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- Title
PIKfyve regulates Ca<sub>v</sub>1.2 degradation and prevents excitotoxic cell death.
- Authors
Tsuruta, Fuminori; Green, Eric M.; Rousset, Matthieu; Dolmetsch, Ricardo E.
- Abstract
Voltage-gated Ca[sup 2+] channels (VGCCs) play a key role in neuronal signaling but can also contribute to cellular dysfunction and death under pathological conditions such as stroke and neurodegenerative diseases. We report that activation of N-methyl-D-aspartic acid receptors causes internalization and degradation of Ca[sub v]1.2 channels, resulting in decreased Ca[sup 2+] entry and reduced toxicity. Ca[sub v]1.2 internalization and degradation requires binding to phosphatidylinositol 3-phosphate 5-kinase (PIKfyve), a lipid kinase which generates phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P[sub 2]) and regulates endosome and lysosome function. Sustained activation of glutamate receptors recruits PIKfyve to Ca[sub v]1.2 channels, increases cellular levels of PtdIns(3,5)P[sub 2], and promotes targeting of Ca[sub v]1.2 to lysosomes. Knockdown of PIKfyve prevents Ca[sub v]1.2 degradation and increases neuronal susceptibility to excitotoxicity. These experiments identify a novel mechanism by which neurons are protected from excitotoxicity and provide a possible explanation for neuronal death in diseases caused by mutations that affect PtdIns(3,5)P[sub 2] regulation.
- Publication
Journal of Cell Biology, 2009, Vol 187, Issue 2, p279
- ISSN
0021-9525
- Publication type
Academic Journal
- DOI
10.1083/jcb.200903028