Characterization of the signalling pathways involved in ATP and basic fibroblast growth factor-induced astrogliosis

Chiara Bolego, Stefania Ceruti, Roberta Brambilla, Lina Puglisi, Flaminio Cattabeni, Geoffrey Burnstock, Maria P. Abbracchio

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

1. A brief challenge of rat astrocytes with either α,β-methyleneATP (α,β-meATP) or basic fibroblast growth factor (bFGF) resulted, three days later, in morphological differentiation of cells, as shown by marked elongation of astrocytic processes. The P2 receptor antagonist suramin prevented α,β-meATP- but not bFGF-induced astrocytic elongation. Similar effects on astrocytic elongation were also observed with ATP and other P2 receptor agonists (β,γmeATP, ADPβS, 2meSATP and, to a lesser extent, UTP). 2. Pertussis toxin completely abolished α,β-meATP- but not bFGF-induced effects. No effects were exerted by α,β-meATP on cyclic AMP production: similarly, neomycin had no effects on elongation of processes induced by the purine analogue, suggesting that adenylyl cyclase and phospholipase C are probably not involved in α,β-meATP-induced effects. The tyrosine-kinase inhibitor genistein greatly reduced bFGF- but not α,β-meATP-induced astrocytic elongation. 3. Challenge of cultures with α,β-meATP rapidly and concentration-dependently increased [3H]-arachidonic acid (AA) release from cells, suggesting that activation of phospholipase A2 (PLA2) may be involved in the long-term functional effects evoked by purine analogues. Consistently, exogenously added AA markedly elongated astrocytic processes. Moreover, various PLA2 inhibitors (e.g. mepacrine and dexamethasone) prevented both the early α,β-meATP-induced [3H]-AA release and/or the associated long-term morphological changes, without affecting the astrocytic elongation induced by bFGF. Finally, the protein kinase C (PKC) inhibitor H7 fully abolished α,β-meATP- but not bFGF-induced effects. 4. Both α,β-meATP and bFGF rapidly and transiently induced the nuclear accumulation of Fos and Jun. Both c-fos and c-jun induction by the purine analogue could be fully prevented by pretreatment with suramin. In contrast, the effects of bFGF were unaffected by this P2 receptor antagonist. 5. It was concluded that α,β-meATP- and bFGF-morphological differentiation of astrocytes occurs via independent transductional pathways. For the purine analogue, signalling involves a G(i)/G(o) protein-coupled P2Y-receptor which may be linked to activation of PLA2 (involvement of an arachidonate-sensitive PKC is speculated); for bFGF, a tyrosine kinase receptor is involved. Both pathways merge on some common intracellular target, as suggested by induction of primary response genes, which in turn may regulate late response genes mediating long-term phenotypic changes of astroglial cells. 6. These findings implicate P2 receptors as novel targets for the pharmacological regulation of reactive astrogliosis, which has intriguing implications in nervous system diseases characterized by degenerative events.

Original languageEnglish
Pages (from-to)1692-1699
Number of pages8
JournalBritish Journal of Pharmacology
Volume121
Issue number8
DOIs
StatePublished - Aug 27 1997
Externally publishedYes

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Fibroblast Growth Factor 2
Adenosine Triphosphate
Arachidonic Acid
Suramin
Phospholipases A2
Astrocytes
Protein Kinase C
Phospholipase A2 Inhibitors
Gi-Go GTP-Binding Protein alpha Subunits
Quinacrine
Uridine Triphosphate
Neomycin
Protein C Inhibitor
Genistein
Pertussis Toxin
Receptor Protein-Tyrosine Kinases
Type C Phospholipases
Protein Kinase Inhibitors
Adenylyl Cyclases
Neurodegenerative Diseases

Keywords

  • Astrocytic differentiation
  • Basic fibroblast growth factor (bFGF) receptors
  • P2 receptors
  • Primary response genes
  • Rat brain astrocytes: glial fibrillary acidic protein (GFAP)

ASJC Scopus subject areas

  • Pharmacology

Cite this

Characterization of the signalling pathways involved in ATP and basic fibroblast growth factor-induced astrogliosis. / Bolego, Chiara; Ceruti, Stefania; Brambilla, Roberta; Puglisi, Lina; Cattabeni, Flaminio; Burnstock, Geoffrey; Abbracchio, Maria P.

In: British Journal of Pharmacology, Vol. 121, No. 8, 27.08.1997, p. 1692-1699.

Research output: Contribution to journalArticle

Bolego, Chiara ; Ceruti, Stefania ; Brambilla, Roberta ; Puglisi, Lina ; Cattabeni, Flaminio ; Burnstock, Geoffrey ; Abbracchio, Maria P. / Characterization of the signalling pathways involved in ATP and basic fibroblast growth factor-induced astrogliosis. In: British Journal of Pharmacology. 1997 ; Vol. 121, No. 8. pp. 1692-1699.
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T1 - Characterization of the signalling pathways involved in ATP and basic fibroblast growth factor-induced astrogliosis

AU - Bolego, Chiara

AU - Ceruti, Stefania

AU - Brambilla, Roberta

AU - Puglisi, Lina

AU - Cattabeni, Flaminio

AU - Burnstock, Geoffrey

AU - Abbracchio, Maria P.

