title: A Ca2+-dependent mechanism of neuronal survival mediated by the microtubule-associated protein p600.
abstract: In acute and chronic neurodegeneration, Ca(2+) mishandling and disruption of the cytoskeleton compromise neuronal integrity, yet abnormalities in the signaling roles of cytoskeletal proteins remain largely unexplored. We now report that the microtubule-associated protein p600 (also known as UBR4) promotes neuronal survival. Following depletion of p600, glutamate-induced Ca(2+) influx through NMDA receptors, but not AMPA receptors, initiates a degenerative process characterized by endoplasmic reticulum fragmentation and endoplasmic reticulum Ca(2+) release via inositol 1,4,5-trisphosphate receptors. Downstream of NMDA receptors, p600 associates with the calmodulin·calmodulin-dependent protein kinase IIα complex. A direct and atypical p600/calmodulin interaction is required for neuronal survival. Thus, p600 counteracts specific Ca(2+)-induced death pathways through regulation of Ca(2+) homeostasis and signaling.
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Camille
authors.initials: C
authors.lastname: Belzil
authors.forename: Gernot
authors.initials: G
authors.lastname: Neumayer
authors.forename: Alex P
authors.initials: AP
authors.lastname: Vassilev
authors.forename: Kyoko L
authors.initials: KL
authors.lastname: Yap
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Konishi
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
authors.forename: Kamon
authors.initials: K
authors.lastname: Sanada
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Ikura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Minh Dang
authors.initials: MD
authors.lastname: Nguyen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D002148:Calmodulin-Binding Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D002118:Calcium
keywords: Calcium; Calmodulin; Cell Biology; Cell Death; Microtubule-associated Protein; Microtubules; Neurodegeneration; UBR4; p600