005) A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol 45(11):1775–1780

    Article  CAS  PubMed  Google Scholar 

  • Ryzhov S, Goldstein AE, Matafonov A, Zeng D, Biaggioni I, Feoktistov I (2004) Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B-mediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma. J Immunol 172:7726–7733

    CAS  PubMed  Google Scholar 

  • Sajjadi FG, Firestein GS (1993) cDNA cloning and sequence analysis of the human A3 adenosine receptor. Biochim Biophys Acta 1179:105–107

    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 Natl Acad Sci USA 90:10365–10369

    Article  CAS  PubMed  Google Scholar 

  • Salvatore CA, Tilley SL, Latour AM, Fletcher DS, Koller BH, Jacobson MA (2000) Disruption of the A3 adenosine receptor gene in mice and its effect on stimulated inflammatory cells. J Biol Chem 275:4429–4434

    Article  CAS  PubMed  Google Scholar 

  • Schlotzer-Schrehardt U, Zenkel M, Decking U, Haubs D, Kruse FE, Junemann A, Coca-Prados M, Naumann GO (2005) Selective upregulation of the A3 adenosine receptor in eyes with pseudoexfoliation syndrome and glaucoma. Invest Ophthalmol Vis Sci 46:2023–2034

    Article  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 58:477–482

    CAS  PubMed  Google Scholar 

  • Schulte G, Fredholm BB (2002) Signaling pathway from the human adenosine A3 receptor expressed in Chinese hamster ovary cells to the extracellular signal-regulated kinase 1/2. Mol Pharmacol 62:1137–1146

    Article  CAS  PubMed  Google Scholar 

  • Sei Y, Von Lubitz DKJE, Abbracchio MP, Ji X-D, Jacobson A (1997) Adenosine A3 receptor agonist-induced neurotoxicity in rat cerebellar granule neurons. Drug Dev Res 40:267–273

    Article  CAS  Google Scholar 

  • Shen H, Chen GJ, Harvey BK, Bickford PC, Wang Y (2005) Inosine reduces ischemic brain injury in rats. Stroke 36:654–659

    Article  CAS  PubMed  Google Scholar 

  • Shepherd RK, Linden J, Duling BR (1996) Adenosine-induced vasoconstriction in vivo. Role of the mast cell and A3 adenosine receptor. Circ Res 78:627–634

    CAS  PubMed  Google Scholar 

  • Shneyvays V, Nawrath H, Jacobson KA, Shainberg A (1998) Induction of apoptosis in cardiac myocytes by an A3 adenosine receptor agonist. Exp Cell Res 243:383–397

    Article  CAS  PubMed  Google Scholar 

  • Shneyvays V, Jacobson KA, Li AH, Nawrath H, Zinman T, Isaac A, Shainberg A (2000) Induction of apoptosis in rat cardiocytes by A3 adenosine receptor activation and its suppression by isoproterenol. Exp Cell Res 257:111–126

    Article  CAS  PubMed  Google Scholar 

  • Shneyvays V, Mamedova LK, Zinman T, Jacobson KA, Shainberg A (2001) Activation of A3 adenosine receptor protects against doxorubicin-induced cardiotoxicity. J Mol Cell Cardiol 33:1249–1261

    Article  CAS  PubMed  Google Scholar 

  • Shneyvays V, Zinman T, Shainberg A (2004) Analysis of calcium responses mediated by the A3 adenosine receptor in cultured newborn rat cardiac myocytes. Cell Calcium 36:387–396

    Article  CAS  PubMed  Google Scholar 

  • Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P (2008) Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a Phase II clinical trial. J Rheumatol 35:41–48

    CAS  PubMed  Google Scholar 

  • Solenkova NV, Solodushko V, Cohen MV, Downey JM (2006) Endogenous adenosine protects preconditioned heart during early minutes of reperfusion by activating Akt. Am J Physiol Heart Circ Physiol 290:H441–H449

    Article  CAS  PubMed  Google Scholar 

  • Spruntulis LM, Broadley KJ (2001) A3 receptors mediate rapid inflammatory cell influx into the lungs of sensitized guinea-pigs. Clin Exp Allergy 31:943–951

    Article  CAS  PubMed  Google Scholar 

  • Suh BC, Kim TD, Lee JU, Seong JK, Kim KT (2001) Pharmacological characterization of adenosine receptors in PGT-beta mouse pineal gland tumour cells. Br J Pharmacol 134:132–142

    Article  CAS  PubMed  Google Scholar 

  • Suleiman M-S, Halestrap AP, Griffiths EJ (2001) Mitochondria: a target for myocardial protection. Pharmacol Ther 89:29–46

    Article  CAS  PubMed  Google Scholar 

  • Szabo C, Scott GS, Virag L, Egnaczyk G, Salzman AL, Shanley TP, Haskó G (1998) Suppression of macrophage inflammatory protein (MIP)-1a production and collagen-induced arthritis by adenosine receptor agonists. Br J Pharmacol 125:379–387

