ArticleProceedings of the National Academy of Sciences of the United States of America2014
Activity-dependent PI(3,5)P2 synthesis controls AMPA receptor trafficking during synaptic depression.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 66 citations in OpenAlex.
- Quantitative comparison of PI(3,5)PMolecular biology of the cell · 2026Article
- Subcellular Cartography of the Phosphoinositide Multiverse.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2026Review
- Dual endomembrane recycling pathways function in parallel to support synapse maintenance and plasticity.Neuroscience · 2025Article
- Quantitative comparison of PI(3,5)PbioRxiv : the preprint server for biology · 2025Article
- PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity.The Journal of cell biology · 2025Article
- VAC14 oligomerization is essential for the function of the FAB1/PIKfyve-VAC14-FIG4 complex.Molecular biology of the cell · 2025Article
- Division of labor among H3K4 methyltransferases defines distinct facets of homeostatic plasticity.Cell reports · 2025Article
- Sorting nexin 10 regulates lysosomal ionic homeostasis via ClC-7 by controlling PI(3,5)P2.The Journal of cell biology · 2025Article
- Article
- Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities.Nature reviews. Cancer · 2025Review
- Neuronal constitutive endolysosomal perforations enable α-synuclein aggregation by internalized PFFs.The Journal of cell biology · 2025Article
- PI(3,5)P2 asymmetry during mitosis is essential for asymmetric vacuolar inheritance.The Journal of cell biology · 2025Article
- Inositol metabolism as a broad-spectrum antiviral target.Frontiers in microbiology · 2025Review
- Article
- Phosphatidylinositol-3-phosphate mediates Arc capsid secretion through the multivesicular body pathway.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux.Biochemistry and biophysics reports · 2024Article
- Constitutive Endolysosomal Perforation in Neurons allows Induction of α-Synuclein Aggregation by Internalized Pre-Formed Fibrils.bioRxiv : the preprint server for biology · 2024Article
- A PI(3,5)P2 reporter reveals PIKfyve activity and dynamics on macropinosomes and phagosomes.The Journal of cell biology · 2023Article
- The signalling lipid PI3,5POpen biology · 2023Article
- Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity.The Journal of cell biology · 2023Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Dynamic regulation of phosphoinositide lipids (PIPs) is crucial for diverse cellular functions, and, in neurons, PIPs regulate membrane trafficking events that control synapse function. Neurons are particularly sensitive to the levels of the low abundant PIP, phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], because mutations in PI(3,5)P2-related genes are implicated in multiple neurological disorders, including epilepsy, severe neuropathy, and neurodegeneration. Despite the importance of PI(3,5)P2 for neural function, surprisingly little is known about this signaling lipid in neurons, or any cell type. Notably, the mammalian homolog of yeast vacuole segregation mutant (Vac14), a scaffold for the PI(3,5)P2 synthesis complex, is concentrated at excitatory synapses, suggesting a potential role for PI(3,5)P2 in controlling synapse function and/or plasticity. PI(3,5)P2 is generated from phosphatidylinositol 3-phosphate (PI3P) by the lipid kinase PI3P 5-kinase (PIKfyve). Here, we present methods to measure and control PI(3,5)P2 synthesis in hippocampal neurons and show that changes in neural activity dynamically regulate the levels of multiple PIPs, with PI(3,5)P2 being among the most dynamic. The levels of PI(3,5)P2 in neurons increased during two distinct forms of synaptic depression, and inhibition of PIKfyve activity prevented or reversed induction of synaptic weakening. Moreover, altering neuronal PI(3,5)P2 levels was sufficient to regulate synaptic strength bidirectionally, with enhanced synaptic function accompanying loss of PI(3,5)P2 and reduced synaptic strength following increased PI(3,5)P2 levels. Finally, inhibiting PI(3,5)P2 synthesis alters endocytosis and recycling of AMPA-type glutamate receptors (AMPARs), implicating PI(3,5)P2 dynamics in AMPAR trafficking. Together, these data identify PI(3,5)P2-dependent signaling as a regulatory pathway that is critical for activity-dependent changes in synapse strength.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.