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,...
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| Format: | Article |
| Language: | English |
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Elsevier
2012-12-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996112002422 |
| _version_ | 1818651618915123200 |
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| author | Rebeca Martínez-Turrillas Elena Puerta Dhrubajyoti Chowdhury Sonia Marco Masahiko Watanabe Norberto Aguirre Isabel Pérez-Otaño |
| author_facet | Rebeca Martínez-Turrillas Elena Puerta Dhrubajyoti Chowdhury Sonia Marco Masahiko Watanabe Norberto Aguirre Isabel Pérez-Otaño |
| author_sort | Rebeca Martínez-Turrillas |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T02:08:59Z |
| format | Article |
| id | doaj.art-aa133f005b8642b99499ef7c25ae255e |
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| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T02:08:59Z |
| publishDate | 2012-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-aa133f005b8642b99499ef7c25ae255e2022-12-21T22:07:37ZengElsevierNeurobiology of Disease1095-953X2012-12-01483290298The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activationRebeca Martínez-Turrillas0Elena Puerta1Dhrubajyoti Chowdhury2Sonia Marco3Masahiko Watanabe4Norberto Aguirre5Isabel Pérez-Otaño6Cellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA), Pamplona, SpainDepartment of Pharmacology, University of Navarra, Pamplona, SpainCellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA), Pamplona, SpainCellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA), Pamplona, SpainDepartment of Anatomy, Hokkaido University School of Medicine, Sapporo, JapanDepartment of Pharmacology, University of Navarra, Pamplona, SpainCellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain; Department of Pharmacology, University of Navarra, Pamplona, Spain; Corresponding author at: Avda Pio XII, 55, 31008 Pamplona, Spain. Fax: +34 948194715.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.http://www.sciencedirect.com/science/article/pii/S0969996112002422GluN3ANeuroprotectionCalpainExtrasynaptic NMDA receptors3-nitropropionic acidHuntington’s disease |
| spellingShingle | Rebeca Martínez-Turrillas Elena Puerta Dhrubajyoti Chowdhury Sonia Marco Masahiko Watanabe Norberto Aguirre Isabel Pérez-Otaño The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation Neurobiology of Disease GluN3A Neuroprotection Calpain Extrasynaptic NMDA receptors 3-nitropropionic acid Huntington’s disease |
| title | The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation |
| title_full | The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation |
| title_fullStr | The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation |
| title_full_unstemmed | The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation |
| title_short | The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation |
| title_sort | nmda receptor subunit glun3a protects against 3 nitroproprionic induced striatal lesions via inhibition of calpain activation |
| topic | GluN3A Neuroprotection Calpain Extrasynaptic NMDA receptors 3-nitropropionic acid Huntington’s disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996112002422 |
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