PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death.

Voltage-gated Ca(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(V)1.2 channels, resulting in decreased Ca(2+) entry and reduced toxicity. Ca(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(2)) and regulates endosome and lysosome function. Sustained activation of glutamate receptors recruits PIKfyve to Ca(V)1.2 channels, increases cellular levels of PtdIns(3,5)P(2), and promotes targeting of Ca(V)1.2 to lysosomes. Knockdown of PIKfyve prevents Ca(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(2) regulation.