scholarly journals Activity-dependent bulk endocytosis proteome reveals a key presynaptic role for the monomeric GTPase Rab11

2018 ◽  
Vol 115 (43) ◽  
pp. E10177-E10186 ◽  
Author(s):  
A. C. Kokotos ◽  
J. Peltier ◽  
E. C. Davenport ◽  
M. Trost ◽  
M. A. Cousin
Keyword(s):  
Physiological Role ◽  
Bioinformatic Analysis ◽  
Subcellular Fractionation ◽  
Dominant Mode ◽  
High Frequency Stimulation ◽  
Rab Gtpases ◽  
Subsequent Investigation ◽  
Presynaptic Function ◽  
Core Proteome ◽  
Activity Dependent

Activity-dependent bulk endocytosis (ADBE) is the dominant mode of synaptic vesicle endocytosis during high-frequency stimulation, suggesting it should play key roles in neurotransmission during periods of intense neuronal activity. However, efforts in elucidating the physiological role of ADBE have been hampered by the lack of identified molecules which are unique to this endocytosis mode. To address this, we performed proteomic analysis on purified bulk endosomes, which are a key organelle in ADBE. Bulk endosomes were enriched via two independent approaches, a classical subcellular fractionation method and isolation via magnetic nanoparticles. There was a 77% overlap in proteins identified via the two protocols, and these molecules formed the ADBE core proteome. Bioinformatic analysis revealed a strong enrichment in cell adhesion and cytoskeletal and signaling molecules, in addition to expected synaptic and trafficking proteins. Network analysis identified Rab GTPases as a central hub within the ADBE proteome. Subsequent investigation of a subset of these Rabs revealed that Rab11 both facilitated ADBE and accelerated clathrin-mediated endocytosis. These findings suggest that the ADBE proteome will provide a rich resource for the future study of presynaptic function, and identify Rab11 as a regulator of presynaptic function.

scholarly journals Roles for α-Synuclein in Gene Expression

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1166
Author(s):  
Mahalakshmi Somayaji ◽  
Zina Lanseur ◽  
Se Joon Choi ◽  
David Sulzer ◽  
Eugene V. Mosharov
Keyword(s):  
Gene Expression ◽  
Physiological Role ◽  
Function Mechanism ◽  
Normal Functions ◽  
Presynaptic Function ◽  
Dependent Signal ◽  
Expression Pathways ◽  
Cellular Compartments ◽  
Activity Dependent ◽  
Familial Parkinson’S Disease

α-Synuclein (α-Syn) is a small cytosolic protein associated with a range of cellular compartments, including synaptic vesicles, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to its physiological role in regulating presynaptic function, the protein plays a central role in both sporadic and familial Parkinson’s disease (PD) via a gain-of-function mechanism. Because of this, several recent strategies propose to decrease α-Syn levels in PD patients. While these therapies may offer breakthroughs in PD management, the normal functions of α-Syn and potential side effects of its depletion require careful evaluation. Here, we review recent evidence on physiological and pathological roles of α-Syn in regulating activity-dependent signal transduction and gene expression pathways that play fundamental role in synaptic plasticity.

DHA supplementation enhances high-frequency, stimulation-induced synaptic transmission in mouse hippocampus

2012 ◽  
Vol 37 (5) ◽  
pp. 880-887 ◽  
Author(s):  
Steve Connor ◽  
Gustavo Tenorio ◽  
Michael Tom Clandinin ◽  
Yves Sauvé
Keyword(s):  
Synaptic Transmission ◽  
High Frequency ◽  
Control Group ◽  
High Frequency Stimulation ◽  
Spatial Learning And Memory ◽  
Mouse Hippocampus ◽  
Spatial Memories ◽  
Frequency Stimulation ◽  
Activity Dependent ◽  
Synaptic Responses

