Selected peptides targeted to the NMDA receptor channel protect neurons from excitotoxic death.
Excitotoxic neuronal death, associated with neurodegeneration and stroke, is triggered primarily by massive Ca2+ influx arising from overactivation of glutamate receptor channels of the N-methyl-D-aspartate (NMDA) subtype. To search for channel blockers, synthetic combinatorial libraries were assayed for block of agonist-evoked currents by the human NR1-NR2A NMDA receptor subunits expressed in amphibian oocytes. A set of arginine-rich hexapeptides selectively blocked the NMDA receptor channel with IC50 approximately 100 nM, a potency similar to clinically tolerated blockers such as memantine, and only marginally blocked on non-NMDA glutamate receptors. These peptides prevent neuronal cell death elicited by an excitotoxic insult on hippocampal cultures.
Ferrer-Montiel
A V
AV
Department of Biology, University of California, San Diego, La Jolla 92093-0366, USA.
Merino
J M
JM
Blondelle
S E
SE
Perez-Payà
E
E
Houghten
R A
RA
Montal
M
M
D000818:Animals; D001120:Arginine; D001667:Binding, Competitive; D016923:Cell Death / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D009474:Neurons / Q000187:drug effects*; D009865:Oocytes / Q000502:physiology; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D014981:Xenopus
D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D001120:Arginine