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PIKfyve regulates Ca_V1.2 degradation and prevents excitotoxic cell death

Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305

Correspondence to Ricardo E. Dolmetsch: ricardo.dolmetsch{at}stanford.edu

Voltage-gated Ca²⁺ 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_V1.2 channels, resulting in decreased Ca²⁺ entry and reduced toxicity. Ca_V1.2 internalization and degradation requires binding to phosphatidylinositol 3-phosphate 5-kinase (PIKfyve), a lipid kinase which generates phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P₂) and regulates endosome and lysosome function. Sustained activation of glutamate receptors recruits PIKfyve to Ca_V1.2 channels, increases cellular levels of PtdIns(3,5)P₂, and promotes targeting of Ca_V1.2 to lysosomes. Knockdown of PIKfyve prevents Ca_V1.2 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)P₂ regulation.

Abbreviations used in this paper: ANOVA, analysis of variance; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LAMP, lysosomal-associated membrane protein; LTC, L-type VGCC; NMDA, N-methyl-D-aspartic acid; PIKfyve, phosphatidylinositol 3-phosphate 5-kinase; PtdIns(3,5)P₂, phosphatidylinositol (3,5)-bisphosphate; ROI, region of interest; shRNA, short hairpin RNA; VGCC, voltage-gated Ca²⁺ channel.

© 2009 Tsuruta et al.
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This article has been cited by other articles:

• Powell, K. (2009). PIKfyve promotes neuron self-preservation. JCB 187: 150-150 [Full Text]  

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