Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways
Open Access
- 1 October 2009
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 122 (19), 3554-3565
- https://doi.org/10.1242/jcs.056473
Abstract
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.Keywords
This publication has 40 references indexed in Scilit:
- PDZ Protein Interactions Underlying NMDA Receptor-Mediated Excitotoxicity and Neuroprotection by PSD-95 InhibitorsJournal of Neuroscience, 2007
- Developmental and activity‐dependent regulation of ARMS/Kidins220 in cultured rat hippocampal neuronsDevelopmental Neurobiology, 2007
- Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95Molecular Psychiatry, 2007
- Identification of a Switch in Neurotrophin Signaling by Selective Tyrosine PhosphorylationOnline Journal of Public Health Informatics, 2006
- Transcription of the NR1 Subunit of the N-Methyl-d-aspartate Receptor Is Down-regulated by Excitotoxic Stimulation and Cerebral IschemiaOnline Journal of Public Health Informatics, 2005
- Cleavage of the Plasma Membrane Na+/Ca2+ Exchanger in ExcitotoxicityCell, 2005
- Lipid Raft Disruption Triggers Protein Kinase C and Src-dependent Protein Kinase D Activation and Kidins220 Phosphorylation in Neuronal CellsOnline Journal of Public Health Informatics, 2004
- A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning proteinThe EMBO Journal, 2004
- EphB Receptors Interact with NMDA Receptors and Regulate Excitatory Synapse FormationCell, 2000
- Glutamate neurotoxicity and diseases of the nervous systemNeuron, 1988