Effect of N-methyl-D-aspartate (NMDA) receptor antagonists on alpha-synuclein-evoked neuronal nitric oxide synthase activation in the rat brain.
alpha-Synuclein (ASN), a small presynaptic protein that is abundant in the brain, is implicated in the pathogenesis of neurodegenerative disorders including Parkinson's and Alzheimer's disease. The central domain of alpha-synuclein, the non-amyloid beta component of the Alzheimer's disease amyloid (NAC) is probably responsible for its toxicity. However, the molecular mechanism of alpha-synuclein action remains largely elusive. The present study examined the effect of alpha-synuclein and the NAC peptide on nitric oxide synthase (NOS) activity in rat brain cortical and hippocampal slices using a radiochemical technique. Moreover, nitrite levels in brain slices incubated in the presence of alpha-synuclein were measured using the Griess reaction. ASN and the NAC stimulated NOS activity by about 70% and 40%, respectively. beta-Synuclein, a homologous protein of ASN that lacks the NAC domain, had no effect on NOS activity. Under the same experimental conditions, alpha-synuclein increased nitrite levels by 27%. alpha-Synuclein and the NAC affected the activity of constitutive neuronal isoform of NOS, but had no impact on the endothelial or inducible NOS isoforms. The effect of alpha-synuclein and the NAC peptide on NOS activity was inhibited by MK-801 and APV, antagonists of the NMDA receptor. These results indicate that the NMDA receptor plays an important role in alpha-synuclein-evoked nitric oxide synthesis. We suggest that nitric oxide liberated by the over-activated neuronal isoform of NOS could react with superoxide to form peroxynitrite, which modulates the function of a variety of biomolecules including proteins, lipids, and DNA.
Adamczyk
Agata
A
Department of Cellular Signaling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, PL 02-106 Warszawa, Poland. agataz@cmdik.pan.pl
Czapski
Grzegorz A
GA
Kaźmierczak
Anna
A
Strosznajder
Joanna B
JB
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*; D051846:beta-Synuclein / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D009573:Nitrites; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D051844:alpha-Synuclein; D051846:beta-Synuclein; D009569:Nitric Oxide; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D052248:Nitric Oxide Synthase Type I