scholarly journals Presynaptic Calcium Channels

2019 ◽  
Vol 20 (9) ◽  
pp. 2217 ◽  
Author(s):  
Sumiko Mochida
Keyword(s):  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Neuronal Firing ◽  
Regulatory Proteins ◽  
Channel Modulation ◽  
Signaling Complex ◽  
Presynaptic Plasticity ◽  
Presynaptic Calcium ◽  
Ca2 Channels ◽  
Α1 Subunit

Presynaptic Ca2+ entry occurs through voltage-gated Ca2+ (CaV) channels which are activated by membrane depolarization. Depolarization accompanies neuronal firing and elevation of Ca2+ triggers neurotransmitter release from synaptic vesicles. For synchronization of efficient neurotransmitter release, synaptic vesicles are targeted by presynaptic Ca2+ channels forming a large signaling complex in the active zone. The presynaptic CaV2 channel gene family (comprising CaV2.1, CaV2.2, and CaV2.3 isoforms) encode the pore-forming α1 subunit. The cytoplasmic regions are responsible for channel modulation by interacting with regulatory proteins. This article overviews modulation of the activity of CaV2.1 and CaV2.2 channels in the control of synaptic strength and presynaptic plasticity.

scholarly journals Neurotransmitter Release Site Replenishment and Presynaptic Plasticity

2020 ◽  
Vol 22 (1) ◽  
pp. 327
Author(s):  
Sumiko Mochida
Keyword(s):  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
High Speed ◽  
Release Site ◽  
Short Term ◽  
Short Term Plasticity ◽  
Multiple Protein ◽  
Presynaptic Plasticity ◽  
Presynaptic Plasma Membrane ◽  
Ca2 Channels

An action potential (AP) triggers neurotransmitter release from synaptic vesicles (SVs) docking to a specialized release site of presynaptic plasma membrane, the active zone (AZ). The AP simultaneously controls the release site replenishment with SV for sustainable synaptic transmission in response to incoming neuronal signals. Although many studies have suggested that the replenishment time is relatively slow, recent studies exploring high speed resolution have revealed SV dynamics with milliseconds timescale after an AP. Accurate regulation is conferred by proteins sensing Ca2+ entering through voltage-gated Ca2+ channels opened by an AP. This review summarizes how millisecond Ca2+ dynamics activate multiple protein cascades for control of the release site replenishment with release-ready SVs that underlie presynaptic short-term plasticity.

scholarly journals Fife organizes synaptic vesicles and calcium channels for high-probability neurotransmitter release

2016 ◽  
Vol 216 (1) ◽  
pp. 231-246 ◽  
Author(s):  
Joseph J. Bruckner ◽  
Hong Zhan ◽  
Scott J. Gratz ◽  
Monica Rao ◽  
Fiona Ukken ◽  
...  
Keyword(s):  
Neural Plasticity ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Motor Behavior ◽  
Molecular Organization ◽  
Electrophysiological Studies ◽  
Circuit Function ◽  
Synaptic Vesicle Release ◽  
Ca2 Channels

The strength of synaptic connections varies significantly and is a key determinant of communication within neural circuits. Mechanistic insight into presynaptic factors that establish and modulate neurotransmitter release properties is crucial to understanding synapse strength, circuit function, and neural plasticity. We previously identified Drosophila Piccolo-RIM-related Fife, which regulates neurotransmission and motor behavior through an unknown mechanism. Here, we demonstrate that Fife localizes and interacts with RIM at the active zone cytomatrix to promote neurotransmitter release. Loss of Fife results in the severe disruption of active zone cytomatrix architecture and molecular organization. Through electron tomographic and electrophysiological studies, we find a decrease in the accumulation of release-ready synaptic vesicles and their release probability caused by impaired coupling to Ca2+ channels. Finally, we find that Fife is essential for the homeostatic modulation of neurotransmission. We propose that Fife organizes active zones to create synaptic vesicle release sites within nanometer distance of Ca2+ channel clusters for reliable and modifiable neurotransmitter release.

scholarly journals Control of neurotransmitter release by two distinctmembrane-binding faces of the Munc13-1 C­1C2B region

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Marcial Camacho ◽  
Bradley Quade ◽  
Thorsten Trimbuch ◽  
Junjie Xu ◽  
Levent Sari ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Point Mutations ◽  
Short Term ◽  
In Vitro Reconstitution ◽  
Presynaptic Plasticity ◽  
Hippocampal Cultures

Munc13-1 plays a central role in neurotransmitter release through its conserved C-terminal region, which includes a diacyglycerol (DAG)-binding C1 domain, a Ca2+/PIP2-binding C2B domain, a MUN domain and a C2C domain. Munc13-1 was proposed to bridge synaptic vesicles to the plasma membrane through distinct interactions of the C­1C2B region with the plasma membrane: i) one involving a polybasic face that is expected to yield a perpendicular orientation of Munc13-1 and hinder release; and ii) another involving the DAG-Ca2+-PIP2-binding face that is predicted to result in a slanted orientation and facilitate release. Here we have tested this model and investigated the role of the C­1C2B region in neurotransmitter release. We find that K603E or R769E point mutations in the polybasic face severely impair Ca2+-independent liposome bridging and fusion in in vitro reconstitution assays, and synaptic vesicle priming in primary murine hippocampal cultures. A K720E mutation in the polybasic face and a K706E mutation in the C2B domain Ca2+-binding loops have milder effects in reconstitution assays and do not affect vesicle priming, but enhance or impair Ca2+-evoked release, respectively. The phenotypes caused by combining these mutations are dominated by the K603E and R769E mutations. Our results show that the C1-C2B region of Munc13-1 plays a central role in vesicle priming and support the notion that two distinct faces of this region control neurotransmitter release and short-term presynaptic plasticity.

