Turbocharging synaptic transmission: 12 SNAREpins are required for rapid release of reconstituted synaptic vesicles
-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes. How SNAREs cooperate to achieve synchronous neurotransmitter release is a long-standing mystery. Rapid release (<7 milliseconds) has been reconstituted from purified synaptic SNAREs, SNARE-assembling chaperones, and calcium ion sensors in a fully-defined, genetically validated system that enables single-molecule counting in docked vesicles before release. SNAREpin complexes (12 ± 0.3) are found in each such ready-release vesicle, suggesting a regular structure. Several genetic conditions (including point mutation of the synaptic vesicle protein Synaptophysin from a Synaptopathy patient and human and mouse disease mutations of the synaptic vesicle protein vesicle-associated membrane protein-2 (VAMP2) reduce the number of SNAREpins to 6 ± 0.3 and result in profoundly delayed release over 0.1 to 1 seconds. Omitting Synaptophysin, whose hexamers preassemble 12 copies of VAMP2, also yields ~6 SNAREpins and delays release.
Authors
- Sathish Ramakrishnan (ORCID: https://orcid.org/0000-0002-7844-2234)
- Amit Koikkarah Aji
- Manindra Bera (ORCID: https://orcid.org/0000-0001-9297-8126)
- Kallol Gupta (ORCID: https://orcid.org/0000-0002-3557-3242)
- Jeff Coleman (ORCID: https://orcid.org/0000-0003-0110-9289)
- Frédéric Pincet (ORCID: https://orcid.org/0000-0002-4243-2157)
- Abhijith Radhakrishnan (ORCID: https://orcid.org/0000-0001-8107-3487)
- Aniruddha Panda (ORCID: https://orcid.org/0000-0002-9447-9547)
- Matthieu Caruel (ORCID: https://orcid.org/0000-0002-6591-2727)
- Henry Houlden (ORCID: https://orcid.org/0000-0002-2866-7777)
- Reza Maroofian (ORCID: https://orcid.org/0000-0001-6763-1542)
- Atrouli Chatterjee (ORCID: https://orcid.org/0000-0002-2591-6213)
- Sudhanshu Gautam (ORCID: https://orcid.org/0000-0003-2550-7548)
- James E. Rothman (ORCID: https://orcid.org/0000-0003-4822-4161)
- Vincenzo Salpietro
- Kirill Grushin
- R. Venkat K. Sundaram
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Paris-Est Créteil (FR)
- Université Paris Cité (FR)
- University of L'Aquila (IT)
- École Normale Supérieure - PSL (FR)
- Yale University (US)
- Sorbonne Université (FR)
- École Normale Supérieure (BI)
- European Brain Research Institute (IT)
- National Hospital for Neurology and Neurosurgery (GB)
- Université Gustave Eiffel (FR)
- Laboratoire Modélisation et Simulation Multi-Echelle (FR)
- University College London (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2026-07-01
- DOI
- https://doi.org/10.1126/sciadv.aea0592
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Pershing Square Foundation
- National Institutes of Health