scholarly journals Roles for the Endoplasmic Reticulum in Regulation of Neuronal Calcium Homeostasis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1232 ◽  
Author(s):  
Nicholas E. Karagas ◽  
Kartik Venkatachalam
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurological Diseases ◽  
Neuronal Function ◽  
Vesicle Release ◽  
Form And Function ◽  
And Function ◽  
Synaptic Vesicle Release ◽  
Activity Dependent ◽  
Ca2 Channels ◽  
Neuronal Compartments

By influencing Ca2+ homeostasis in spatially and architecturally distinct neuronal compartments, the endoplasmic reticulum (ER) illustrates the notion that form and function are intimately related. The contribution of ER to neuronal Ca2+ homeostasis is attributed to the organelle being the largest reservoir of intracellular Ca2+ and having a high density of Ca2+ channels and transporters. As such, ER Ca2+ has incontrovertible roles in the regulation of axodendritic growth and morphology, synaptic vesicle release, and neurotransmission activity dependent gene expression, synaptic plasticity, and mitochondrial bioenergetics. Not surprisingly, many neurological diseases arise from ER Ca2+ dyshomeostasis, either directly due to alterations in ER resident proteins, or indirectly via processes that are coupled to the regulators of ER Ca2+ dynamics. In this review, we describe the mechanisms involved in the establishment of ER Ca2+ homeostasis in neurons. We elaborate upon how changes in the spatiotemporal dynamics of Ca2+ exchange between the ER and other organelles sculpt neuronal function and provide examples that demonstrate the involvement of ER Ca2+ dyshomeostasis in a range of neurological and neurodegenerative diseases.

Ca2+ channels: diversity of form and function

1992 ◽  
Vol 2 (3) ◽  
pp. 247-253 ◽  
Author(s):  
Terry P. Snutch ◽  
Peter B. Reiner
Keyword(s):  
Form And Function ◽  
And Function ◽  
Ca2 Channels

scholarly journals Nutrient limitation affects presynaptic structures through dissociable Bassoon autophagic degradation and impaired vesicle release

2018 ◽  
Vol 38 (11) ◽  
pp. 1924-1939 ◽  
Author(s):  
Alberto Catanese ◽  
Débora Garrido ◽  
Paul Walther ◽  
Francesco Roselli ◽  
Tobias M Boeckers
Keyword(s):  
Protein Degradation ◽  
Nutrient Limitation ◽  
Synaptic Activity ◽  
Neuronal Function ◽  
Vesicle Release ◽  
Vesicle Pools ◽  
Synaptic Structure ◽  
Highly Sensitive ◽  
Autophagic Degradation ◽  
And Function

Acute mismatch between metabolic requirements of neurons and nutrients/growth factors availability characterizes several neurological conditions such as traumatic brain injury, stroke and hypoglycemia. Although the effects of this mismatch have been investigated at cell biological level, the effects on synaptic structure and function are less clear. Since synaptic activity is the most energy-demanding neuronal function and it is directly linked to neuronal networks functionality, we have explored whether nutrient limitation (NL) affects the ultrastructure, function and composition of pre and postsynaptic terminals. We show that upon NL, presynaptic terminals show disorganized vesicle pools and reduced levels of the active zone protein Bassoon (but not of Piccolo). Moreover, NL triggers an impaired vesicle release, which is reversed by re-administration of glucose but not by the blockade of autophagic or proteasomal protein degradation. This reveals a dissociable correlation between presynaptic architecture and vesicle release, since restoring vesicle fusion does not necessarily depend from the rescue of Bassoon levels. Thus, our data show that the presynaptic compartment is highly sensitive to NL and the rescue of presynaptic function requires re-establishment of the metabolic supply rather than preventing local protein degradation.

scholarly journals Munc13 controls the location and efficiency of dense-core vesicle release in neurons

2012 ◽  
Vol 199 (6) ◽  
pp. 883-891 ◽  
Author(s):  
Rhea van de Bospoort ◽  
Margherita Farina ◽  
Sabine K. Schmitz ◽  
Arthur de Jong ◽  
Heidi de Wit ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Dense Core ◽  
Dense Core Vesicle ◽  
Wild Type ◽  
Vesicle Release ◽  
Prolonged Stimulation ◽  
And Function ◽  
Activity Dependent ◽  
Single Vesicle

Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2–null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically.

Ca2+ channels: diversity of form and function

1992 ◽  
Vol 2 (6) ◽  
pp. 292 ◽  
Author(s):  
Terry P Snutch ◽  
Peter B Reiner
Keyword(s):  
Form And Function ◽  
And Function ◽  
Ca2 Channels

scholarly journals Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

2016 ◽  
Author(s):  
Belgin Yalçın ◽  
Lu Zhao ◽  
Martin Stofanko ◽  
Niamh C O’Sullivan ◽  
Zi Han Kang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Peripheral Nerves ◽  
Hereditary Spastic Paraplegia ◽  
Membrane Curvature ◽  
Degenerative Disease ◽  
Spastic Paraplegia ◽  
Partial Loss ◽  
Form And Function ◽  
Rough Er ◽  
And Function