While some studies on dietary supplementation with docosahexaenoic acid (DHA, 22:6n-3) have reported a beneficial effect on memory as a function of age, others have failed to find any effect. To clarify this issue, we sought to determine whether supplementing mice with a DHA-enriched diet could alter the ability of synapses to undergo activity-dependent changes in the hippocampus, a brain structure involved in forming new spatial memories. We found that DHA was increased by 29% ± 5% (mean ± SE) in the hippocampus for the supplemented (DHA+) versus nonsupplemented (control) group (n = 5 mice per group; p < 0.05). Such DHA elevation was associated with enhanced synaptic transmission (p < 0.05) as assessed by application of a high-frequency electrical stimulation protocol (100 Hz stimulation, which induced transient (<2 h) increases in synaptic strength) to slices from DHA+ (n = 4 mice) hippocampi when compared with controls (n = 4 mice). Increased synaptic responses were evident 60 min poststimulation. These results suggest that dietary DHA supplementation facilitates synaptic plasticity following brief high-frequency stimulation. This increase in synaptic transmission might provide a physiological correlation for the improved spatial learning and memory observed following DHA supplementation.

Increased nuclear translocation of catalytically active PKC-ζ during mouse colonocyte hyperproliferation

2000 ◽  
Vol 279 (1) ◽  
pp. G223-G237 ◽  
Author(s):  
Shahid Umar ◽  
Joseph H. Sellin ◽  
Andrew P. Morris
Keyword(s):  
Kinase Activity ◽  
Nuclear Translocation ◽  
Physiological Role ◽  
Subcellular Fractionation ◽  
Nuclear Antigen ◽  
Nuclear Staining ◽  
Catalytically Active ◽  
Pkc Ζ

Protein kinase (PK) C-ζ is implicated in the control of colonic epithelial cell proliferation in vitro. However, less is known about its physiological role in vivo. Using the transmissible murine colonic hyperplasia (TMCH) model, we determined its expression, subcellular localization, and kinase activity during native crypt hyperproliferation. Enhanced mitosis was associated with increased cellular 72-kDa holoenzyme (PKC-ζ, 3.2-fold), 48-kDa catalytic subunit (PKM-ζ, 3- to 9-fold), and 24-kDa membrane-bound fragment (Mf-ζ, >10-fold) expression. Both PKC-ζ and PKM-ζ exhibited intrinsic kinase activity, and substrate phosphorylation increased 4.5-fold. No change in cellular PKC-ι/PKM-ι expression occurred. The subcellular distribution of immunoreactive PKC-ζ changed significantly: neck cells lost their basal subcellular pole filamentous staining, whereas proliferating cell nuclear antigen-positive cells exhibited elevated cytoplasmic, lateral membrane, and nuclear staining. Subcellular fractionation revealed increased PKC-ζ and PKM-ζ expression and activity within nuclei, which preferentially accumulated PKM-ζ. These results suggest separate cellular and nuclear roles, respectively, for PKC-ζ in quiescent and mitotically active colonocytes. PKM-ζ may specifically act as a modulator of proliferation during TMCH.

scholarly journals Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity in Drosophila

2016 ◽  
Author(s):  
Matthew C. W. Oswald ◽  
Paul S. Brooks ◽  
Maarten F. Zwart ◽  
Amrita Mukherjee ◽  
Ryan J. H. West ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Structural Changes ◽  
Second Messengers ◽  
Physiological Role ◽  
Reactive Oxygen ◽  
Structural Plasticity ◽  
Activity Level ◽  
Oxygen Species ◽  
Network Output ◽  
Activity Dependent

AbstractNeurons are inherently plastic, adjusting their structure, connectivity and excitability in response to changes in activity. How neurons sense changes in their activity level and then transduce these to structural changes remains to be fully elucidated. Working with the Drosophila larval locomotor network, we show that neurons use reactive oxygen species (ROS), metabolic byproducts, to monitor their activity. ROS signals are both necessary and sufficient for activity-dependent structural adjustments of both pre- and postsynaptic terminals and for network output, as measured by larval crawling behavior. We find the highly conserved Parkinson’s disease-linked protein DJ-1ß acts as a redox sensor in neurons where it regulates pre- and postsynaptic structural plasticity, in part via modulation of the PTEN-PI3Kinase pathway. Neuronal ROS thus play an important physiological role as second messengers required for neuronal and network tuning, whose dysregulation in the ageing brain and under neurodegenerative conditions may contribute to synaptic dysfunction.

