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Roles of P2 receptors in glial cells: focus on astrocytes

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Abstract

Central nervous system glial cells release and respond to nucleotides under both physiological and pathological conditions, suggesting that these molecules play key roles in both normal brain function and in repair after damage. In particular, ATP released from astrocytes activates P2 receptors on astrocytes and other brain cells, allowing a form of homotypic and heterotypic signalling, which also involves microglia, neurons and oligodendrocytes. Multiple P2X and P2Y receptors are expressed by both astrocytes and microglia; however, these receptors are differentially recruited by nucleotides, depending upon specific pathophysiological conditions, and also mediate the long-term trophic changes of these cells during inflammatory gliosis. In astrocytes, P2-receptor-induced gliosis occurs via activation of the extracellular-regulated kinases (ERK) and protein kinase B/Akt pathways and involves induction of inflammatory and anti-inflammatory genes, cyclins, adhesion and antiapoptotic molecules. While astrocytic P2Y1 and P2Y2,4 are primarily involved in short-term calcium-dependent signalling, multiple P2 receptor subtypes seem to cooperate to astrocytic long-term changes. Conversely, in microglia, exposure to inflammatory and immunological stimuli results in differential functional changes of distinct P2 receptors, suggesting highly specific roles in acquisition of the activated phenotype. We believe that nucleotide-induced activation of astrocytes and microglia may originally start as a defence mechanism to protect neurons from cytotoxic and ischaemic insults; dysregulation of this process in chronic inflammatory diseases eventually results in neuronal cell damage and loss. On this basis, full elucidation of the specific roles of P2 receptors in these cells may help exploit the beneficial neuroprotective features of activated glia while attenuating their harmful properties and thus provide the basis for novel neuroprotective strategies that specifically target the purinergic system.

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Abbreviations

α,βmeATP:

alpha-beta-methylene-ATP

AA:

arachidonic acid

bFGF:

basic fibroblast growth factor

βγmeATP:

beta-gamma-methylene-ATP

COX-2:

cyclooxygenase-2

ERK1/2:

extracellular-regulated kinases 1/2

GFAP:

glial fibrillary acidic protein

LPS:

lipopolysaccharide

2meSATP:

2-methylthio-ATP

OPs:

oligodendrocyte progenitors

PLA2 :

phospholipase A2

PLC:

phospholipase C

PLD:

phospholipase D

PPADS:

pyridoxalphosphate-6-azophenyl-2′4′disulphonic acid

TNP-ATP:

2′3′O-(2,4,6-trinitrophenyl)-ATP

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Acknowledgement

Part of the work described here has been supported by the Italian Ministry of Education (Project of National Research Interest PRIN-COFIN 2002 and 2004 and FIRB RBAUO19-ZEN to MPA). Authors are grateful to Prof. Joseph T. Neary, University of Miami, USA, for useful discussion.

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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milano, Italy

    Maria P. Abbracchio & Stefania Ceruti

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  1. Maria P. Abbracchio
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  2. Stefania Ceruti
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Correspondence to Maria P. Abbracchio.

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Abbracchio, M.P., Ceruti, S. Roles of P2 receptors in glial cells: focus on astrocytes. Purinergic Signalling 2, 595–604 (2006). https://doi.org/10.1007/s11302-006-9016-0

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