Phosphorylation of presynaptic PLPPR3 controls synaptic vesicle release

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Signaling

Background:

• Phospholipid-phosphatase-related protein 3 (PLPPR3) is a transmembrane protein crucial for axonal growth in the nervous system.
• Its function in synapses and regulatory signaling pathways remain largely uncharacterized.

Purpose of the Study:

• To investigate the role of PLPPR3 in synaptic function and identify signaling events regulating its activity.
• To characterize the phosphorylation of PLPPR3 and its impact on presynaptic activity.

Main Methods:

• Mass spectrometry was employed to identify phosphorylation sites on PLPPR3.
• Biochemical assays confirmed S351 as a protein kinase A (PKA) phosphorylation site.
• Electrophysiological recordings were performed in hippocampal neurons from wild-type and Plppr3 knockout mice.

Main Results:

• Twenty-six high-confidence phosphorylation sites were identified in the intracellular domain of PLPPR3.
• PLPPR3 is localized to presynaptic terminals and negatively regulates depolarization-induced synaptic vesicle release.
• Deletion of PLPPR3 leads to enhanced synaptic vesicle release, which is rescued by wild-type PLPPR3 but not a S351A mutant.

Conclusions:

• PLPPR3 phosphorylation, regulated by PKA, acts as a signaling integrator at presynaptic terminals.
• This phosphorylation modulates presynaptic activity and synaptic vesicle release in hippocampal neurons.
• PLPPR3 plays a critical role in synaptic function and neurotransmission.