Trophic actions of extracellular ATP: gene expression profiling by DNA array analysis

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Abstract

In addition to Professor Burnstock’s work on the short-term signaling actions of extracellular nucleotides and nucleosides, Geoff has had a long-standing interest in trophic actions of purines in development and in pathophysiological conditions which has been instrumental in encouraging my work in this area. The trophic actions of extracellular ATP, alone or in combination with polypeptide growth factors, may play an important role in brain development and may contribute to the reactive gliosis that accompanies brain injury and neurodegeneration. P2Y receptors in astrocytes are coupled to the ERK/MAPK cascade, a signal transduction mechanism crucial for cellular proliferation and differentiation. The mitogenic signaling pathway from P2Y receptors to ERK involves phospholipase D and a calcium-independent PKC isoform, PKCδ. DNA array analysis reveals a number of changes in gene expression after P2Y receptor occupancy, indicating that this methodology will be a powerful tool in understanding the mechanisms underlying the trophic actions of extracellular nucleotides and nucleosides.

Section snippets

Trophic actions of purines

In addition to Prof. Burnstock’s well known work in the short-term, neurotransmitter actions of extracellular nucleotides and nucleosides, he has also had an interest in the long-term, trophic actions of purines, including studies in the enteric nervous system and in astrocytes. In work which is of particular relevance to neural regeneration, transplantation of enteric ganglia into the CNS promoted sprouting of host neurons (Tew et al., 1994). Subsequent co-culture experiments indicated

Signal transduction mechanisms

Our group has been exploring the signaling mechanisms that underlie the trophic actions of extracellular nucleotides in rat cortical astrocytes. Extracellular signal regulated protein kinase (ERK) is a key member of a mitogen-activated protein kinase (MAPK) cascade that is crucial to cellular proliferation and differentiation. MAPK cascades are composed of at least three cytosolic protein kinases that are activated sequentially. These cascades relay information from the plasma membrane to the

Purinergic receptor activation and gene expression

As mentioned above, activated ERK can translocate to the nucleus where it can activate or induce transcription factors and complexes, leading to expression of genes crucial for cellular proliferation or differentiation. Stimulation of purinergic receptors in many cell types causes the induction of immediate early response genes such as c-fos, c-jun, junB, and c-myc (for review, see Neary and Abbracchio, 2000). In astrocytes, α, β-methylene ATP increased nuclear Fos and Jun immunostaining

Acknowledgements

The author is grateful to Yuan Kang for excellent assistance with the ERK and DNA array studies. This work is supported by the Department of Veterans Affairs.

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