Complexin has a dual synaptic function as checkpoint protein in vesicle priming and as a promoter of vesicle fusion

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  • Francisco José López-Murcia
  • Kun Han Lin
  • Berns, Manon Monique Maria
  • Mrinalini Ranjan
  • Noa Lipstein
  • Erwin Neher
  • Nils Brose
  • Kerstin Reim
  • Holger Taschenberger
The presynaptic SNARE-complex regulator complexin (Cplx) enhances the fusogenicity of primed synaptic vesicles (SVs). Consequently, Cplx deletion impairs action potential-evoked transmitter release. Conversely, though, Cplx loss enhances spontaneous and delayed asynchronous release at certain synapse types. Using electrophysiology and kinetic modeling, we show that such seemingly contradictory transmitter release phenotypes seen upon Cplx deletion can be explained by an additional of Cplx in the control of SV priming, where its ablation facilitates the generation of a “faulty” SV fusion apparatus. Supporting this notion, a sequential two-step priming scheme, featuring reduced vesicle fusogenicity and increased transition rates into the faulty primed state, reproduces all aberrations of transmitter release modes and short-term synaptic plasticity seen upon Cplx loss. Accordingly, we propose a dual presynaptic function for the SNARE-complex interactor Cplx, one as a “checkpoint” protein that guarantees the proper assembly of the fusion machinery during vesicle priming, and one in boosting vesicle fusogenicity.
OriginalsprogEngelsk
Artikelnummere2320505121
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind121
Udgave nummer15
Antal sider12
ISSN0027-8424
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We thank Ina Herfort for excellent technical assistance, Bianca Nickel for mouse husbandry, and the AGCT laboratory for genotyping. This work was supported by the German Research Foundation (Cluster of Excellence EXC 2067 \u201CMultiscale Bioimaging\u201D, E.N., N.B.; Excellence Strategy-EXC-2049-390688087, N.L.; CRC 1286 \u201CQuantitative Synaptology\u201D projects A09 and A11, N.L., E.N., and N.B.), and by the Agencia Estatal de Investigaci\u00F3n (PID2022-141685NA-I00) and an Alexander von Humboldt Foundation postdoctoral fellowship (F.J.L.-M.).

Funding Information:
ACKNOWLEDGMENTS. We thank Ina Herfort for excellent technical assistance, Bianca Nickel for mouse husbandry,and theAGCTlaboratory for genotyping.This work was supported by the German Research Foundation (Cluster of Excellence EXC 2067 \u201CMultiscale Bioimaging\u201D, E.N., N.B.; Excellence Strategy\u2014EXC-2049\u2013 390688087, N.L.; CRC 1286 \u201CQuantitative Synaptology\u201D projects A09 and A11, N.L., E.N., and N.B.), and by the Agencia Estatal de Investigaci\u00F3n (PID2022-141685NA-I00) and an Alexander von Humboldt Foundation postdoctoral fellowship (F.J.L.-M.).

Publisher Copyright:
Copyright © 2024 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

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