Evolutionarily conserved and divergent mechanisms of dual Ca²⁺ sensors in synaptic vesicle exocytosis.

Authors

Lei Li, Jiafan Wang, Jingyao Xia, Xiaochun Yu, Jiayi Hu, Qinrong Zhang, Janet E Richmond, Haowen Liu, Zhitao Hu

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 25. Pages e2532992123. Jun 23, 2026. Epub Jun 18, 2026.

Abstract

Neurotransmitter release at the Caenorhabditis elegans neuromuscular junction is governed by a dual Ca²⁺ sensor system composed of SNT-1 and SNT-3, which function analogously to the Ca²⁺ sensor systems found in certain mammalian neurons, such as synaptotagmin-1 and -7 (Syt1/Syt7) in the hippocampus. In this study, we investigated how SNT-1 and SNT-3 mediate fast and slow neurotransmitter release through their potential interactions with the SNARE complex and their polybasic motifs. AlphaFold 3 models of SNT-1-SNARE and SNT-3-SNARE complexes predicted a C2B-SNARE arrangement consistent with the canonical Syt1-SNARE primary interface [Zhou et al., Nature 525, 62-67 (2015)] and precisely identified conserved binding residues within the C2B domains, as well as in SNAP-25 and Syntaxin, highlighting the evolutionary conservation of this interaction. Electrophysiological analyses using targeted mutagenesis demonstrated that both SNT-1 and SNT-3 require C2B-SNARE interactions and polybasic motifs within their C2 domains to drive evoked fast and slow neurotransmitter release. Notably, SNT-1 and SNT-3 exhibited differential dependence on distinct regions of the C2B-SNARE interface and their respective polybasic motifs, suggesting that Ca²⁺-triggered fast and slow release operate via distinct mechanistic strategies. Furthermore, we found that SNT-1 mediates spontaneous neurotransmitter release through multiple pathways, involving not only the primary C2B-SNARE interface but also additional putative SNARE-binding interactions. Together, our findings uncover both conserved and divergent mechanisms for synaptic exocytosis regulated by the dual Ca²⁺ sensors in C. elegans.

PMID:
42313926
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.