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First published online September 16, 2009
doi: 10.1242/10.1242/jcs.056473

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

Celia López-Menéndez^1,2, Sergio Gascón^1,*, Mónica Sobrado^1,, Oscar G. Vidaurre¹, Alonso M. Higuero^1,2,, Ángeles Rodríguez-Peña¹, Teresa Iglesias^1,2,¶,** and Margarita Díaz-Guerra^1,¶,**

¹ Instituto de Investigaciones Biomédicas de Madrid `Alberto Sols', Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), C/Arturo Duperier, 4, 28029 Madrid, Spain
² CIBERNED, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain

^** Authors for correspondence (tiglesias{at}iib.uam.es; mdiazguerra{at}iib.uam.es)

Accepted 27 July 2009

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.

Key words: Kidins220/ARMS (ARMS), NMDAR, Excitotoxicity, Ischemia, Neurotrophins, Trk receptors, Eph receptors, Calpain, ERK, Neuronal death, Survival

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