Synaptotagmin‐11 inhibits spontaneous neurotransmission through vti1a

Abstract

Recent work has revealed that spontaneous release plays critical roles in the central nervous system, but how it is regulated remains elusive. Here, we report that synaptotagmin-11 (Syt11), a Ca 2+ -independent Syt isoform associated with schizophrenia and Parkinson's disease, suppressed spontaneous release. Syt11-knockout hippocampal neurons showed an increased frequency of miniature excitatory post-synaptic currents while over-expression of Syt11 inversely decreased the frequency. Neither knockout nor over-expression of Syt11 affected the average amplitude, suggesting the pre-synaptic regulation of spontaneous neurotransmission by Syt11. Glutathione Stransferase pull-down, co-immunoprecipitation, and affinity-purification experiments demonstrated a direct interaction of Syt11 with vps10p-tail-interactor-1a (vti1a), a non-canonical SNARE protein that maintains spontaneous release. Importantly, knockdown of vti1a reversed the phenotype of Syt11 knockout, identifying vti1a as the main target of Syt11 inhibition. Domain analysis revealed that the C2A domain of Syt11 bound vti1a with high affinity. Consistently, expression of the C2A domain alone rescued the phenotype of elevated spontaneous release in Syt11-knockout neurons similar to the full-length protein. Altogether, our results suggest that Syt11 inhibits vti1a-containing vesicles during spontaneous release.

The Role of Vti1a in Biological Functions and Its Possible Role in Nervous System Disorders

“…Vti1a exhibits robust trafficking under neuronal resting conditions, which selectively maintains spontaneous neurotransmitter release ( Ramirez et al, 2012 ). In addition, studies have shown that synaptotagmin-11 inhibits spontaneous release primarily by inhibiting Vti1a-containing vesicles ( Li et al, 2021 ). The evidences suggest that spontaneous synaptic transmission is independent of evoked synaptic transmission and that Vti1a is a joint regulator of this process.…”

Palmitoylation of the Parkinson’s disease–associated protein synaptotagmin-11 links its turnover to α-synuclein homeostasis

“…Functionally, forebrain-specific SYT11 -knockout mice show impaired synaptic plasticity and memory (conventional, whole-body knockouts are lethal within 24 hours of birth) ( 8 ). Others have found that Syt11 inhibits clathrin-mediated and bulk endocytosis ( 9 ) and suppresses spontaneous neurotransmission ( 10 ). In disease models, overexpression of Syt11 in the substantia nigrae of mice results in defective release of dopamine and death of dopaminergic neurons, consistent with its possible role in PD ( 11 ).…”

Nanocomposite proton conducting membranes based on sulfonated polystyrene/imidazole‐2‐acetic acid blend for direct methanol fuel cell application

“…Sulfonated non‐fluorinated hydrocarbon PEMs are one of the promising alternatives for replacing Nafion 5 . In this regard, sulfonated aromatic polymers, such as SPS, 6–8 sulfonated poly ether ether ketone (SPEEK), 9–12 and sulfonated polyimide (SPI), 13–15 were introduced as candidate PEMs for DMFC applications. The sulfonation method is employed to increase proton conductivity and hydrophilicity by introducing sulfonic acid functional groups to the structures of polymers like PEEK, PS, and PI, which inherently have low proton conductivity and low hydrophilicity 15 .…”