Journal
SCIENCE ADVANCES
Volume 7, Issue 18, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abf3873
Keywords
-
Categories
Funding
- Wellcome Trust [FC001201, 204954/Z/16/Z, 212947/Z/18/Z]
- RS Macdonald Seedcorn Fund
- Francis Crick Institute
- Cancer Research UK [FC001201]
- U.K. Medical Research Council [FC001201]
- Wellcome Trust [204954/Z/16/Z, 212947/Z/18/Z] Funding Source: Wellcome Trust
Ask authors/readers for more resources
The study reveals that regulating the copy number of the noncanonical vesicular SNARE protein VAMP4 on synaptic vesicles is crucial for controlling neurotransmitter release probability. VAMP4, with high synaptic turnover, is selectively sorted to endolysosomes during activity-dependent bulk endocytosis, disrupting which can lead to an increase in VAMP4 abundance in the SV pool and inhibition of SV fusion.
Synaptic vesicle (SV) release probability (Pr), determines the steady state and plastic control of neurotransmitter release. However, how diversity in SV composition arises and regulates the Pr of individual SVs is not understood. We found that modulation of the copy number of the noncanonical vesicular SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor), vesicle-associated membrane protein 4 (VAMP4), on SVs is key for regulating Pr. Mechanistically, this is underpinned by its reduced ability to form an efficient SNARE complex with canonical plasma membrane SNAREs. VAMP4 has unusually high synaptic turnover and is selectively sorted to endolysosomes during activity-dependent bulk endocytosis. Disruption of endolysosomal trafficking and function markedly increased the abundance of VAMP4 in the SV pool and inhibited SV fusion. Together, our results unravel a new mechanism for generating SV heterogeneity and control of Pr through coupling of SV recycling to a major clearing system that regulates protein homeostasis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available