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PIKfyve promotes neuron self-preservation

With glutamate stimulation (right), CaV1.2 channels (red) are internalized and degraded by cortical neurons under PIKfyve's direction.

Tsuruta et al. find that a lipid kinase directs a voltage-gated calcium channel's degradation to save neurons from a lethal dose of overexcitement.

An important player in cellular signaling, calcium is also terribly toxic at high levels. Neurons have evolved ways to protect themselves against the calcium influxes that come during periods of intense electrical activity. One way to limit the calcium flood is to remove the gatekeepers, calcium channels, from the cell surface. How neurons direct this is clinically important in a range of disorders from stroke to Alzheimer's disease.

In a proteomic screen for binding partners of the Ca_V1.2 channel, Tsuruta et al. extracted what seemed a strange companion at first: PIKfyve, the lipid kinase that generates PtdIns(3,5)P₂ and promotes the maturation of endosomes into lysosomes. Other groups had recently shown that mutations affecting PtdIns(3,5)P₂ production cause degeneration of excitable cells in both mice and humans, including mutants found in ALS and Charcot-Marie-Tooth disease. The team hypothesized that PIKfyve might be directing Ca_V1.2 degradation. Using glutamate excitation to simulate excitotoxic stress, the authors showed that Ca_V1.2 is internalized, associates with PIKfyve, and is degraded in the lysosome. When Tsuruta et al. squelched levels of PIKfyve or PtdIns(3,5)P₂, excess channels stayed at the surface and left neurons vulnerable to apoptosis.

The findings clarify how this neuroprotective mechanism unfolds and suggest that existing calcium channel-blocking drugs might aid patients with neurodegenerative disorders stemming from a PtdIns(3,5)P₂ defect.

References

Tsuruta, F., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200903028.[Abstract/Free Full Text]

kendall2{at}nasw.org

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This Article Full Text (PDF, 481K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Powell, K. PubMed Articles by Powell, K. Social Bookmarking                            What's this?