scholarly journals Purification and Initial Characterization of the Salmonella enterica PduO ATP:Cob(I)alamin Adenosyltransferase

2004 ◽  
Vol 186 (23) ◽  
pp. 7881-7887 ◽  
Author(s):  
Celeste L. V. Johnson ◽  
Marian L. Buszko ◽  
Thomas A. Bobik
Keyword(s):  
Escherichia Coli ◽  
Salmonella Enterica ◽  
Physiological Role ◽  
Kinetic Studies ◽  
Bioinformatic Analysis ◽  
Biochemical Properties ◽  
Terminal Domain ◽  
Apparent Homogeneity ◽  
Measurable Activity ◽  
Coenzyme B

ABSTRACT The PduO enzyme of Salmonella enterica is an ATP:cob(I)alamin adenosyltransferase that catalyzes the final step in the conversion of vitamin B12 to coenzyme B12. The primary physiological role of this enzyme is to support coenzyme B12-dependent 1,2-propanediol degradation, and bioinformatic analysis has indicated that it has two domains. Here the PduO adenosyltransferase was produced in Escherichia coli, solubilized from inclusion bodies, purified to apparent homogeneity, and partially characterized biochemically. The Km values of PduO for ATP and cob(I)alamin were 19.8 and 4.5 μM, respectively, and the enzyme V max was 243 nmol min−1 mg of protein−1. Further investigations showed that PduO was active with ATP and partially active with deoxy-ATP, but lacked measurable activity with other nucleotides. 31P nuclear magnetic resonance established that triphosphate was a product of the PduO reaction, and kinetic studies indicated a ternary complex mechanism. A series of truncated versions of the PduO protein were produced in Escherichia coli, partially purified, and used to show that adenosyltransferase activity is associated with the N-terminal domain. The N-terminal domain was purified to near homogeneity and shown to have biochemical properties and kinetic constants similar to those of the full-length enzyme. This indicated that the C-terminal domain was not directly involved in catalysis or substrate binding and may have another role.

scholarly journals Activity-Dependent Activation of TrkB Neurotrophin Receptors in the Adult CNS

1999 ◽  
Vol 6 (3) ◽  
pp. 216-231 ◽  
Author(s):  
Raquel Aloyz ◽  
James P. Fawcett ◽  
David R. Kaplan ◽  
Richard A. Murphy ◽  
Freda D. Miller
Keyword(s):  
Cortical Neurons ◽  
Subcellular Fractionation ◽  
Neurotrophin Receptors ◽  
Noradrenergic Neurons ◽  
Trkb Receptors ◽  
Transient Activation ◽  
Pharmacological Blockade ◽  
Fast Activation ◽  
Rapid Activation ◽  
Activity Dependent

In this paper we have investigated the hypothesis that neural activity causes rapid activation of TrkB neurotrophin receptors in the adult mammalian CNS. These studies demonstrate that kainic acid-induced seizures led to a rapid and transient activation of TrkB receptors in the cortex. Subcellular fractionation demonstrated that these activated Trk receptors were preferentially enriched in the synaptosomal membrane fraction that also contained postsynaptic glutamate receptors. The fast activation of synaptic TrkB receptors could be duplicated in isolated cortical synaptosomes with KCl, presumably as a consequence of depolarization-induced BDNF release. Importantly, TrkB activation was also observed following pharmacological activation of brain-stem noradrenergic neurons, which synthesize and anterogradely transport BDNF; treatment with yohimbine led to activation of cortical TrkB receptors within 30 min. Pharmacological blockade of the postsynaptic α1-adrenergic receptors with prazosin only partially inhibited this effect, suggesting that the TrkB activation was partially due to a direct effect on postsynaptic cortical neurons. Together, these data support the hypothesis that activity causes release of BDNF from presynaptic terminals, resulting in a rapid activation of postsynaptic TrkB receptors. This activity-dependent TrkB activation could play a major role in morphological growth and remodelling in both the developing and mature nervous systems.

