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Title

Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways

AuthorsLópez-Menéndez, Celia ; Gascón, Sergio ; Sobrado, Mónica ; Vidaurre, Oscar G.; Higuero, Alonso M. ; Rodríguez-Peña, Ángeles ; Iglesias, Teresa ; Díaz-Guerra, Margarita
KeywordsKidins220/arms (arms)
Nmdar
Excitotoxicity
Ischemia
Neurotrophins
Trk receptors
Eph receptors
Calpain
Erk
Neuronal death
Survival
Issue Date1-Oct-2009
PublisherCompany of Biologists
CitationJournal of Cell Science 122(19): 3554-3565 (2009)
AbstractFunctional and protein interactions between the N-methyl-D-aspartate type of glutamate receptor (NMDAR) and neurotrophin or ephrin receptors play essential roles in neuronal survival and differentiation. A shared downstream effector for neurotrophin- and ephrin-receptor signaling is kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS). Because this molecule is obligatory for neurotrophin-induced differentiation, we investigated whether Kidins220/ARMS and NMDAR functions were related. Here, we identify an association between these proteins and discover that excitotoxicity, a specific form of neuronal death induced by NMDAR overstimulation, dramatically decreases Kidins220/ARMS levels in cortical neurons and in a model of cerebral ischemia. Kidins220/ARMS downregulation is triggered by overactivation of NMDARs containing NR2B subunits and subsequent Ca2+ influx, and involves a dual mechanism: rapid cleavage by the Ca2+-dependent protease calpain and calpain-independent silencing of Kidins220/Arms gene transcription. Additionally, Kidins220/ARMS knockdown decreases ERK activation and basal neuronal viability, and enhances neuronal death under excitotoxic conditions. Our results demonstrate Kidins220/ARMS participation in neuronal life and death pathways, and constitute the first report of its regulation under pathological conditions.
Description12 pages, 7 figures.
Publisher version (URL)http://dx.doi.org/10.1242/jcs.056473
URIhttp://hdl.handle.net/10261/24881
DOI10.1242/jcs.056473
ISSN0021-9533
Appears in Collections:(IIBM) Artículos
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