The neuronal calcium sensor Synaptotagmin-1 and SNARE proteins cooperate to dilate fusion pores
- University of Wisconsin, United States
- Columbia University, United States
- Yale University School of Medicine, United States
Abstract
All membrane fusion reactions proceed through an initial fusion pore, including calcium-triggered release of neurotransmitters and hormones. Expansion of this small pore to release cargo is energetically costly and regulated by cells, but the mechanisms are poorly understood. Here we show that the neuronal/exocytic calcium sensor Synaptotagmin-1 (Syt1) promotes expansion of fusion pores induced by SNARE proteins. Pore dilation relied on calcium-induced insertion of the tandem C2 domain hydrophobic loops of Syt1 into the membrane, previously shown to reorient the C2 domain. Mathematical modelling suggests that C2B reorientation rotates a bound SNARE complex so that it exerts force on the membranes in a mechanical lever action that increases the height of the fusion pore, provoking pore dilation to offset the bending energy penalty. We conclude that Syt1 exerts novel non-local calcium-dependent mechanical forces on fusion pores that dilate pores and assist neurotransmitter and hormone release.
Data availability
All data associated with the plots shown in this study are included in the manuscript and supporting files. Source data files have been provided for all figures, in the form of a .zip file containing mostly matlab .fig and/or .mat files corresponding to the data presented in the manuscript and the Appendix. The raw data can be extracted for every plot from the .fig file. In a few cases, we included excel or Igor Pro files.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (R01NS113236)
- Erdem Karatekin
National Eye Institute (R01EY010542)
- Erdem Karatekin
National Institute of General Medical Sciences (R01GM117046)
- Ben O'Shaughnessy
Columbia University (Shared Research Computing Facility)
- Ben O'Shaughnessy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Felix Campelo, The Barcelona Institute of Science and Technology, Spain
Publication history
- Received: March 9, 2021
- Accepted: June 29, 2021
- Accepted Manuscript published: June 30, 2021 (version 1)
- Version of Record published: July 21, 2021 (version 2)
Copyright
© 2021, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,158
- Page views
-
- 238
- Downloads
-
- 10
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
The neuronal calcium sensor Synaptotagmin-1 and SNARE proteins cooperate to dilate fusion pores
eLife 10:e68215.
https://doi.org/10.7554/eLife.68215
Further reading
-
- Neuroscience
Artificial neural networks could pave the way for efficiently simulating large-scale models of neuronal networks in the nervous system.
-
- Neuroscience
A key question in decision making is how humans arbitrate between competing learning and memory systems to maximize reward. We address this question by probing the balance between the effects, on choice, of incremental trial-and-error learning versus episodic memories of individual events. Although a rich literature has studied incremental learning in isolation, the role of episodic memory in decision making has only recently drawn focus, and little research disentangles their separate contributions. We hypothesized that the brain arbitrates rationally between these two systems, relying on each in circumstances to which it is most suited, as indicated by uncertainty. We tested this hypothesis by directly contrasting contributions of episodic and incremental influence to decisions, while manipulating the relative uncertainty of incremental learning using a well-established manipulation of reward volatility. Across two large, independent samples of young adults, participants traded these influences off rationally, depending more on episodic information when incremental summaries were more uncertain. These results support the proposal that the brain optimizes the balance between different forms of learning and memory according to their relative uncertainties and elucidate the circumstances under which episodic memory informs decisions.