PY - 1997/8/27

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N2 - 1. A brief challenge of rat astrocytes with either α,β-methyleneATP (α,β-meATP) or basic fibroblast growth factor (bFGF) resulted, three days later, in morphological differentiation of cells, as shown by marked elongation of astrocytic processes. The P2 receptor antagonist suramin prevented α,β-meATP- but not bFGF-induced astrocytic elongation. Similar effects on astrocytic elongation were also observed with ATP and other P2 receptor agonists (β,γmeATP, ADPβS, 2meSATP and, to a lesser extent, UTP). 2. Pertussis toxin completely abolished α,β-meATP- but not bFGF-induced effects. No effects were exerted by α,β-meATP on cyclic AMP production: similarly, neomycin had no effects on elongation of processes induced by the purine analogue, suggesting that adenylyl cyclase and phospholipase C are probably not involved in α,β-meATP-induced effects. The tyrosine-kinase inhibitor genistein greatly reduced bFGF- but not α,β-meATP-induced astrocytic elongation. 3. Challenge of cultures with α,β-meATP rapidly and concentration-dependently increased [3H]-arachidonic acid (AA) release from cells, suggesting that activation of phospholipase A2 (PLA2) may be involved in the long-term functional effects evoked by purine analogues. Consistently, exogenously added AA markedly elongated astrocytic processes. Moreover, various PLA2 inhibitors (e.g. mepacrine and dexamethasone) prevented both the early α,β-meATP-induced [3H]-AA release and/or the associated long-term morphological changes, without affecting the astrocytic elongation induced by bFGF. Finally, the protein kinase C (PKC) inhibitor H7 fully abolished α,β-meATP- but not bFGF-induced effects. 4. Both α,β-meATP and bFGF rapidly and transiently induced the nuclear accumulation of Fos and Jun. Both c-fos and c-jun induction by the purine analogue could be fully prevented by pretreatment with suramin. In contrast, the effects of bFGF were unaffected by this P2 receptor antagonist. 5. It was concluded that α,β-meATP- and bFGF-morphological differentiation of astrocytes occurs via independent transductional pathways. For the purine analogue, signalling involves a G(i)/G(o) protein-coupled P2Y-receptor which may be linked to activation of PLA2 (involvement of an arachidonate-sensitive PKC is speculated); for bFGF, a tyrosine kinase receptor is involved. Both pathways merge on some common intracellular target, as suggested by induction of primary response genes, which in turn may regulate late response genes mediating long-term phenotypic changes of astroglial cells. 6. These findings implicate P2 receptors as novel targets for the pharmacological regulation of reactive astrogliosis, which has intriguing implications in nervous system diseases characterized by degenerative events.

AB - 1. A brief challenge of rat astrocytes with either α,β-methyleneATP (α,β-meATP) or basic fibroblast growth factor (bFGF) resulted, three days later, in morphological differentiation of cells, as shown by marked elongation of astrocytic processes. The P2 receptor antagonist suramin prevented α,β-meATP- but not bFGF-induced astrocytic elongation. Similar effects on astrocytic elongation were also observed with ATP and other P2 receptor agonists (β,γmeATP, ADPβS, 2meSATP and, to a lesser extent, UTP). 2. Pertussis toxin completely abolished α,β-meATP- but not bFGF-induced effects. No effects were exerted by α,β-meATP on cyclic AMP production: similarly, neomycin had no effects on elongation of processes induced by the purine analogue, suggesting that adenylyl cyclase and phospholipase C are probably not involved in α,β-meATP-induced effects. The tyrosine-kinase inhibitor genistein greatly reduced bFGF- but not α,β-meATP-induced astrocytic elongation. 3. Challenge of cultures with α,β-meATP rapidly and concentration-dependently increased [3H]-arachidonic acid (AA) release from cells, suggesting that activation of phospholipase A2 (PLA2) may be involved in the long-term functional effects evoked by purine analogues. Consistently, exogenously added AA markedly elongated astrocytic processes. Moreover, various PLA2 inhibitors (e.g. mepacrine and dexamethasone) prevented both the early α,β-meATP-induced [3H]-AA release and/or the associated long-term morphological changes, without affecting the astrocytic elongation induced by bFGF. Finally, the protein kinase C (PKC) inhibitor H7 fully abolished α,β-meATP- but not bFGF-induced effects. 4. Both α,β-meATP and bFGF rapidly and transiently induced the nuclear accumulation of Fos and Jun. Both c-fos and c-jun induction by the purine analogue could be fully prevented by pretreatment with suramin. In contrast, the effects of bFGF were unaffected by this P2 receptor antagonist. 5. It was concluded that α,β-meATP- and bFGF-morphological differentiation of astrocytes occurs via independent transductional pathways. For the purine analogue, signalling involves a G(i)/G(o) protein-coupled P2Y-receptor which may be linked to activation of PLA2 (involvement of an arachidonate-sensitive PKC is speculated); for bFGF, a tyrosine kinase receptor is involved. Both pathways merge on some common intracellular target, as suggested by induction of primary response genes, which in turn may regulate late response genes mediating long-term phenotypic changes of astroglial cells. 6. These findings implicate P2 receptors as novel targets for the pharmacological regulation of reactive astrogliosis, which has intriguing implications in nervous system diseases characterized by degenerative events.

KW - Astrocytic differentiation

KW - Basic fibroblast growth factor (bFGF) receptors

KW - P2 receptors

KW - Primary response genes

KW - Rat brain astrocytes: glial fibrillary acidic protein (GFAP)

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