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The Journal of Neuroscience, June 1, 1999, 19(11):4211-4220
Mitogenic Signaling by ATP/P2Y Purinergic Receptors in
Astrocytes: Involvement of a Calcium-Independent Protein Kinase C,
Extracellular Signal-Regulated Protein Kinase Pathway Distinct from the
Phosphatidylinositol-Specific Phospholipase C/Calcium Pathway
Joseph T.
Neary,
Yuan
Kang,
Yurong
Bu,
Esther
Yu,
Katherine
Akong, and
Christopher M.
Peters
Research Service, Veterans Affairs Medical Center, and Departments
of Pathology and Biochemistry and Molecular Biology, University of
Miami School of Medicine, Miami, Florida 33125
Activation of ATP/P2Y purinergic receptors stimulates proliferation
of astrocytes, but the mitogenic signaling pathway linked to these
G-protein-coupled receptors is unknown. We have investigated the role
of extracellular signal-regulated protein kinase (ERK) in P2Y
receptor-stimulated mitogenic signaling as well as the pathway that
couples P2Y receptors to ERK. Downregulation of protein kinase C (PKC)
in primary cultures of rat cerebral cortical astrocytes greatly reduced
the ability of extracellular ATP to stimulate ERK. Because occupancy of
P2Y receptors also leads to inositol phosphate formation, calcium
mobilization, and PKC activation, we explored the possibility that
signaling from P2Y receptors to ERK is mediated by a
phosphatidylinositol-specific phospholipase C (PI-PLC)/calcium pathway.
However, neither inhibition of PI-PLC nor chelation of calcium
significantly reduced ATP-stimulated ERK activity. Moreover, a
preferential inhibitor of calcium-dependent PKC isoforms, Gö
6976, was significantly less effective in blocking ATP-stimulated ERK
activity than GF102903X, an inhibitor of both calcium-dependent and
-independent PKC isoforms. Furthermore, ATP stimulated a rapid
translocation of PKC , a calcium-independent PKC isoform, but not
PKC , a calcium-dependent PKC isoform. ATP also stimulated a rapid
increase in choline, and inhibition of phosphatidylcholine hydrolysis
blocked ATP-evoked ERK activation. These results indicate that P2Y
receptors in astrocytes are coupled independently to PI-PLC/calcium and
ERK pathways and suggest that signaling from P2Y receptors to ERK
involves a calcium-independent PKC isoform and hydrolysis of
phosphatidylcholine by phospholipase D. In addition, we found that
inhibition of ERK activation blocked extracellular ATP-stimulated DNA
synthesis, thereby indicating that the ERK pathway mediates mitogenic
signaling by P2Y receptors.
Key words:
purinergic receptors; MAP kinase; protein kinase C; proliferation; phospholipases; astrocytes
Copyright © 1999 Society for Neuroscience 0270-6474/99/19114211-10$05.00/0
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