A Hyperactive Form of unc-13 Enhances Ca2+ Sensitivity and Synaptic Vesicle Release Probability in C. elegans

• Published in: Cell reports (Cambridge) 2019-09, Vol.28 (11), p.2979-2995.e4
• Main Authors: Li, Lei, Liu, Haowen, Hall, Qi, Wang, Wei, Yu, Yi, Kaplan, Joshua M., Hu, Zhitao
• Format: Article
• Language: English
• Subjects: Ca2+ sensitivity; evoked release; synaptic depression; synaptic transmission; syntaxin-1A; tonic release; unc-13
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.08.018

Munc13 proteins play several roles in regulating short-term synaptic plasticity. However, the underlying molecular mechanisms remain largely unclear. Here we report that C. elegans UNC-13L, a Munc13-1 ortholog, has three domains that inhibit synaptic vesicle (SV) exocytosis. These include the X (sequence between C2A and C1), C1, and C2B domains. Deleting all three inhibitory domains produces a hyperactive UNC-13 (sUNC-13) that exhibits dramatically increased neurotransmitter release, Ca2+ sensitivity of release, and release probability. The vesicular pool in unc-13 mutants rescued by sUNC-13 exhibits a faster synaptic recovery and replenishment rate, demonstrating an important role of sUNC-13 in regulating synaptic plasticity. Analysis of double mutants suggests that sUNC-13 enhances tonic release by increasing the open probability of UNC-64/syntaxin-1A, whereas its effects on evoked release appear to be mediated by additional functions, presumably by further regulating the activity of the assembled soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) complex. [Display omitted] •UNC-13L exhibits both facilitatory and inhibitory regulation in synaptic transmission•Removing all inhibitory domains in UNC-13L produces a hyperactive UNC-13•Synaptic recovery is accelerated in sUNC-13 transgenic animals•sUNC-13 increases release probability by opening syntaxin in a highly efficient manner Li et al. identify three domains in UNC-13L that inhibit neurotransmitter release. Removal of the three inhibitory domains produces a hyperactive UNC-13 that dramatically increases Ca2+ sensitivity and release probability of vesicle exocytosis by opening syntaxin in a highly efficient manner.