Biology subjects

Wozney, M.

Publications and source records attributed to Wozney, M..

2 recordsLinked to original sources

bioRxiv2026

Functional mapping of synaptotagmin 1 Ca2+ ligands that mediate excitation-secretion coupling in neurons

Synaptotagmin (SYT) 1 is a Ca2+ sensor that triggers rapid synaptic vesicle exocytosis, but how it is activated by Ca2+ remains enigmatic. SYT1 contains two Ca2+-sensing motifs, C2A and C2B. Structural studies have proposed that five acidic residues in each C2 domain mediate Ca2+-binding, but their functional relevance remains unclear. Here, we mutated each of the ten putative ligands and conducted side-by-side comparisons of Ca2+-binding activity and evoked glutamate release. Remarkably, all ten putative ligands are crucial for evoked synchronous release, overturning the view that binding of Ca2+ to C2A is dispensable. Importantly, Ca2+ binding to C2B is essential for synchronization. Furthermore, we report that two new human mutations, corresponding to Ca2+ ligands in C2B, are dominant-negative. Finally, four new crystal structures reveal how the choice of neutralizing substitution differentially alters SYT1 structure and, consequently, function.

neuroscience↗

bioRxiv2025

Alternative splicing of synaptotagmin 7 regulates oligomerization and short-term synaptic plasticity

Synaptic plasticity is crucial for learning and memory. The presynaptic calcium sensor synaptotagmin 7 (syt7) regulates aspects of short-term plasticity (STP), but the underlying mechanisms remain unclear. Here, we show that alternative splicing of the syt7 juxtamembrane linker acts as a molecular switch at both biochemical and functional levels. The and {beta} variants undergo liquid-liquid phase separation to form condensates, while the {gamma} variant forms aggregates. Using iGluSnFR imaging, we found that when expressed at equal levels, these three isoforms also diverge regarding their abilities to regulate two key aspects of STP: paired-pulse facilitation and synaptic depression. STED microscopy showed that all three isoforms form active zone-associated clusters that colocalize with syt1, while MINFLUX super-resolution microscopy resolved syt7 clusters within the active zone, well-positioned to directly control synaptic vesicle dynamics. Thus, alternative splicing might fine-tune STP by differentially impacting syt7 oligomerization.

neuroscience↗