scholarly journals A proline-rich motif on VGLUT1 reduces synaptic vesicle super-pool and spontaneous release frequency

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Xiao Min Zhang ◽  
Urielle François ◽  
Kätlin Silm ◽  
Maria Florencia Angelo ◽  
Maria Victoria Fernandez-Busch ◽  
...  
Keyword(s):  
Active Zone ◽  
Synaptic Vesicles ◽  
Weak Interactions ◽  
Synaptic Proteins ◽  
Excitatory Synapses ◽  
Spontaneous Release ◽  
Rich Domain ◽  
Quantal Size ◽  
Src Homology ◽  
Vesicular Glutamate Transporters

Glutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active-zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through the interaction of VGLUT1 second proline-rich domain, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between Src homology three and proline-rich domains of synaptic proteins. In mammals, VGLUT1 gained a proline-rich sequence that recruits endophilinA1 and turns the transporter into a regulator of SV organization and spontaneous release.

scholarly journals Mammalian vesicular glutamate transporter VGLUT1 reduces synaptic vesicle super-pool size and spontaneous release frequency

2018 ◽  
Author(s):  
Xiao-Min Zhang ◽  
Urielle François ◽  
Katlin Silm ◽  
Maria Florencia Angelo ◽  
Maria Victoria Fernández Busch ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Weak Interactions ◽  
Glutamate Transporter ◽  
Pool Size ◽  
Synaptic Proteins ◽  
Excitatory Synapses ◽  
Vesicular Glutamate Transporter ◽  
Spontaneous Release ◽  
Quantal Size ◽  
Dual Regulator

ABSTRACTGlutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through a tripartite interaction of VGLUT1, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between SH3 domains and proline rich sequences of synaptic proteins. In mammals, VGLUT1 gained a poly-proline sequence that recruits endophilinA1 and turns the transporter into a dual regulator of quantal release parameters at excitatory synapses.

scholarly journals Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

2017 ◽  
Vol 2017 ◽  
pp. 1-25 ◽  
Author(s):  
Viviana I. Torres ◽  
Daniela Vallejo ◽  
Nibaldo C. Inestrosa
Keyword(s):  
Central Nervous System ◽  
Neurological Disorders ◽  
Neuronal Development ◽  
Protein Complexes ◽  
Synaptic Proteins ◽  
Excitatory Synapses ◽  
Complex Structures ◽  
Disease Phenotype ◽  
The Central Nervous System ◽  
Invertebrate Models

Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype.

A Simple Depletion Model of the Readily Releasable Pool of Synaptic Vesicles Cannot Account for Paired-Pulse Depression

2007 ◽  
Vol 97 (1) ◽  
pp. 948-950 ◽  
Author(s):  
Jane M. Sullivan
Keyword(s):  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Synaptic Activity ◽  
Excitatory Synapses ◽  
Short Term ◽  
Paired Pulse ◽  
Short Term Plasticity ◽  
Releasable Pool ◽  
Readily Releasable Pool ◽  
Paired Pulse Depression

Paired-pulse depression (PPD) is a form of short-term plasticity that plays a central role in processing of synaptic activity and is manifest as a decrease in the size of the response to the second of two closely timed stimuli. Despite mounting evidence to the contrary, PPD is still commonly thought to reflect depletion of the pool of synaptic vesicles available for release in response to the second stimulus. Here it is shown that PPD cannot be accounted for by depletion at excitatory synapses made by hippocampal neurons because PPD is unaffected by changes in the fraction of the readily releasable pool (RRP) released by the first of a pair of pulses.

scholarly journals An essential role of acetylcholine-glutamate synergy at habenular synapses in nicotine dependence

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Silke Frahm ◽  
Beatriz Antolin-Fontes ◽  
Andreas Görlich ◽  
Johannes-Friedrich Zander ◽  
Gudrun Ahnert-Hilger ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Critical Role ◽  
Conditioned Reward ◽  
Quantal Size ◽  
Medial Habenula ◽  
Vesicular Transporters ◽  
Circuit Function ◽  
And Behavior ◽  
Presynaptic Facilitation

A great deal of interest has been focused recently on the habenula and its critical role in aversion, negative-reward and drug dependence. Using a conditional mouse model of the ACh-synthesizing enzyme choline acetyltransferase (Chat), we report that local elimination of acetylcholine (ACh) in medial habenula (MHb) neurons alters glutamate corelease and presynaptic facilitation. Electron microscopy and immuno-isolation analyses revealed colocalization of ACh and glutamate vesicular transporters in synaptic vesicles (SVs) in the central IPN. Glutamate reuptake in SVs prepared from the IPN was increased by ACh, indicating vesicular synergy. Mice lacking CHAT in habenular neurons were insensitive to nicotine-conditioned reward and withdrawal. These data demonstrate that ACh controls the quantal size and release frequency of glutamate at habenular synapses, and suggest that the synergistic functions of ACh and glutamate may be generally important for modulation of cholinergic circuit function and behavior.

