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The Journal of Neuroscience, November 15, 1999, 19(22):10014-10025
Platelet-Derived Growth Factor-Mediated Signal Transduction
Underlying Astrocyte Proliferation: Site of Ethanol Action
Jia
Luo1 and
Michael W.
Miller1, 2, 3
1 Department of Psychiatry, University of Iowa College of Medicine,
Iowa City, Iowa 52242-1000, 2 Research Service,
Veterans Affairs Medical Center, Iowa City, Iowa 52246-2208, and
3 Department of Pharmacology, University of Iowa
College of Medicine, Iowa City, Iowa 52242-1109
Platelet-derived growth factor (PDGF) is a critical regulator of
cell proliferation. Because ethanol inhibits cell proliferation in vivo and in vitro, we hypothesize that
ethanol-induced inhibition results from differential interference with
signal transduction pathways activated by PDGF. Cultured cortical
astrocytes were used to examine the effects of ethanol on PDGF-mediated
signal transduction, on the expression of two PDGF monomers (A- and
B-chains), and on the expression of two PDGF receptor subunits
(PDGF r and PDGF r). PDGF-B chain homodimer (PDGF-BB), and to a
lesser extent PDGF-A chain homodimer (PDGF-AA), stimulated the
proliferation of astrocytes raised in a serum-free medium. Ethanol
attenuated these actions in a concentration-dependent manner. Ethanol
inhibited both PDGF-AA- and PDGF-BB-mediated phosphorylation of
PDGFr, but it had little effect on PDGFr autophosphorylation.
Likewise, ethanol abolished the association of PDGFr to Ras
GTPase-activating protein (Ras-GAP), but it did not affect the binding
of Ras-GAP to PDGFr. PDGF stimulated the activities of
mitogen-activated protein kinase (MAPK) in protein kinase C (PKC)
independent and dependent manners. Ethanol inhibited the
PKC-independent, acute activation of MAPK; however, it stimulated the
PKC-dependent, sustained activation of MAPK. The expression of neither
ligand was altered by exposure to ethanol for 3 d. Moreover, such
treatment specifically upregulated PDGFr expression in a
concentration-dependent manner. It did not, however, affect the binding
affinity of either receptor. Thus, the signal transduction pathways
initiated by PDGF-AA and PDGF-BB were differentially affected by
ethanol. This differential vulnerability resulted from the preferential
effects of ethanol on PDGFr autophosphorylation. Hence,
ethanol-induced alterations are transduced through specific receptors
of mitogenic growth factors.
Key words:
alcohol; cell proliferation; cerebral cortex; fetal
alcohol syndrome; glia; MAP kinase; phosphorylation; protein kinase C; Scatchard analysis
Copyright © 1999 Society for Neuroscience 0270-6474/99/192210014-12$05.00/0
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