Vesicular Release
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Toxics ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 206
Karl F. W. Foley ◽  
Daniel Barnett ◽  
Deborah A. Cory-Slechta ◽  
Houhui Xia

Arsenic is a well-established carcinogen known to increase mortality, but its effects on the central nervous system are less well understood. Epidemiological studies suggest that early life exposure is associated with learning deficits and behavioral changes. Studies in arsenic-exposed rodents have begun to shed light on potential mechanistic underpinnings, including changes in synaptic transmission and plasticity. However, previous studies relied on extended exposure into adulthood, and little is known about the effect of arsenic exposure in early development. Here, we studied the effects of early developmental arsenic exposure in juvenile mice on synaptic transmission and plasticity in the hippocampus. C57BL/6J females were exposed to arsenic (0, 50 ppb, 36 ppm) via drinking water two weeks prior to mating, with continued exposure throughout gestation and parturition. Electrophysiological recordings were then performed on juvenile offspring prior to weaning. In this paradigm, the offspring are exposed to arsenic indirectly, via the mother. We found that high (36 ppm) and relatively low (50 ppb) arsenic exposure both decreased basal synaptic transmission. A compensatory increase in pre-synaptic vesicular release was only observed in the high-exposure group. These results suggest that indirect, ecologically relevant arsenic exposure in early development impacts hippocampal synaptic transmission and plasticity that could underlie learning deficits reported in epidemiological studies.

eLife ◽  
2021 ◽  
Vol 10 ◽  
Gülçin Vardar ◽  
Andrea Salazar-Lázaro ◽  
Marisa M Brockmann ◽  
Marion Weber-Boyvat ◽  
Sina Zobel ◽  

Syntaxin-1 (STX1) and Munc18-1 are two requisite components of synaptic vesicular release machinery, so much so synaptic transmission cannot proceed in their absence. They form a tight complex through two major binding modes: through STX1's N-peptide and through STX's closed conformation driven by its Habc- domain. However, physiological roles of these two reportedly different binding modes in synapses are still controversial. Here we characterized the roles of STX1's N-peptide, Habc-domain, and open conformation with and without N-peptide deletion using our STX1-null mouse model system and exogenous reintroduction of STX1A mutants. We show, on the contrary to the general view, that the Habc-domain is absolutely required and N-peptide is dispensable for synaptic transmission. However, STX1A's N-peptide plays a regulatory role, particularly in the Ca2+-sensitivity and the short-term plasticity of vesicular release, whereas STX1's open-conformation governs the vesicle fusogenicity. Strikingly, we also show neurotransmitter release still proceeds when the two interaction modes between STX1A and Munc18-1 are presumably intervened, necessitating a refinement of the conceptualization of STX1A-Munc18-1 interaction.

Biology ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 743
Egor A. Turovsky ◽  
Elena G. Varlamova

To date, there are practically no data on the mechanisms of the selenium nanoparticles action on calcium homeostasis, intracellular signaling in cancer cells, and on the relationship of signaling pathways activated by an increase in Ca2+ in the cytosol with the induction of apoptosis, which is of great importance. The study of these mechanisms is important for understanding the cytotoxic effect of selenium nanoparticles and the role of this microelement in the regulation of carcinogenesis. The work is devoted to the study of the role of selenium nanoparticles obtained by laser ablation in the activation of the calcium signaling system and the induction of apoptosis in human glioblastoma cells (A-172 cell line). In this work, it was shown for the first time that the generation of Ca2+ signals in A-172 cells occurs in response to the application of various concentrations of selenium nanoparticles. The intracellular mechanism responsible for the generation of these Ca2+ signals has also been established. It was found that nanoparticles promote the mobilization of Ca2+ ions from the endoplasmic reticulum through the IP3-receptor. This leads to the activation of vesicular release of ATP through connexin hemichannels (Cx43) and paracrine cell activation through purinergic receptors (mainly P2Y). In addition, it was shown that the activation of this signaling pathway is accompanied by an increase in the expression of pro-apoptotic genes and the induction of apoptosis. For the first time, the role of Cx43 in the regulation of apoptosis caused by selenium nanoparticles in glioblastoma cells has been shown. It was found that inhibition of Cx43 leads to a significant suppression of the induction of apoptosis in these cells after 24 h treatment of cells with selenium nanoparticles at a concentration of 5 µg/mL.

