Phosphorylation of presynaptic PLPPR3 controls synaptic vesicle release
Phospholipid-phosphatase-related protein 3 (PLPPR3) belongs to a family of transmembrane proteins highly expressed in the nervous system where it regulates critical axonal growth processes during guidance, filopodia formation, and branching. However, little is known regarding its role in synapses and the signaling events regulating PLPPR3 function. Here, we identify 26 high-confidence phosphorylation sites in the intracellular domain of PLPPR3 using mass spectrometry. Biochemical characterization established one of these-S351-as a <i>bona fide</i> phosphorylation site of protein kinase A (PKA). PLPPR3 is enriched at presynaptic terminals, and deletion of PLPPR3 results in increased depolarization-induced synaptic vesicle release in hippocampal neurons. This tonic inhibitory signal toward depolarization-induced presynaptic activity is corrected by expression of PLPPR3 intracellular domain, but not a S351A phospho-dead mutant, in <i>Plppr3</i> <sup>-/-</sup> hippocampal neurons. We propose that PLPPR3 phosphorylation under the control of PKA activity is a signaling integrator of presynaptic activity in hippocampal neurons.
Authors
- George Leondaritis (ORCID: https://orcid.org/0000-0001-8385-8341)
- Kathrin Textoris‐Taube (ORCID: https://orcid.org/0000-0002-1224-8236)
- Annika Brosig (ORCID: https://orcid.org/0000-0002-4606-9017)
- Philipp Mertins (ORCID: https://orcid.org/0000-0002-2245-528X)
- Dragomir Milovanović (ORCID: https://orcid.org/0000-0002-6625-1879)
- Shannon Bareesel
- Willem Bintig
- Timothy A. Zolnik (ORCID: https://orcid.org/0000-0002-9076-4041)
- Marieluise Kirchner (ORCID: https://orcid.org/0000-0002-7049-534X)
- Vasiliki Syropoulou
- Cristina Kroon (ORCID: https://orcid.org/0000-0001-9977-5188)
- Niclas Gimber (ORCID: https://orcid.org/0000-0001-9456-3063)
- Jan Schmoranzer (ORCID: https://orcid.org/0000-0002-4482-7080)
- Britta J. Eickholt (ORCID: https://orcid.org/0000-0001-7873-8687)
- Dimitra Ranti (ORCID: https://orcid.org/0000-0002-8693-5207)
- Gerard Aguilar Pérez
- Georg Braune
- Domonkos Nagy-Herczeg
- Sandra Coveney
Institutions
- University of Ioannina (GR)
- Max Delbrück Center (DE)
- German Center for Neurodegenerative Diseases (DE)
- Cell Signaling Technology (United States) (US)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- iScience
- Published
- 2025-08-27
- DOI
- https://doi.org/10.1016/j.isci.2025.113435
- Citations
- 1
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 1.15
Funders
- Deutsche Forschungsgemeinschaft
- Hellenic Foundation for Research and Innovation