| Home > Articles > Published articles > N -Methyl--Aspartate Receptor Link to the MAP Kinase Pathway in Cortical and Hippocampal Neurons and Microglia Is Dependent on Calcium Sensors and Is Blocked by α-Synuclein, Tau, and Phospho-Tau in Non-transgenic and Transgenic APP Mice |
(Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular) (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular) (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular) (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular) (Universitat de Barcelona. Departament de Bioquímica i Biologia Molecular) (Tokyo Metropolitan Institute of Medical Science. Department of Dementia and Higher Brain Function) (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular) (Universitat Autònoma de Barcelona. Institut de Neurociències) (Universitat de Barcelona. Departament de Bioquímica i Biologia Molecular)
| Date: | 2018 |
| Abstract: | N -methyl--aspartate receptors (NMDARs) respond to glutamate to allow the influx of calcium ions and the signaling to the mitogen-activated protein kinase (MAPK) cascade. Both MAPK- and Ca 2+ -mediated events are important for both neurotransmission and neural cell function and fate. Using a heterologous expression system, we demonstrate that NMDAR may interact with the EF-hand calcium-binding proteins calmodulin, calneuron-1, and NCS1 but not with caldendrin. NMDARs were present in primary cultures of both neurons and microglia from cortex and hippocampus. Calmodulin in microglia, and calmodulin and NCS1 in neurons, are necessary for NMDA-induced MAP kinase pathway activation. Remarkably, signaling to the MAP kinase pathway was blunted in primary cultures of cortical and hippocampal neurons and microglia from wild-type animals by proteins involved in neurodegenerative diseases: α-synuclein, Tau, and p-Tau. A similar blockade by pathogenic proteins was found using samples from the APP transgenic Alzheimer's disease model. Interestingly, a very marked increase in NMDAR-NCS1 complexes was identified in neurons and a marked increase of both NMDAR-NCS1 and NMDAR-CaM complexes was identified in microglia from the transgenic mice. The results show that α-synuclein, Tau, and p-Tau disrupt the signaling of NMDAR to the MAPK pathway and that calcium sensors are important for NMDAR function both in neurons and microglia. Finally, it should be noted that the expression of receptor-calcium sensor complexes, specially those involving NCS1, is altered in neural cells from APP mouse embryos/pups. |
| Grants: | Ministerio de Sanidad y Consumo CB06/05/0042 Ministerio de Economía y Competitividad BFU2015-64405-R Ministerio de Economía y Competitividad BFU2015-67777-R Agencia Estatal de Investigación BFU2017-82047-R Agencia Estatal de Investigación SAF2016-80027-R Agencia Estatal de Investigación SAF2017-84117-R Agència de Gestió d'Ajuts Universitaris i de Recerca SGR/2017-648 |
| Note: | Altres ajuts: CiberNed's intramural program (Ref. No. PI2016/02); Fundació la Marató de TV3 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Alzheimer's disease ; Calmodulin ; Calneuron-1 ; Caldendrin ; NCS1 ; Extracellular signal-regulated kinase ; Glutamate receptor ; Proximity ligation assay |
| Published in: | Frontiers in molecular neuroscience, Vol. 11 (August 2018) , art. 273, ISSN 1662-5099 |
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