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1867
Balázs Sonkodi ◽  
Zsolt Kopa ◽  
Péter Nyirády

Post orgasmic illness syndrome is a rare, mysterious condition with an unknown pathomechanism and uncertain treatment. The symptoms of post orgasmic illness syndrome last about 2–7 days after an ejaculation. The current hypothesis proposes that the primary injury in post orgasmic illness syndrome is an acute compression proprioceptive axonopathy in the muscle spindle, as is suspected in delayed onset muscle soreness. The terminal arbor degeneration-like lesion of delayed onset muscle soreness is theorized to be an acute stress response energy-depleted dysfunctional mitochondria-induced impairment of Piezo2 channels and glutamate vesicular release. The recurring symptoms of post orgasmic illness syndrome after each ejaculation are suggested to be analogous to the repeated bout effect of delayed onset muscle soreness. However, there are differences in the pathomechanism, mostly attributed to the extent of secondary tissue damage and to the extent of spermidine depletion. The spermidine depletion-induced differences are as follows: modulation of the acute stress response, flu-like symptoms, opioid-like withdrawal and enhanced deregulation of the autonomic nervous system. The longitudinal dimension of delayed onset muscle soreness, in the form of post orgasmic illness syndrome and the repeated bout effect, have cognitive and memory consequences, since the primary injury is learning and memory-related.

2021 ◽  
Manindra Bera ◽  
Sathish Ramakrishnan ◽  
Jeff Coleman ◽  
Shyam S Krishnakumar ◽  
James E Rothman

Previously we reported that Synaptotagmin-1 and Complexin synergistically clamp the SNARE assembly process to generate and maintain a pool of docked vesicles that fuse rapidly and synchronously upon Ca2+ influx (Ramakrishnan et al. 2020). Here using the same in vitro single-vesicle fusion assay, we establish the molecular details of the Complexin clamp and its physiological relevance. We find that a delay in fusion kinetics, likely imparted by Synaptotagmin-1, is needed for Complexin to block fusion. Systematic truncation/mutational analyses reveal that continuous alpha-helical accessory-central domains of Complexin are essential for its inhibitory function and specific interaction of the accessory helix with the SNAREpins, analogous to the trans clamping model, enhances this functionality. The c-terminal domain promotes clamping by locally elevating Complexin concentration through interactions with the membrane. Further, we find that Complexin likely contributes to rapid Ca2+-synchronized vesicular release by preventing un-initiated fusion rather than by directly facilitating vesicle fusion.

2021 ◽  
Lihao Ge ◽  
Wonchul Shin ◽  
Ling-Gang Wu

Vesicle fusion is assumed to occur at flat membrane of excitable cells. In live neuroendocrine cells, we visualized vesicle fusion at Ω-shape membrane generated by preceding fusion, termed sequential compound fusion, which may be followed by fusion pore closure, termed compound kiss-and-run. These novel fusion modes contribute to vesicle docking, multi-vesicular release, asynchronous release, and endocytosis. We suggest modifying current models of exo-endocytosis to include these new fusion modes.

2021 ◽  
Philipe Mendonca ◽  
Erica Tagliatti ◽  
Helen Langley ◽  
Dimitrios Kotzadimitriou ◽  
Criseida Zamora-Chimal ◽  

Abstract The balance between fast synchronous and delayed asynchronous release of neurotransmitters has a major role in defining computational properties of neuronal synapses and regulation of neuronal network activity. However, how it is tuned at the single synapse level remains poorly understood. Here, using the fluorescent glutamate sensor SF-iGluSnFR, we image quantal vesicular release in tens to hundreds of individual synaptic outputs from single pyramidal cells with 4 millisecond temporal and 75 nm spatial resolution. We find that the ratio between synchronous and asynchronous synaptic vesicle exocytosis varies extensively among synapses supplied by the same axon, and that and that synchronicity of release is reduced at low release probability synapses. We further demonstrate that asynchronous exocytosis sites are more widely distributed within the release area than synchronous sites. Together, our results reveal a universal relationship between the two major functional properties of synapses – the timing and the probability of neurotransmitter release.

