The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation.
Excitotoxicity due to excessive activation of glutamate receptors is a primary mediator of cell death in acute and chronic neurological disorders, and NMDA-type glutamate receptors (NMDARs) are thought to be involved. NMDARs assemble from heteromeric combinations of GluN1, GluN2 and GluN3 subunits, yielding a variety of receptor subtypes that differ in biophysical properties, signaling, and synaptic targeting. Inclusion of inhibitory GluN3 subunits reduces Ca2+ influx via NMDAR channels and alters their synaptic targeting, thus modifying the two hallmarks of NMDARs that are critical for their roles on neuronal death and survival. Here we evaluated the neuroprotective potential of GluN3A subunits by analyzing the susceptibility to striatal excitotoxic damage of transgenic mice overexpressing GluN3A. We found that mild GluN3A overexpression protected susceptible striatal neurons from lesions induced by the neurotoxin 3-nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II/succinate dehydrogenase. GluN3A-mediated neuroprotection was dose-dependent, and correlated with the levels of transgenic GluN3A expressed by two different mice strains. Neuroprotection was associated with a potent reduction of the activation of calpain, a Ca2+-dependent protease, which was measured as a decrease in 3-NP-induced fodrin and STEP cleavage in GluN3A transgenic mice relative to controls. We further show that transgenic GluN3A subunits incorporate into extrasynaptic compartments in mouse striatum, suggesting that reductions of toxic calpain activation might be linked to inhibition by GluN3A of pathological extrasynaptic NMDAR activity.
Cellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain.
Rebeca
R
Martínez-Turrillas
Elena
E
Puerta
Dhrubajyoti
D
Chowdhury
Sonia
S
Marco
Masahiko
M
Watanabe
Norberto
N
Aguirre
Isabel
I
Pérez-Otaño
D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000378:metabolism*; D003292:Convulsants / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009574:Nitro Compounds / Q000633:toxicity; D011422:Propionates / Q000633:toxicity; D021122:Protein Subunits / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D003292:Convulsants; D009574:Nitro Compounds; D011422:Propionates; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D002154:Calpain; C015392:3-nitropropionic acid