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.

scholarly journals Normal Biogenesis and Cycling of Empty Synaptic Vesicles in Dopamine Neurons of Vesicular Monoamine Transporter 2 Knockout Mice

2005 ◽  
Vol 16 (1) ◽  
pp. 306-315 ◽  
Author(s):  
Benjamin G. Croft ◽  
Gabriel D. Fortin ◽  
Amadou T. Corera ◽  
Robert H. Edwards ◽  
Alain Beaudet ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Knockout Mice ◽  
Synaptic Vesicles ◽  
Dopamine Neurons ◽  
Vesicular Monoamine Transporter ◽  
Wild Type ◽  
Monoamine Transporter ◽  
Vesicle Biogenesis ◽  
And Function ◽  
Activity Dependent

The neuronal isoform of vesicular monoamine transporter, VMAT2, is responsible for packaging dopamine and other monoamines into synaptic vesicles and thereby plays an essential role in dopamine neurotransmission. Dopamine neurons in mice lacking VMAT2 are unable to store or release dopamine from their synaptic vesicles. To determine how VMAT2-mediated filling influences synaptic vesicle morphology and function, we examined dopamine terminals from VMAT2 knockout mice. In contrast to the abnormalities reported in glutamatergic terminals of mice lacking VGLUT1, the corresponding vesicular transporter for glutamate, we found that the ultrastructure of dopamine terminals and synaptic vesicles in VMAT2 knockout mice were indistinguishable from wild type. Using the activity-dependent dyes FM1-43 and FM2-10, we also found that synaptic vesicles in dopamine neurons lacking VMAT2 undergo endocytosis and exocytosis with kinetics identical to those seen in wild-type neurons. Together, these results demonstrate that dopamine synaptic vesicle biogenesis and cycling are independent of vesicle filling with transmitter. By demonstrating that such empty synaptic vesicles can cycle at the nerve terminal, our study suggests that physiological changes in VMAT2 levels or trafficking at the synapse may regulate dopamine release by altering the ratio of fillable-to-empty synaptic vesicles, as both continue to cycle in response to neural activity.

scholarly journals The Phosphoprotein Synapsin Ia Regulates the Kinetics of Dense-Core Vesicle Release

2021 ◽  
Vol 41 (13) ◽  
pp. 2828-2841
Author(s):  
Hui-Ju Yang ◽  
Pin-Chun Chen ◽  
Chien-Ting Huang ◽  
Tzu-Lin Cheng ◽  
Sheng-Ping Hsu ◽  
...  
Keyword(s):  
Dense Core ◽  
Dense Core Vesicle ◽  
Vesicle Release ◽  
Kinetics Of

scholarly journals Dense Core Vesicle Release: Controlling the Where as Well as the When

Genetics ◽  
2014 ◽  
Vol 196 (3) ◽  
pp. 601-604 ◽  
Author(s):  
Stephen Nurrish
Keyword(s):  
Dense Core ◽  
Dense Core Vesicle ◽  
Vesicle Release

scholarly journals Disruption of the Transmembrane Dense Core Vesicle Proteins IA-2 and IA-2β Causes Female Infertility

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 811-815 ◽  
Author(s):  
Atsutaka Kubosaki ◽  
Shinichiro Nakamura ◽  
Anne Clark ◽  
John F. Morris ◽  
Abner L. Notkins
Keyword(s):  
Present Report ◽  
Female Infertility ◽  
Neuroendocrine Cells ◽  
Dense Core ◽  
Structural Proteins ◽  
Corpora Lutea ◽  
Dense Core Vesicle ◽  
Wild Type ◽  
Double Knockout ◽  
Female Mice

Female infertility is a worldwide problem affecting 10–15% of the population. The cause of the infertility in many cases is not known. In the present report, we demonstrate that alterations in two transmembrane structural proteins, IA-2 and IA-2β, located in dense core secretory vesicles (DCV) of many endocrine and neuroendocrine cells, can result in female infertility. IA-2 and IA-2β are best known as major autoantigens in type 1 diabetes, but their normal function has remained an enigma. Recently we showed in mice that deletion of IA-2 and/or IA-2β results in impaired insulin secretion and glucose intolerance. We now report that double knockout (DKO), but not single knockout, female mice are essentially infertile. Vaginal smears showed a totally abnormal estrous cycle, and examination of the ovaries revealed normal-appearing oocytes but the absence of corpora lutea. The LH surge that is required for ovulation occurred in wild-type mice but not in DKO mice. Additional studies showed that the LH level in the pituitary of DKO female mice was decreased compared with wild-type mice. Treatment of DKO females with gonadotropins restored corpora lutea formation. In contrast to DKO female mice, DKO male mice were fertile and LH levels in the serum and pituitary were within the normal range. From these studies we conclude that the DCV proteins, IA-2 and IA-2β, play an important role in LH secretion and that alterations in structural proteins of DCV can result in female infertility.

scholarly journals Activity-Dependent Regulation of the K/Cl Transporter KCC2 Membrane Diffusion, Clustering, and Function in Hippocampal Neurons

2013 ◽  
Vol 33 (39) ◽  
pp. 15488-15503 ◽  
Author(s):  
Ingrid Chamma ◽  
Martin Heubl ◽  
Quentin Chevy ◽  
Marianne Renner ◽  
Imane Moutkine ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Membrane Diffusion ◽  
And Function ◽  
Activity Dependent

scholarly journals Activation of intracellular transport by relieving KIF1C autoinhibition