2021 ◽  
Vol 11 (1) ◽  
Kouya Uchino ◽  
Hiroyuki Kawano ◽  
Yasuyoshi Tanaka ◽  
Yuna Adaniya ◽  
Ai Asahara ◽  

AbstractDravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This study investigated the synaptic pathogenesis of this disease in terms of excitatory/inhibitory balance using a mouse model of DS. We show that excitatory postsynaptic currents were similar between Scn1a knock-in neurons (Scn1a+/− neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in Scn1a+/− neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in Scn1a+/− neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca2+ concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a+/− neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. These data suggest that Ca2+ tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms.

2021 ◽  
Edward C Harding ◽  
Wei Ba ◽  
Reesha Zahir ◽  
Xiao Yu ◽  
Raquel Yustos ◽  

When mice are exposed to external warmth, nitric oxide synthase (NOS1) neurons in the median and medial preoptic (MnPO/MPO) hypothalamus induce sleep and concomitant body cooling. However, how these neurons regulate baseline sleep and body temperature is unknown. Using calcium photometry, we show that NOS1 neurons in MnPO/MPO are predominantly NREM active. This is the first instance of a predominantly NREM-active population in the PO area, or to our knowledge, elsewhere in the brain. In addition to releasing nitric oxide, NOS1 neurons in MnPO/MPO can release GABA, glutamate and peptides. We expressed tetanus-toxin light-chain in MnPO/MPO NOS1 cells to reduce vesicular release of transmitters. This induced changes in sleep structure: over 24 hours, mice had less NREM sleep in their dark (active) phase, and more NREM sleep in their light (sleep) phase. REM sleep episodes in the dark phase were longer, and there were fewer REM transitions between other vigilance states. REM sleep had less theta power. Mice with synaptically-blocked MnPO/MPO NOS1 neurons were also warmer. In particular, mice were warmer than control mice at the dark-light transition (ZT0), as well as during the dark phase siesta (ZT16-20), where there is usually a body temperature dip. Also, at this siesta point of cooled body temperature, mice usually have more NREM, but mice with synaptically-blocked MnPO/MPO NOS1 cells showed reduced NREM sleep at this time. Overall, MnPO/MPO NOS1 neurons promote both NREM and REM sleep and contribute to chronically lowering body temperature, particularly at transitions where the mice normally enter NREM sleep.

2021 ◽  
Farzaneh Asadpour ◽  
Xinwei Zhang ◽  
Mohammad Mazloum-Ardakani ◽  
Maysam Mirzaei ◽  
Soodabeh Majdi ◽  

We used liposomes loaded with different monoamines, dopamine (DA) and serotonin (5-HT), to simulate vesicular release and to monitor the dynamics of chemical release from isolated vesicles during vesicle impact electrochemical cytometry (VIEC). The release of DA from liposomes presents a longer release time compared to 5-HT. Modelling the release time showed that DA filled vesicles had a higher percentage of events where the time for the peak fall was better fit to a double exponential (DblExp) decay function, suggesting multiple kinetic steps in the release. By fitting to a desorption-release model, where the transmitters adsorbed to the vesicle membrane, the dissociation rates of DA and 5-HT from liposome membrane were estimated. DA has a lower desorption rate constant, which leads to slower DA release than that observed for 5-HT, whereas there is little difference in pore size. The alteration of vesicular release dynamics due to the interaction between chemical cargo and vesicle membrane lipids provides an important mechanism to regulate vesicular release in chemical and physiological processes. It is highly possible that this introduces a fundamental chemical regulation difference between transmitters during exocytosis.

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