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

• 成果类型: Article
• 署名作者: Murcia, Francisco Jose Lopez -; Lin, Kun - Han; Berns, Manon M. M.; Ranjan, Mrinalini; Lipstein, Noa; Neher, Erwin; Brose, Nils; Reim, Kerstin; Taschenberger, Holger
• 署名单位: University of Gottingen; University of Gottingen; University of Barcelona; Institut d'Investigacio Biomedica de Bellvitge (IDIBELL); University of Copenhagen
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11636
• DOI: 10.1073/pnas.2320505121
• 发表日期: 2024-04-09
• 关键词: gating pore currents; hypokalemic periodic paralysis; action-potential initiation; autism spectrum disorder; gated sodium-channels; voltage sensor; cerebrospinal-fluid; slow inactivation; ion permeation; mouse model

摘要

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.