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A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics pp 165–188Cite as

Adenosine A3 Receptor Signaling in the Central Nervous System

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Abstract

Adenosine A3 receptors are widely distributed in the central nervous system but are expressed at a low level and have lower affinity for adenosine in comparison to the A1 and A2A receptors. Nevertheless, they appear to tonically modulate motor activity as pointed out in A3 receptor-deleted mice.

The role of A3 receptor in several pathophysiological conditions is often controversial. In conditions such as seizures or ischemia, when extracellular concentrations of adenosine increase, A3 receptors may contribute to neurotransmission and cell damage. A pro-convulsant effect of A3 receptor is feasible, especially in the immature brain, thus raising the possibility that A3 receptor might facilitate seizure-induced neuronal damage and activity-dependent plastic changes. Most data support a pro-nociceptive role of A3 receptor involving both central nervous system and pro-inflammatory effects at peripheral tissues. The outcome of A3 receptor stimulation on synaptic transmission during hypoxic/ischemic phenomena appears to depend on the duration and intensity of the ischemic episode. While A3 receptor may play a protective role in the first phase of ischemia by decreasing synaptic transmission, prolonged A3AR stimulation by high adenosine concentrations could be pivotal in transforming the A3AR-mediated effects from protective to injurious. Detrimental effects of A3AR activation may be due, at least in part, to increased excitoxicity. Glial A3AR stimulated by high adenosine levels caused by a prolonged central trauma may well be implicated in neuroinflammatory tissue responses.

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Abbreviations

AK:

Adenosine-kinase

AD:

Anoxic depolarization

aCSF:

Artificial cerebrospinal fluid

APNEA:

N(6)-2-(4 Aminophenyl)ethyladenosine

AR:

Adenosine Receptor

AR132:

N6-methyl-2-Phenylethynyladenosine

CADO:

2-Chloroadenosine

CNS:

Central nervous system

CCL-2:

Chemokine (C-C motif) ligand 2

cAMP:

Cyclic AMP

CHA:

N6-cyclohexyladenosine

Cl-IB-MECA:

1-[2-Chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-p-yl]-1-deoxy-N-methyl-beta-D-ribofuranuronamide

EHNA:

Erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride

ERK1/2:

Extracellular signal-regulated kinases

NECA:

5-N-Ethylcarboxyamidoadenosine

D-PIA:

D(-)N(6)-(2-Phenylisopropyl)adenosine

DPCPX:

8-Cyclopentyl-1,3-dipropylxanthine

GABAA :

Gamma-aminobutyric acid A

GFAP:

Glial fibrillary acidic protein

KO:

Knockout

5-HT:

5-Hydroxytryptamine

IB-MECA:

1-Deoxy-1-[6-[[(3-iodophenyl)-methyl]amino]-9H-purin-9-yl]-N-methyl-beta-D-ribofuranuronamide

LJ1251:

(2R,3R,4S)-2-(2-chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol

L-PIA:

L(-)N(6)-(2-Phenylisopropyl)adenosine

LPS:

Lipopolysaccharide

LTD:

Long-term depression

LTP:

Long-term potentiation

Map-2:

Microtubule-associated protein 2

MCAo:

Middle cerebral artery occlusion

MAPK:

Mitogen activated protein kinase

MRS1191:

3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/−)-dihydropyridine-3,5-dicarboxylate

MRS1220:

9-Chloro-2-(2-furanyl)-5-((phenylacetyl)amino)-[1,2,4]triazolo[1,5-c]quinazoline

MRS1340:

1,4-Dihydro-2-methyl-6-phenyl-4-(phenylethynyl)-3,5-pyr idinedicarboxylic acid 3-ethyl-5-[(3-nitrophenyl)methyl] ester

MRS1523:

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

NMDA:

N-Methyl-D-aspartate

NBTI:

S-(4-Nitrobenzyl)-6-theoinosine

OGD:

Oxygen–glucose deprivation

PKC:

Protein kinase C

PKG:

cGMP-dependent protein kinase

PLC:

Phospholipase C

RT-PCR:

Reverse transcription–polymerase chain reaction

SERT:

Serotonin-selective reuptake transporter

TNF alpha:

Tumour necrosis factor alpha

VT72:

N6-Methoxy-2-phenylethynyl

VT158:

N6-Methoxy-2-phenylethynyl

VT160:

N6-Methoxy-2-(2-pyridinyl)-ethynyl

VT163:

N6-Methoxy-2-p-acetylphenylethynyl

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Acknowledgements

The laboratory work of the authors is supported by research grants from Fundação para a Ciência e Tecnologia (FCT), Gulbenkian Foundation, PRIN-MIUR Ministero dell’Istruzione, dell’Università e della Ricerca, Ente Cassa di Risparmio, Firenze, Italy and European Union (COST B30).

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Authors and Affiliations

  1. Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

    Felicita Pedata & Anna Maria Pugliese

  2. Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisboa, Portugal

    Ana M. Sebastião & Joaquim A. Ribeiro

  3. Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisboa, Portugal

    Ana M. Sebastião & Joaquim A. Ribeiro

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  1. Felicita Pedata
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  2. Anna Maria Pugliese
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  3. Ana M. Sebastião
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  4. Joaquim A. Ribeiro
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Correspondence to Felicita Pedata .

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

    Pier Andrea Borea

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Pedata, F., Pugliese, A.M., Sebastião, A.M., Ribeiro, J.A. (2010). Adenosine A3 Receptor Signaling in the Central Nervous System. 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_9

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