Lysophosphatidic acid-induced proliferation-related signals in astrocytes.
Lysophosphatidic acid (LPA) is a potent lipid biomediator that is likely to have diverse roles in the brain. Thus, LPA-induced events in astrocytes were defined. As little as 1 nM LPA induced a rapid increase in the concentration of intracellular free calcium ([Ca2+]i) in astrocytes from neonatal rat brains. This increase was followed by a slow return to the basal level. Intracellular calcium stores were important for the initial rise in [Ca2+]i, whereas the influx of extracellular calcium contributed significantly to the extended elevation of [Ca2+]i. LPA treatment also resulted in increases in lipid peroxidation and DNA synthesis. These increases in [Ca2+]i, lipid peroxidation, and DNA synthesis were inhibited by pretreatment of cells with pertussis toxin or H7, a serine/threonine protein kinase inhibitor. Moreover, the LPA-induced increase in [Ca2+]i was inhibited by a protein kinase C inhibitor, Ro 31-8220, and a calcium-dependent protein kinase C inhibitor, Gö 6976. The increase in [Ca2+]i was important for the LPA-induced increase in lipid peroxidation, whereas the antioxidant, propyl gallate, inhibited the LPA-stimulated increases in lipid peroxidation and DNA synthesis. In contrast, pertussis toxin, H7, and propyl gallate had no effect on LPA-induced inhibition of glutamate uptake. Thus, LPA appears to signal via at least two distinctive mechanisms in astrocytes. One is a novel pathway, namely, activation of a pertussis toxin-sensitive G protein and participation of a protein kinase, leading to sequential increases in [Ca2+]i, lipid peroxidation, and DNA synthesis.
Keller
J N
JN
Molecular and Cell Biology Group, T. H. Morgan School of Biological Sciences, University of Kentucky, Lexington 40506, U.S.A.
Steiner
M R
MR
Holtsberg
F W
FW
Mattson
M P
MP
Steiner
S M
SM
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D037342:Pertussis Toxin; D010712:Phosphatidic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D010712:Phosphatidic Acids; D017392:Thiobarbituric Acid Reactive Substances; D010566:Virulence Factors, Bordetella; C026223:lysophosphatidylglycerol; D016222:Fibroblast Growth Factor 2; D018698:Glutamic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D004247:DNA; D037342:Pertussis Toxin; D002118:Calcium