scholarly journals Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle

2021 ◽  
Author(s):  
Jessica Laiman ◽  
Julie Loh ◽  
Wei-Chun Tang ◽  
Mei-Chun Chuang ◽  
Hui-Kang Liu ◽  
...  
Keyword(s):  
Direct Interaction ◽  
Membrane Curvature ◽  
Membrane Dynamics ◽  
Src Homology 3 ◽  
Rich Domain ◽  
Hereditary Myopathy ◽  
Src Homology ◽  
T Tubules ◽  
Endocytic Regulation ◽  
Dynamin 2

Tight regulation of endocytosis ensures accurate control of cellular signaling and membrane dynamics, which are crucial for tissue morphogenesis and functions. Mutations of Bin1 and dynamin-2 (Dyn2), proteins that generate membrane curvature and sever endocytic invaginations, respectively, cause progressive hereditary myopathy. Here, we show that Bin1 inhibits Dyn2 via direct interaction of its SRC Homology 3 (SH3) domain with the proline-rich domain (PRD) of Dyn2. Phosphorylation of S848 of Dyn2 by GSK3α, a kinase downstream of insulin signaling, relieves Dyn2 from the inhibition of Bin1 and promotes endocytosis in muscle. Mutations of Bin1 associated with centronuclear myopathy disrupt its inhibition of Dyn2, thereby exaggerating Dyn2 fission activity and causing excessive fragmentation of T-tubules in the muscle cells. Our work reveals how Bin1-Dyn2 interaction fine-tunes membrane remodeling at the molecular level, and lay the foundation for future exploration of endocytic regulation and hereditary muscle diseases.

scholarly journals Nanoscale dynamics of synaptic vesicle trafficking and fusion at the presynaptic active zone

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Thirumalini Vaithianathan ◽  
Diane Henry ◽  
Wendy Akmentin ◽  
Gary Matthews
Keyword(s):  
Active Zone ◽  
Synaptic Vesicles ◽  
Super Resolution ◽  
Visual Signals ◽  
Dual Function ◽  
Macromolecular Complex ◽  
Synaptic Ribbon ◽  
Modes Of Transmission ◽  
Resolution Imaging ◽  
Specialized Structure

The cytomatrix at the active zone (CAZ) is a macromolecular complex that facilitates the supply of release-ready synaptic vesicles to support neurotransmitter release at synapses. To reveal the dynamics of this supply process in living synapses, we used super-resolution imaging to track single vesicles at voltage-clamped presynaptic terminals of retinal bipolar neurons, whose CAZ contains a specialized structure—the synaptic ribbon—that supports both fast, transient and slow, sustained modes of transmission. We find that the synaptic ribbon serves a dual function as a conduit for diffusion of synaptic vesicles and a platform for vesicles to fuse distal to the plasma membrane itself, via compound fusion. The combination of these functions allows the ribbon-type CAZ to achieve the continuous transmitter release required by synapses of neurons that carry tonic, graded visual signals in the retina.

scholarly journals Depolarization-Induced Ca2+ Entry Preferentially Evokes Release of Large Quanta in the Developing Xenopus Neuromuscular Junction

2010 ◽  
Vol 104 (5) ◽  
pp. 2730-2740 ◽  
Author(s):  
Xiao-Ping Sun ◽  
Bo-Ming Chen ◽  
Olav Sand ◽  
Yoshi Kidokoro ◽  
Alan D. Grinnell
Keyword(s):  
Synaptic Vesicles ◽  
Channel Blocker ◽  
Direct Injection ◽  
External Solution ◽  
Neuromuscular Synapses ◽  
Quantal Size ◽  
Amplitude Histogram ◽  
Wide Range ◽  
Patch Pipette ◽  
Second Peak

The amplitude histogram of spontaneously occurring miniature synaptic currents (mSCs) is skewed positively at developing Xenopus neuromuscular synapses formed in culture. To test whether the quantal size of nerve-evoked quanta (eSCs) distributes similarly, we compared the amplitude histogram of single quantum eSCs in low external Ca2+ with that of mSCs and found that nerve stimulation preferentially released large quanta. Depolarization of presynaptic terminals by elevating [K+] in the external solution or by direct injection of current through a patch pipette increased the mSC frequency and preferentially, but not exclusively, evoked the release of large quanta, resulting in a second broad peak in the amplitude histogram. Formation of the second peak under these conditions was blocked by the N-type Ca2+ channel blocker, ω-conotoxin GVIA. In contrast, when the mSC frequency was elevated by thapsigargin- or caffeine-induced mobilization of internal Ca2+, formation of the second peak did not occur. We conclude that the second peak in the amplitude histogram is generated by Ca2+ influx through N-type Ca2+ channels, causing a local elevation of internal Ca2+. The mSC amplitude in the positively skewed portion of the histogram varied over a wide range. A competitive blocker of acetylcholine (ACh) receptors, d-tubocurarine, reduced the amplitude of smaller mSCs in this range relatively more than that of larger mSCs, suggesting that this variation in the mSC amplitude is due to variable amounts of ACh released from synaptic vesicles. We suggest that Ca2+ influx through N-type Ca2+ channels preferentially induces release of vesicles with large ACh content.

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