Quinolinic acid modulates the activity of src family kinases in rat striatum: in vivo and in vitro studies.
Quinolinic acid (QA) has been shown to evoke neurotoxic events via NMDA receptor (NMDAR) overactivation and oxidative stress. NMDARs are particularly vulnerable to free radicals, which can modulate protein tyrosine kinase (PTK) and phosphotyrosine phosphatase (PTP) activities. The src family of tyrosine kinases are associated with the NMDAR complex and regulate NMDA channel function. Because QA is an NMDAR agonist as well as a pro-oxidant agent, we investigated whether it may affect the activity of PTKs and PTPs in vivo and in vitro. In synaptosomes prepared from striata dissected 15 min, 30 min or 15 days after bilateral injection of QA we observed modulation of the phosphotyrosine pattern; a significant decrease in PTP activity; and a sustained increase in c-src and lyn activity at 15 and 30 min after treatment with QA, followed by a decrease 2 weeks later. Striatal synaptosomes treated in vitro with QA showed time- and dose-dependent modulation of c-src and lyn kinase activities. Moreover, the nitric oxide synthase inhibitor NG-nitro-L-arginine-methyl ester, the NMDAR antagonist d-2-amino-5-phosphonovaleric acid and pyruvate suppressed the QA-induced modulation of c-src activity. These findings suggest a novel feature of QA in regulating src kinase activity through the formation of reactive radical species and/or NMDAR overactivation.
Metere
Alessio
A
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanita, Rome, Italy.
Mallozzi
Cinzia
C
Minetti
Maurizio
M
Domenici
Maria Rosaria
MR
Pèzzola
Antonella
A
Popoli
Patrizia
P
Di Stasi
A M Michela
AM
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000201:enzymology*; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism / Q000494:pharmacology; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes; D013997:Time Factors; D019061:src-Family Kinases / Q000187:drug effects* / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D005609:Free Radicals; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D019289:Pyruvic Acid; D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases; D017378:Quinolinic Acid