2018 ◽  
Author(s):  
Nida Siddiqui ◽  
Alice Bachmann ◽  
Alexander James Zwetsloot ◽  
Hamdi Hussain ◽  
Daniel Roth ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Intracellular Transport ◽  
Tyrosine Phosphatase ◽  
Dense Core ◽  
Release Mechanism ◽  
Dense Core Vesicle ◽  
Ferm Domain ◽  
Cargo Transport ◽  
Binding Surface

AbstractThe kinesin-3 KIF1C is a fast organelle transporter implicated in the transport of dense core vesicles in neurons and the delivery of integrins to cell adhesions. Here we report the mechanisms of autoinhibition and release that control the activity of KIF1C. We show that the microtubule binding surface of KIF1C motor domain interacts with its stalk and that these autoinhibitory interactions are released upon binding of protein tyrosine phosphatase PTPN21. The FERM domain of PTPN21 stimulates dense core vesicle transport in primary hippocampal neurons and rescues integrin trafficking in KIF1C-depleted cells. In vitro, human full-length KIF1C is a processive, plus-end directed motor. Its landing rate onto microtubules increases in the presence of either PTPN21 FERM domain or the cargo adapter Hook3 that binds the same region of KIF1C tail. This autoinhibition release mechanism allows cargo-activated transport and might enable motors to participate in bidirectional cargo transport without undertaking a tug-of-war.

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.

scholarly journals UNC-108/RAB-2 and its effector RIC-19 are involved in dense core vesicle maturation in Caenorhabditis elegans

2009 ◽  
Vol 186 (6) ◽  
pp. 897-914 ◽  
Author(s):  
Marija Sumakovic ◽  
Jan Hegermann ◽  
Ling Luo ◽  
Steven J. Husson ◽  
Katrin Schwarze ◽  
...  
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Vesicular Trafficking ◽  
Dense Core ◽  
Dense Core Vesicle ◽  
Vesicle Release ◽  
C Elegans ◽  
Golgi Membranes ◽  
Human Diabetes ◽  
Synaptic Vesicle Release

Small guanosine triphosphatases of the Rab family regulate intracellular vesicular trafficking. Rab2 is highly expressed in the nervous system, yet its function in neurons is unknown. In Caenorhabditis elegans, unc-108/rab-2 mutants have been isolated based on their locomotory defects. We show that the locomotion defects of rab-2 mutants are not caused by defects in synaptic vesicle release but by defects in dense core vesicle (DCV) signaling. DCVs in rab-2 mutants are often enlarged and heterogeneous in size; however, their number and distribution are not affected. This implicates Rab2 in the biogenesis of DCVs at the Golgi complex. We demonstrate that Rab2 is required to prevent DCV cargo from inappropriately entering late endosomal compartments during DCV maturation. Finally, we show that RIC-19, the C. elegans orthologue of the human diabetes autoantigen ICA69, is also involved in DCV maturation and is recruited to Golgi membranes by activated RAB-2. Thus, we propose that RAB-2 and its effector RIC-19 are required for neuronal DCV maturation.

scholarly journals The synaptic vesicle cycle: a single vesicle budding step involving clathrin and dynamin.

1996 ◽  
Vol 133 (6) ◽  
pp. 1237-1250 ◽  
Author(s):  
K Takei ◽  
O Mundigl ◽  
L Daniell ◽  
P De Camilli
Keyword(s):  
Plasma Membrane ◽  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Coated Vesicles ◽  
Coated Vesicle ◽  
Nerve Terminals ◽  
Vesicle Budding ◽  
Vesicle Cycle ◽  
Single Vesicle

Strong evidence implicates clathrin-coated vesicles and endosome-like vacuoles in the reformation of synaptic vesicles after exocytosis, and it is generally assumed that these vacuoles represent a traffic station downstream from clathrin-coated vesicles. To gain insight into the mechanisms of synaptic vesicle budding from endosome-like intermediates, lysed nerve terminals and nerve terminal membrane subfractions were examined by EM after incubations with GTP gamma S. Numerous clathrin-coated budding intermediates that were positive for AP2 and AP180 immunoreactivity and often collared by a dynamin ring were seen. These were present not only on the plasma membrane (Takei, K., P.S. McPherson, S.L.Schmid, and P. De Camilli. 1995. Nature (Lond.). 374:186-190), but also on internal vacuoles. The lumen of these vacuoles retained extracellular tracers and was therefore functionally segregated from the extracellular medium, although narrow connections between their membranes and the plasmalemma were sometimes visible by serial sectioning. Similar observations were made in intact cultured hippocampal neurons exposed to high K+ stimulation. Coated vesicle buds were generally in the same size range of synaptic vesicles and positive for the synaptic vesicle protein synaptotagmin. Based on these results, we suggest that endosome-like intermediates of nerve terminals originate by bulk uptake of the plasma membrane and that clathrin- and dynamin-mediated budding takes place in parallel from the plasmalemma and from these internal membranes. We propose a synaptic vesicle recycling model that involves a single vesicle budding step mediated by clathrin and dynamin.

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