期刊
JOURNAL OF CELL SCIENCE
卷 122, 期 19, 页码 3554-3565出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.056473
关键词
Kidins220/ARMS (ARMS); NMDAR; Excitotoxicity; Ischemia; Neurotrophins; Trk receptors; Eph receptors; Calpain; ERK; Neuronal death; Survival
类别
资金
- Ministerio de Ciencia e Innovacion [BFU2007-67695, SAF2008-01951]
- Fundacion Mutua Madrilena
- Comunidad de Madrid [CAM S-SAL-0202-2006-01]
- Instituto de Salud Carlos III [CIBERNED]
- Formacion de Personal Investigador (FPI)
- Formacion de Profesorado Universitario (FPU)
Functional 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.
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