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PMID: 22842785 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P₂ and PI(5)P.

The EMBO journal ·Vol. 31 ·No. 16 ·2012-08-15 ·Pages 3442-56

Zhang Y, McCartney AJ, Zolov SN, Ferguson CJ, Meisler MH, Sutton MA, Weisman LS

Abstract

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.

MeSH Terms
Animals Excitatory Postsynaptic Potentials Fibroblasts/chemistry Genetic Complementation Test Intracellular Signaling Peptides and Proteins/analysis,genetics Membrane Proteins Mice Mice, Knockout Models, Biological Neurons/chemistry,metabolism,physiology Organelles/chemistry Phosphatidylinositols/metabolism Synapses/physiology
Chemicals
Intracellular Signaling Peptides and Proteins Membrane Proteins Phosphatidylinositols Vac14 protein, mouse
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Zhang Yanling
1] Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA [2] Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
McCartney Amber J
Zolov Sergey N
Ferguson Cole J
Meisler Miriam H
Sutton Michael A
Weisman Lois S
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2012.200
Published
2012-08-15
Epub
2012-00-27
Pages
3442-56
Language
English
Region
England
NLM ID
8208664
PMCID
PMC3419932
Subset
IM
Grants
NIMH NIH HHS · R01-MH085798 · United States
PHS HHS · K020572 · United States
NINDS NIH HHS · T32 NS076401 · United States
NEI NIH HHS · T32EY017878 · United States
NINDS NIH HHS · F31NS074740-01 · United States
NINDS NIH HHS · R01 NS064015 · United States
NIGMS NIH HHS · R01 GM024872 · United States
NIDDK NIH HHS · P30 DK020572 · United States
NINDS NIH HHS · F31 NS074740 · United States
NINDS NIH HHS · R01-NS064015 · United States
NIGMS NIH HHS · R01-GM24872 · United States
NIGMS NIH HHS · R01 GM050403 · United States
NEI NIH HHS · T32 EY017878 · United States
NIMH NIH HHS · R01 MH085798 · United States
External Links
PubMed source DOI: 10.1038/emboj.2012.200 PMC Full Text View journal details
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