Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways.
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 Ca(2+) influx, and involves a dual mechanism: rapid cleavage by the Ca(2+)-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.
López-Menéndez
Celia
C
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.
Gascón
Sergio
S
Sobrado
Mónica
M
Vidaurre
Oscar G
OG
Higuero
Alonso M
AM
Rodríguez-Peña
Angeles
A
Iglesias
Teresa
T
Díaz-Guerra
Margarita
M
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology*; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
C418610:Kidins220 protein, rat; D008565:Membrane Proteins; D010750:Phosphoproteins; D016194:Receptors, N-Methyl-D-Aspartate