Activity-Dependent Release of Adenosine Contributes to Short-Term Depression at CA3-CA1 Synapses in Rat Hippocampus

2003 ◽  
Vol 89 (1) ◽  
pp. 22-26 ◽  
Author(s):  
Darrin H. Brager ◽  
Scott M. Thompson
Keyword(s):  
Receptor Antagonist ◽  
High Frequency ◽  
High Frequency Stimulation ◽  
Short Term ◽  
Transport Inhibitor ◽  
Vesicular Release ◽  
Organotypic Slice Cultures ◽  
Adenosine Transport ◽  
Frequency Stimulation ◽  
Activity Dependent

High-frequency stimulation results in a transient, presynaptically mediated decrease in synaptic efficacy called short-term depression (STD). Stimulation of Schaffer-collateral axons at 10 Hz for 5 s resulted in approximately 75% depression of excitatory postsynaptic current (EPSC) slope recorded from CA1 cells in rat organotypic slice cultures. An adenosine A1 receptor antagonist decreased the magnitude of STD elicited with 10-Hz stimulation by approximately 30%. The A1 receptor antagonist had no effect on STD elicited with 3-Hz stimulation. The activation of A1 receptors during 10-Hz stimulation was not due to the extracellular conversion of released ATP to adenosine, because block of 5′-ectonucleotidases did not significantly affect STD. The adenosine transport inhibitor dipyridamole did not reduce STD, indicating that adenosine was not released by facilitated transport. We conclude that 10-Hz, but not 3-Hz, stimulation causes the vesicular release of adenosine and the rapid (<3 s) activation of presynaptic inhibitory A1 receptors, which account for approximately 40% of homosynaptic EPSC depression.

scholarly journals Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-d-aspartate receptor activity in hippocampal CA3 circuits

2002 ◽  
Vol 158 (2) ◽  
pp. 215-220 ◽  
Author(s):  
Sayaka Ueno ◽  
Masako Tsukamoto ◽  
Tomoya Hirano ◽  
Kazuya Kikuchi ◽  
Maki K. Yamada ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Mossy Fiber ◽  
Hippocampal Slices ◽  
Physiological Role ◽  
Chelating Agent ◽  
Stratum Radiatum ◽  
High Frequency Stimulation ◽  
Dependent Manner ◽  
Synaptic Terminals ◽  
Stratum Lucidum

Although Zn2+ is contained in large amounts in the synaptic terminals of hippocampal mossy fibers (MFs), its physiological role in synaptic transmission is poorly understood. By using the newly developed high-sensitivity Zn2+ indicator ZnAF-2, the spatiotemporal dynamics of Zn2+ was monitored in rat hippocampal slices. When high-frequency stimulation was delivered to the MFs, the concentration of extracellular Zn2+ was immediately elevated in the stratum lucidum, followed by a mild increase in the stratum radiatum adjacent to the stratum lucidum, but not in the distal area of stratum radiatum. The Zn2+ increase was insensitive to a non–N-methyl-d-aspartate (NMDA) receptor antagonist but was efficiently attenuated by tetrodotoxin or Ca2+-free medium, suggesting that Zn2+ is released by MF synaptic terminals in an activity-dependent manner, and thereafter diffuses extracellularly into the neighboring stratum radiatum. Electrophysiological analyses revealed that NMDA receptor–mediated synaptic responses in CA3 proximal stratum radiatum were inhibited in the immediate aftermath of MF activation and that this inhibition was no longer observed in the presence of a Zn2+-chelating agent. Thus, Zn2+ serves as a spatiotemporal mediator in imprinting the history of MF activity in contiguous hippocampal networks. We predict herein a novel form of metaplasticity, i.e., an experience-dependent non-Hebbian modulation of synaptic plasticity.