    Article  CAS  PubMed  Google Scholar 

  • Takano H, Bolli R, Black RG, Modani E, Tang X-L, Yang Z, Bhattacharya S, Auchampach JA (2001) A1 or A3 adenosine receptors induce late preconditioning against infarction in conscious rabbits by different mechanisms. Circ Res 88:520–528

    CAS  PubMed  Google Scholar 

  • Thiele A, Kronstein R, Wetzel A, Gerth A, Nieber K, Hauschildt S (2004) Regulation of adenosine receptor subtypes during cultivation of human monocytes: role of receptors in preventing lipopolysaccharide-triggered respiratory burst. Infect Immun 72:1349–1357

    Article  CAS  PubMed  Google Scholar 

  • Thourani VH, Nakamura M, Ronson RS, Jordan JE, Zhao Z-Q, Levy JH, Szlam F, Guyton R, Vinten-Johansen J (1999) Adenosine A3 receptor stimulation attenuates postischemic dysfunction through KATP channels. Am J Physiol 46:H228–H235

    Google Scholar 

  • Tilg H, Moschen A, Kaser A (2007) Mode of function of biological anti-TNF agents in the treatment of inflammatory bowel diseases. Expert Opin Biol Ther 7:1051–1059

    Article  CAS  PubMed  Google Scholar 

  • Toussirot E, Wendling D (2007) The use of TNF-alpha blocking agents in rheumatoid arthritis: an update. Expert Opin Pharmacother 8:2089–2107

    Article  CAS  PubMed  Google Scholar 

  • Tracey WR, Magee W, Masamune H, Kennedy SP, Knight DR, Bucholz RA, Hill RJ (1997) Selective adenosine A3 receptor stimulation reduces ischemic myocardial injury in the rabbit heart. Cardiovasc Res 33:410–415

    Article  CAS  PubMed  Google Scholar 

  • Tracey WR, Magee W, Masamune H, Oleynek JJ, Hill RJ (1998) Selective activation of adenosine A3 receptors with N 6-(3-chlorobenzyl)-5′-N-methylcarboxamidoadenosine (Cl-IBMECA) provides cardioprotection via KATP channel activation. Cardiovasc Res 40:138–145

    Article  CAS  PubMed  Google Scholar 

  • Trincavelli ML, Tuscano D, Cecchetti P, Falleni A, Benzi L, Klotz KN, Gremigni V, Cattabeni F, Lucacchini A, Martini C (2000) Agonist-induced internalization and recycling of the human A(3) adenosine receptors: role in receptor desensitization and resensitization. J Neurochem 75:1493–1501

    Article  CAS  PubMed  Google Scholar 

  • Trincavelli ML, Tuscano D, Marroni M, Falleni A, Gremigni V, Ceruti S, Abbracchio MP, Jacobson KA, Cattabeni F, Martini C (2002a) A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation. Mol Pharmacol 62:1373–1384

    Article  CAS  PubMed  Google Scholar 

  • Trincavelli ML, Tuscano D, Marroni M, Klotz K-N, Lucacchini A, Martini C (2002b) Involvement of mitogen protein kinase cascade in agonist-mediated human A3 adenosine receptor regulation. Biochim Biophys Acta 1591:55–62

    Article  CAS  PubMed  Google Scholar 

  • Valesini G, Iannuccelli C, Marocchi E, Pascoli L, Scalzi V, Di Franco M (2007) Biological and clinical effects of anti-TNFalpha treatment. Autoimmune Rev 7:35–41

    Article  CAS  Google Scholar 

  • van Troostenburg AR, Clark EV, Carey WD, Warrington SJ, Kerns WD, Cohn I, Silverman MH, Bar-Yehuda S, Fong KL, Fishman P (2004) Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men. Int J Clin Pharmacol Ther 42:534–542

    PubMed  Google Scholar 

  • von Lubitz DKJE (1999) Adenosine and cerebral ischemia: therapeutic future or death of a brave concept? Eur J Pharmacol 371:85–102

    Article  Google Scholar 

  • von Lubitz DKJE, Lin RC-S, Popik P, Carter MF, Jacobson KA (1994) Adenosine A3 receptor stimulation and cerebral ischemia. Eur J Pharmacol 263:59–67

    Article  Google Scholar 

  • Walker BAM, Jacobson MA, Knight DA, Salvatore CA, Weir T, Zhou D, Bai TR (1997) Adenosine A3 receptor expression and function in eosinophils. Am J Respir Cell Mol Biol 16:531–537

    CAS  PubMed  Google Scholar 

  • Wan TC, Ge ZD, Tampo A, Mio Y, Bienengraeber MW, Tracey WR, Gross GJ, Kwok WM, Auchampach JA (2008) The A3 adenosine receptor agonist CP-532,903 [N 6-(2,5-dichlorobenzyl)-3′-aminoadenosine-5′-N-methylcarboxamide] protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP-sensitive potassium channel. J Pharmacol Exp Ther 324:234–243

