Role of mitogen‐activated protein kinase cascades in P2Y receptor‐mediated trophic activation of astroglial cells

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Abstract
The trophic actions of extracellular nucleotides and nucleosides on astroglial cells in the central nervous system may be important in development as well as injury and repair. Here we summarize recent findings on the signal transduction mechanisms and gene expression that mediate the trophic effects of extracellular ATP on astrocyte cultures, with a particular emphasis on mitogenesis. Activation of ATP/P2Y receptors leads to the stimulation of mitogen‐activated protein kinase (MAPK) cascades, which play a crucial role in cellular proliferation, differentiation, and survival. Inhibition of ERK and p38, members of two distinct MAPK cascades, interferes with the ability of extracellular ATP to stimulate astrocyte proliferation, thereby indicating their importance in mitogenic signaling by P2Y receptors. Signaling from P2Y receptors to ERK involves phospholipase D and a calcium‐independent protein kinase C isoform, PKC; this pathway is independent of the phosphatidylinositol‐phospholipase C / calcium pathway which is also coupled to P2Y receptors. Pharmacological studies suggest that astrocytes may express an as‐yet uncloned P2Y receptor that recruits a novel MEK activator in the ERK cascade. Extracellular ATP can also potentiate fibroblast growth factor (FGF)‐2‐induced proliferation, and studies on interactions between ATP and FGF‐2 signaling pathways have revealed that although ATP does not activate cRaf‐1, the first protein kinase in the ERK cascade, it can reduce cRaf‐1 activation by FGF‐2. As intermediate levels of Raf activity stimulate the cell cycle, the partial inhibition of FGF‐induced Raf activity by ATP may contribute to the enhancing effect of ATP on FGF‐2‐induced astrocyte proliferation. Activation of P2Y receptors also leads to nuclear signaling, and the use of DNA arrays has shown that treatment of astrocytes with extracellular ATP results in the up‐ and downregulation of a number of genes; studies to determine which of these genes are regulated by MAPKs are now in progress. Elucidation of the components of MAPK pathways linked to P2Y receptors and subsequent changes in gene expression may provide targets for a new avenue of drug development aimed at the management of astrogliosis which occurs in many types of neurological disorders and neurodegeneration. Drug Dev. Res. 53:158–165, 2001. Published 2001 Wiley‐Liss, Inc.

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