Premium
Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P 2 and PI(5)P
Author(s) -
Zhang Yanling,
McCartney Amber J,
Zolov Sergey N,
Ferguson Cole J,
Meisler Miriam H,
Sutton Michael A,
Weisman Lois S
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2012.200
Subject(s) - endocytic cycle , biology , ampa receptor , microbiology and biotechnology , postsynaptic potential , excitatory postsynaptic potential , glutamate receptor , neurodegeneration , neurotransmission , postsynaptic density , endocytosis , neuroscience , receptor , inhibitory postsynaptic potential , biochemistry , medicine , disease
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‐Marie‐Tooth 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 −/− and Fig4 −/− neurons. Re‐introduction of VAC14 in postsynaptic Vac14 −/− cells reverses this effect. These changes in synaptic strength in Vac14 −/− 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.