Impact of Time-Dependent Changes in Spine Density and Spine Shape on the Input-Output Properties of a Dendritic Branch: A Computational Study

2005 ◽  
Vol 93 (4) ◽  
pp. 2073-2089 ◽  
Author(s):  
D. W. Verzi ◽  
M. B. Rheuben ◽  
S. M. Baer
Keyword(s):  
Computational Study ◽  
Long Term Potentiation ◽  
Synaptic Activity ◽  
High Frequency Stimulation ◽  
Spine Density ◽  
Dendritic Branch ◽  
Input Output ◽  
Stem Resistance ◽  
Rate Of Increase ◽  
Activity Dependent

Populations of dendritic spines can change in number and shape quite rapidly as a result of synaptic activity. Here, we explore the consequences of such changes on the input–output properties of a dendritic branch. We consider two models: one for activity-dependent spine densities and the other for calcium-mediated spine-stem restructuring. In the activity-dependent density model we find that for repetitive synaptic input to passive spines, changes in spine density remain local to the input site. For excitable spines, the spine density increases both inside and outside the input region. When the spine stem resistances are relatively high, the transition to higher dendritic output is abrupt; when low, the rate of increase is gradual and resembles long-term potentiation. In the second model, spine density is held constant, but the stem dimensions are allowed to change as a result of stimulation-induced calcium influxes. The model is formulated so that a moderate amount of synaptic activation results in spine stem elongation, whereas high levels of activation result in stem shortening. Under these conditions, passive spines receiving modest stimulation progressively increase their spine stem resistance and head potentials, but little change occurs in the dendritic output. For excitable spines, modest stimulation frequencies cause a lengthening of both stimulated and neighboring spines and the stimulus eventually propagates. High-frequency stimulation that causes spines to shorten in the stimulated region decreases the amplitude of the dendritic output slightly or drastically, depending on initial spine densities and stem resistances.

Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain

2006 ◽  
Vol 34 (4) ◽  
pp. 600-604 ◽  
Author(s):  
J. Soulé ◽  
E. Messaoudi ◽  
C.R. Bramham
Keyword(s):  
Gene Expression ◽  
Neurotrophic Factor ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Brain Derived Neurotrophic Factor ◽  
Adult Brain ◽  
Memory Storage ◽  
Early Gene ◽  
High Frequency Stimulation ◽  
Activity Dependent

Interest in BDNF (brain-derived neurotrophic factor) as an activity-dependent modulator of neuronal structure and function in the adult brain has intensified in recent years. Localization of BDNF and its receptor tyrosine kinase TrkB (tropomyosin receptor kinase B) to glutamate synapses makes this system attractive as a dynamic, activity-dependent regulator of excitatory transmission and synaptic plasticity in the adult brain. Development of stable LTP (long-term potentiation) in response to high-frequency stimulation requires new gene expression and protein synthesis, a process referred to as synaptic consolidation. Several lines of evidence have implicated endogenous BDNF–TrkB signalling in synaptic consolidation. This mini-review emphasizes new insights into the molecular mechanisms underlying this process. The immediate early gene Arc (activity-regulated cytoskeleton-associated protein) is strongly induced and transported to dendritic processes after LTP induction in the dentate gyrus in live rats. Recent work suggests that sustained synthesis of Arc during a surprisingly protracted time-window is required for hyperphosphorylation of actin-depolymerizing factor/cofilin and local expansion of the actin cytoskeleton in vivo. Moreover, this process of Arc-dependent synaptic consolidation is activated in response to brief infusion of BDNF. Microarray expression profiling has also revealed a panel of BDNF-regulated genes that may co-operate with Arc during LTP maintenance. In addition to regulating gene expression, BDNF signalling modulates the fine localization and biochemical activation of the translation machinery. By modulating the spatial and temporal translation of newly induced (Arc) and constitutively expressed mRNA in neuronal dendrites, BDNF may effectively control the window of synaptic consolidation. These findings have implications for mechanisms of memory storage and mood control.

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