scholarly journals Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Junjie Xu ◽  
Marcial Camacho ◽  
Yibin Xu ◽  
Victoria Esser ◽  
Xiaoxia Liu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Binding Sites ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Plasma Membranes ◽  
Helical Structure ◽  
Membrane Interface ◽  
Short Term ◽  
Presynaptic Plasticity ◽  
Multiple Domains

Munc13–1 acts as a master regulator of neurotransmitter release, mediating docking-priming of synaptic vesicles and diverse presynaptic plasticity processes. It is unclear how the functions of the multiple domains of Munc13–1 are coordinated. The crystal structure of a Munc13–1 fragment including its C1, C2B and MUN domains (C1C2BMUN) reveals a 19.5 nm-long multi-helical structure with the C1 and C2B domains packed at one end. The similar orientations of the respective diacyglycerol- and Ca2+-binding sites of the C1 and C2B domains suggest that the two domains cooperate in plasma-membrane binding and that activation of Munc13–1 by Ca2+ and diacylglycerol during short-term presynaptic plasticity are closely interrelated. Electrophysiological experiments in mouse neurons support the functional importance of the domain interfaces observed in C1C2BMUN. The structure imposes key constraints for models of neurotransmitter release and suggests that Munc13–1 bridges the vesicle and plasma membranes from the periphery of the membrane-membrane interface.

scholarly journals The Coupling between Synaptic Vesicles and Ca2+ Channels Determines Fast Neurotransmitter Release

Neuron ◽  
2007 ◽  
Vol 53 (4) ◽  
pp. 563-575 ◽  
Author(s):  
Kristian Wadel ◽  
Erwin Neher ◽  
Takeshi Sakaba
Keyword(s):  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Ca2 Channels

scholarly journals Analysis of protein phosphorylation in nerve terminal reveals extensive changes in active zone proteins upon exocytosis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Mahdokht Kohansal-Nodehi ◽  
John JE Chua ◽  
Henning Urlaub ◽  
Reinhard Jahn ◽  
Dominika Czernik
Keyword(s):  
Active Zone ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Wistar Rats ◽  
Nerve Terminals ◽  
Calcium Dependent ◽  
Presynaptic Plasticity ◽  
Presynaptic Plasma Membrane ◽  
Quantitative Phosphoproteomics ◽  
Presynaptic Proteins

Neurotransmitter release is mediated by the fast, calcium-triggered fusion of synaptic vesicles with the presynaptic plasma membrane, followed by endocytosis and recycling of the membrane of synaptic vesicles. While many of the proteins governing these processes are known, their regulation is only beginning to be understood. Here we have applied quantitative phosphoproteomics to identify changes in phosphorylation status of presynaptic proteins in resting and stimulated nerve terminals isolated from the brains of Wistar rats. Using rigorous quantification, we identified 252 phosphosites that are either up- or downregulated upon triggering calcium-dependent exocytosis. Particularly pronounced were regulated changes of phosphosites within protein constituents of the presynaptic active zone, including bassoon, piccolo, and RIM1. Additionally, we have mapped kinases and phosphatases that are activated upon stimulation. Overall, our study provides a snapshot of phosphorylation changes associated with presynaptic activity and provides a foundation for further functional analysis of key phosphosites involved in presynaptic plasticity.

scholarly journals Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity

2018 ◽  
Author(s):  
Gaël Barthet ◽  
Tomàs Jordà-Siquier ◽  
Julie Rumi-Masante ◽  
Fanny Bernadou ◽  
Ulrike Müller ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Secretase Activity ◽  
Presynaptic Mechanisms ◽  
Presynaptic Plasticity ◽  
Functional Consequences ◽  
Familial Alzheimer Disease ◽  
Genetic Deletion ◽  
Main Substrate

SUMMARYPresenilin (PS), the catalytic subunit of γ-secretase and its main substrate the amyloid precursor protein (APP) are mutated in a large majority of patients with familial Alzheimer disease. PS and APP interact with proteins of the neurotransmitter release machinery but the functional consequences of these interactions are unknown. Here we report that genetic deletion of presynaptic PS markedly decreases the axonal expression of the Ca2+ sensor synaptotagmin-7 (Syt7), and impairs synaptic facilitation and replenishment of release-competent synaptic vesicles. These properties are fully restored by presynaptic re-expression of Syt7. The regulation of Syt7 expression occurs post-transcriptionally and depends on γ-secretase activity. In the combined absence of both APP and PS1, the loss of Syt7 is prevented, indicating that the action of γ-secretase on presynaptic mechanisms depends on its substrate APP. The molecular mechanism involves the substrate of PS, APP-βCterminal (APP-βCTF), which interacts with Syt7 and accumulates in synaptic terminals under conditions of pharmacological or genetic inhibition of γ-secretase. These results reveal a role of PS in presynaptic mechanisms through regulation of Syt7 by APP-dependent cleavage, and highlight aberrant synaptic vesicle processing as a possible new pathway in AD.

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