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Drake L, Sajjadi F, Firestein GS, Mullane KM, Bullough DA (1997) Dual activation of adenosine A1 and A3 receptors mediates preconditioning of isolated cardiac myocytes. Eur J Pharmacol 320:241–248

    Article  CAS  PubMed  Google Scholar 

  • Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, Trentham DE (1985) Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 312:818–822

    CAS  PubMed  Google Scholar 

  • Weiss JN, Korge P, Honda HM, ping P (2003) Role of the mitochondrial permeability transition in myocardial disease. Circ Res 93:292–301

    Article  CAS  PubMed  Google Scholar 

  • Wittendorp MC, Boddeke HWGM, Biber K (2004) Adenosine A3 receptor-induced CCl2 synthesis in cultured mouse astrocytes. Glia 46:410–418

    Article  PubMed  Google Scholar 

  • Wolber C, Fozard JR (2005) The receptor mechanism mediating the contractile response to adenosine on lung parenchymal strips from actively sensitised, allergen-challenged Brown Norway rats. Naunyn–Schmiedeberg’s Arch Pharmacol 371:158–168

    Article  CAS  Google Scholar 

  • Xu Z, Jang Y, Mueller RA, Norfleet EA (2006) IB-MECA and cardioprotection. Cardiovasc Drug Rev 24:227–238

    Article  CAS  PubMed  Google Scholar 

  • Yamano K, Mori K, Nakano R, Kusunoki M, Inoue M, Satoh M (2007) Identification of the functional expression of adenosine A3 receptor in pancreas using transgenic mice expressing jellyfish apoaequorin. Transgenic Res16:429–435

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Avila MY, Peterson-Yantorno K, Coca-Prados M, Stone RA, Jacobson KA, Civan MM (2005) The cross-species A3 adenosine-receptor antagonist MRS 1292 inhibits adenosine-triggered human nonpigmented ciliary epithelial cell fluid release and reduces mouse intraocular pressure. Curr Eye Res 30:747–754

    Article  CAS  PubMed  Google Scholar 

  • Young HWJ, Molina JG, Dimina D, Zhong H, Jacobson M, Chan L-NL, Chan T-S, Lee JJ, Blackburn MR (2004) A3 adenosine receptor signalling contributes to airway inflammation and mucus production in adenosine deaminase-deficient mice. J Immunol 173:1380–1389

    CAS  PubMed  Google Scholar 

  • Zhang X, Zhang M, Laties AM, Mitchell CH (2006) Balance of purines may determine life or death of retinal ganglion cells as A3 adenosine receptors prevent loss following P2X7 receptor stimulation. J Neurochem 98:566–575

    Article  CAS  PubMed  Google Scholar 

  • Zhao TC, Kukreja RC (2002) Late preconditioning elicited by activation of adenosine A3 receptor in heart: role of NF-kB, iNOS and mitochondrial KATP channel. J Mol Cell Cardiol 34:263–277

    Article  CAS  PubMed  Google Scholar 

  • Zheng J, Wang R, Zambraski E, Wu D, Jacobson KA, Liang BT (2007) Protective roles of adenosine A1, A2A, and A3 receptors in skeletal muscle ischemia and reperfusion injury. Am J Physiol Heart Circ Physiol 293:H3685–H3691

    Article  CAS  PubMed  Google Scholar 

  • Zhong H, Shlykov SG, Molina JG, Sanborn BM, Jacobson MA, Tilley S L, Blackburn MR (2003) Activation of murine lung mast cells by the adenosine A3 receptor. J Immunol 170:338–345

    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 USA 89:7432–7436

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, Chair of Pharmacology, Faculty of Medicine, University of Ferrara, Pharmacology Unit Via Fossato di Mortara 17–19, 44100, Ferrara, Italy

    P.A. Borea

  2. Department of Clinical and Experimental Medicine, University of Ferrara, Pharmacology Unit Via Fossato di Mortara 17–19, 44100, Ferrara, Italy

    S. Gessi

  3. Can-Fite BioPharma, 10 Bareket St., Kiryat Matalon, Petach Tikva, 49170, Israel

    S. Bar-Yehuda

  4. Can-Fite BioPharma, 10 Bareket St., Kiryat Matalon, Petach Tikva, 49170, Israel

    P. Fishman

Authors
  1. P.A. Borea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Gessi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Bar-Yehuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Fishman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P.A. Borea .

Editor information

Editors and Affiliations

  1. Endacea, Inc.,, Davis Drive 2, Research Triangle Park, 27709-2076, U.S.A.

    Constance N. Wilson

  2. Health Sciences Center, West Virginia University, Health Sciences S. 2267, Morgantown, 26506-9104, U.S.A.

    S. Jamal Mustafa

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Borea, P., Gessi, S., Bar-Yehuda, S., Fishman, P. (2009). A3 Adenosine Receptor: Pharmacology and Role in Disease. In: Wilson, C., Mustafa, S. (eds) Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-89615-9_10

Download citation

Publish with us

Policies and ethics

Search

Navigation