AbstractAxons contain an endoplasmic reticulum (ER) network that is largely smooth and tubular, thought to be continuous with ER throughout the neuron, and distinct in form and function from rough ER; the mechanisms that form this continuous network in axons are not well understood. Mutations affecting proteins of the reticulon or REEP families, which contain intramembrane hairpin domains that can model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). Here, we show that these proteins are required for modeling the axonal ER network in Drosophila. Loss of reticulon or REEP proteins can lead to expansion of ER sheets, and to partial loss of ER from distal motor axons. Ultrastructural analysis reveals an extensive ER network in every axon of peripheral nerves, which is reduced in larvae that lack reticulon and REEP proteins, with defects including larger and fewer tubules, and occasional gaps in the ER network, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of the axonal ER network, suggesting an important role for ER modeling in axon maintenance and function.

scholarly journals Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

2020 ◽  
Author(s):  
Zoe Butti ◽  
Jean Giacomotto ◽  
Kessen (Shunmoogum) Patten
Keyword(s):  
Synaptic Vesicle ◽  
Neuromuscular Junctions ◽  
Loss Of Function ◽  
Vesicle Release ◽  
Hexanucleotide Repeat ◽  
Presynaptic Vesicle ◽  
C9orf72 Gene ◽  
Reduced Rate ◽  
And Function ◽  
Synaptic Vesicle Release

Abstract A hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). Reduced levels of C9orf72 mRNA and protein have been found in ALS/FTD patients, but the role of this protein in disease pathogenesis is still poorly understood. Here, we report the generation and characterization of a stable C9orf72 loss-of-function (LOF) model in the zebrafish. We show that reduced C9orf72 function leads to motor defects, muscle atrophy, motor neuron loss and mortality in early larval and adult stages. Analysis of the structure and function of the neuromuscular junctions (NMJs) of the larvae, reveal a significant reduction in the number of presynaptic and postsynaptic structures and an impaired release of quantal synaptic vesicles at the NMJ. Strikingly, we demonstrate a downregulation of SV2a upon C9orf72-LOF and a reduced rate of synaptic vesicle cycling. Furthermore, we show a reduced number and size of Rab3a-postive synaptic puncta at NMJs. Altogether, these results reveal a key function for C9orf72 in the control of presynaptic vesicle trafficking and release at the zebrafish larval NMJ. Our study demonstrates a novel role for C9orf72 in ALS/FTD pathogenesis, where it regulates synaptic vesicle release and neuromuscular functions.

scholarly journals Control of synaptic vesicle release probability via VAMP4 targeting to endolysosomes

2021 ◽  
Vol 7 (18) ◽  
pp. eabf3873
Author(s):  
Daniela Ivanova ◽  
Katharine L. Dobson ◽  
Akshada Gajbhiye ◽  
Elizabeth C. Davenport ◽  
Daniela Hacker ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Snare Complex ◽  
Release Probability ◽  
Clearing System ◽  
Protein Receptor ◽  
Sensitive Factor ◽  
And Function ◽  
Synaptic Vesicle Release ◽  
And Control ◽  
Activity Dependent

Synaptic vesicle (SV) release probability (Pr), determines the steady state and plastic control of neurotransmitter release. However, how diversity in SV composition arises and regulates the Pr of individual SVs is not understood. We found that modulation of the copy number of the noncanonical vesicular SNARE (soluble N-ethylmaleimide–sensitive factor attachment protein receptor), vesicle-associated membrane protein 4 (VAMP4), on SVs is key for regulating Pr. Mechanistically, this is underpinned by its reduced ability to form an efficient SNARE complex with canonical plasma membrane SNAREs. VAMP4 has unusually high synaptic turnover and is selectively sorted to endolysosomes during activity-dependent bulk endocytosis. Disruption of endolysosomal trafficking and function markedly increased the abundance of VAMP4 in the SV pool and inhibited SV fusion. Together, our results unravel a new mechanism for generating SV heterogeneity and control of Pr through coupling of SV recycling to a major clearing system that regulates protein homeostasis.

scholarly journals Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Zoé Butti ◽  
Yingzhou Edward Pan ◽  
Jean Giacomotto ◽  
Shunmoogum A. Patten
Keyword(s):  
Synaptic Vesicle ◽  
Neuromuscular Junctions ◽  
Loss Of Function ◽  
Vesicle Release ◽  
Hexanucleotide Repeat ◽  
Presynaptic Vesicle ◽  
Hexanucleotide Repeat Expansion ◽  
Reduced Rate ◽  
And Function ◽  
Synaptic Vesicle Release

AbstractThe most common genetic cause of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is a hexanucleotide repeat expansion within the C9orf72 gene. Reduced levels of C9orf72 mRNA and protein have been found in ALS/FTD patients, but the role of this protein in disease pathogenesis is still poorly understood. Here, we report the generation and characterization of a stable C9orf72 loss-of-function (LOF) model in the zebrafish. We show that reduced C9orf72 function leads to motor defects, muscle atrophy, motor neuron loss and mortality in early larval and adult stages. Analysis of the structure and function of the neuromuscular junctions (NMJs) of the larvae, reveal a marked reduction in the number of presynaptic and postsynaptic structures and an impaired release of quantal synaptic vesicles at the NMJ. Strikingly, we demonstrate a downregulation of SV2a upon C9orf72-LOF and a reduced rate of synaptic vesicle cycling. Furthermore, we show a reduced number and size of Rab3a-postive synaptic puncta at NMJs. Altogether, these results reveal a key function for C9orf72 in the control of presynaptic vesicle trafficking and release at the zebrafish larval NMJ. Our study demonstrates an important role for C9orf72 in ALS/FTD pathogenesis, where it regulates synaptic vesicle release and neuromuscular functions.

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