Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102191/1/embj2012200.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102191/2/embj2012200-sup-0001.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102191/3/embj2012200-reviewer_comments.pd

Ferguson, Cole J.

McCartney, Amber J.

Meisler, Miriam H.

Sutton, Michael A.

Weisman, Lois S.

Zhang, Yanling

Zolov, Sergey N.

The EMBO Journal

English

PubMed

Yanling Zhang

Amber J McCartney

Sergey N Zolov

Cole J Ferguson

Miriam H Meisler

Michael A Sutton

Lois S Weisman

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Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P<sub>2</sub>and PI(5)P

Normal steady-state levels of the signalling lipids PI(3,5)P 2 and PI(5)P require the lipid kinase FAB1/PIKfyve and its regulators, VAC14 and FIG4. Mutations in the PIKfyve/ VAC14/FIG4 pathway are associated with Charcot-MarieTooth syndrome and amyotrophic lateral sclerosis in humans, and profound neurodegeneration in mice. Hence, tight regulation of this pathway is critical for neural function. Here, we examine the localization and physiological role of VAC14 in neurons. We report that endogenous VAC14 localizes to endocytic organelles in fibroblasts and neurons. Unexpectedly, VAC14 exhibits a pronounced synaptic localization in hippocampal neurons, suggesting a role in regulating synaptic function. Indeed, the amplitude of miniature excitatory postsynaptic currents is enhanced in both Vac14 À / À and Fig4 neurons. Re-introduction of VAC14 in postsynaptic Vac14 À / À cells reverses this effect. These changes in synaptic strength in Vac14 À / À neurons are associated with enhanced surface levels of the AMPA-type glutamate receptor subunit GluA2, an effect that is due to diminished regulated endocytosis of AMPA receptors. Thus, VAC14, PI(3,5)P 2 and/or PI(5)P play a role in controlling postsynaptic function via regulation of endocytic cycling of AMPA receptors

Amber J Mccartney

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Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P 2 and PI(5)P

Deep Blue Documents at the University of Michigan

Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P 2  and PI(5)P

Biol 143: 65–79 Gong L-W, De Camilli P

Chem 286: 13404–13413 Ikonomov

Distinct pathogenic processes between

Phosphoinositide-derived messengers in endocrine signaling.

Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P 2 and PI(5)P

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