scholarly journals Regulation of Somatodendritic GABAA Receptor Channels in Rat Hippocampal Neurons: Evidence for a Role of the Small GTPase Rac1

2000 ◽  
Vol 20 (18) ◽  
pp. 6743-6751 ◽  
Author(s):  
Dieter K. Meyer ◽  
Claudia Olenik ◽  
Fred Hofmann ◽  
Holger Barth ◽  
Jost Leemhuis ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Hippocampal Neurons ◽  
Small Gtpase

scholarly journals RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

2021 ◽  
Author(s):  
Tal Keren-Kaplan ◽  
Amra Saric ◽  
Saikat Ghosh ◽  
Chad Williamson ◽  
Rui Jia ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Retrograde Transport ◽  
Small Gtpase ◽  
Serum Starvation ◽  
Anterograde Transport ◽  
Fyve Domain ◽  
Axon Development ◽  
Necessary And Sufficient

Abstract The small GTPase ARL8 associates with lysosomes and recruits several effectors that mediate coupling to kinesins for anterograde transport, as well as tethering for eventual fusion with other organelles. Herein we report the identification of the “RUN- and FYVE-domain-containing” proteins RUFY3 and RUFY4 as novel ARL8 effectors that couple lysosomes to dynein-dynactin for retrograde transport. Using various biochemical approaches, we find that RUFY3/4 interact with both GTP-bound ARL8 and dynein-dynactin. In addition, we show that RUFY3/4 are both necessary and sufficient for concentration of lysosomes in the juxtanuclear area of the cell. RUFY3/4 also promote retrograde transport of lysosomes in the axon of hippocampal neurons. The function of RUFY3/4 in retrograde transport is required for juxtanuclear redistribution of lysosomes upon serum starvation or cytoplasmic alkalinization, and may underlie the reported roles of RUFY3/4 in axon development/degeneration, cancer and immunity. These studies thus establish RUFY3/4 as novel ARL8-dependent, dynein-dynactin adaptors, and highlight the role of ARL8 in the regulation of both anterograde and retrograde lysosome transport.  

scholarly journals Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation

2021 ◽  
Vol 22 (7) ◽  
pp. 3787
Author(s):  
Hussam Ibrahim ◽  
Philipp Reus ◽  
Anna Katharina Mundorf ◽  
Anna-Lena Grothoff ◽  
Valerie Rudenko ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Transcriptional Repression ◽  
Small Gtpase ◽  
Main Role ◽  
Interacting Proteins ◽  
Casein Kinase 1 ◽  
Bona Fide ◽  
Kinetics Of

Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock.

scholarly journals RhoA- and Actin-Dependent Functions of Macrophages from the Rodent Cardiac Transplantation Model Perspective -Timing Is the Essence

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 70
Author(s):  
Malgorzata Kloc ◽  
Ahmed Uosef ◽  
Martha Villagran ◽  
Robert Zdanowski ◽  
Jacek Z. Kubiak ◽  
...  
Keyword(s):  
Immune Response ◽  
Circadian Rhythm ◽  
Immune Cells ◽  
Chronic Rejection ◽  
Cardiac Transplantation ◽  
Small Gtpase ◽  
Eukaryotic Cells ◽  
Transplantation Model

The small GTPase RhoA, and its down-stream effector ROCK kinase, and the interacting Rac1 and mTORC2 pathways, are the principal regulators of the actin cytoskeleton and actin-related functions in all eukaryotic cells, including the immune cells. As such, they also regulate the phenotypes and functions of macrophages in the immune response and beyond. Here, we review the results of our and other’s studies on the role of the actin and RhoA pathway in shaping the macrophage functions in general and macrophage immune response during the development of chronic (long term) rejection of allografts in the rodent cardiac transplantation model. We focus on the importance of timing of the macrophage functions in chronic rejection and how the circadian rhythm may affect the anti-chronic rejection therapies.

The role of GABAA receptor biogenesis, structure and function in epilepsy

2006 ◽  
Vol 34 (5) ◽  
pp. 863-867 ◽  
Author(s):  
S. Mizielinska ◽  
S. Greenwood ◽  
C.N. Connolly
Keyword(s):  
Gabaa Receptor ◽  
Structure And Function ◽  
Inhibitory Synapses ◽  
Normal Brain ◽  
Synaptic Targeting ◽  
Acid Type ◽  
Normal Brain Function ◽  
And Function ◽  
The Brain

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (γ-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with α and β subunits being the minimal requirement, and the incorporation of a γ subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.

scholarly journals Epipregnanolone as a Positive Modulator of GABAA Receptor in Rat Cerebellar and Hippocampus Neurons

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 791
Author(s):  
Julia Bukanova ◽  
Elena Solntseva ◽  
Rodion Kondratenko ◽  
Eva Kudova
Keyword(s):  
Gabaa Receptor ◽  
Purkinje Cells ◽  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Patch Clamp Technique ◽  
Dual Effect ◽  
Combined Application ◽  
Gabaa Receptor Antagonist ◽  
Positive Modulator ◽  
Endogenous Steroid

Epipregnanolone (3β-hydroxy-5β-pregnan-20-one, Epi) is an endogenous steroid with important physiological effects and high affinity for GABAA receptors. The effect of Epi on GABA-induced chloride current (IGABA) in native neurons has hardly been studied. In this work, we studied the influence of Epi on the IGABA in the Purkinje cells of rat cerebellum and pyramidal neurons of rat hippocampus with the patch clamp technique. We showed that Epi is a positive modulator of the IGABA with EC50 of 5.7 µM in Purkinje cells and 9.3 µM in hippocampal neurons. Epi-induced potentiation of the IGABA was more potent at low vs. high GABA concentrations. Isopregnanolone (3β-hydroxy-5α-pregnan-20-one, Iso) counteracted Epi, reducing its potentiating effect by 2–2.3 times. Flumazenil, a nonsteroidal GABAA receptor antagonist, does not affect the Epi-induced potentiation. Comparison of the potentiating effects of Epi and allopregnanolone (3α-hydroxy-5α-pregnan-20-one, ALLO) showed that ALLO is, at least, a four times more potent positive modulator than Epi. The combined application of ALLO and Epi showed that the effects of these two steroids are not additive. We conclude that Epi has a dual effect on the IGABA increasing the current in the control solution and decreasing the stimulatory effect of ALLO.

scholarly journals Downregulation of miR-383 reduces depression-like behavior through targeting Wnt family member 2 (Wnt2) in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shanshan Liu ◽  
Qing Liu ◽  
Yanjie Ju ◽  
Lei Liu
Keyword(s):  
Inflammatory Response ◽  
Family Member ◽  
Chronic Stress ◽  
Hippocampal Neurons ◽  
Luciferase Reporter ◽  
Mild Stress ◽  
Neural Injury ◽  
Expression Levels ◽  
Qrt Pcr

AbstractThis study aimed to evaluate the role of miR-383 in the regulation of Wnt-2 signaling in the rat model of chronic stress. The male SD rats with depressive-like behaviors were stimulated with chronic unpredictable mild stress (CUMS) including ice-water swimming for 5 min, food deprivation for 24 h, water deprivation for 24 h, stimulating tail for 1 min, turning night into day, shaking for 15 min (once/s), and wrap restraint (5 min/time) every day for 21 days. The expression levels of miRNAs were detected by qRT-PCR, and the expression levels of Wnt2, depression-impacted proteins (GFAP, BDNF, CREB), brain neurotransmitters (5-HT, NE, DA) and apoptosis-related proteins (Bax and Bcl-2) were evaluated by qRT-PCR and western blot. Bioinformatic analysis and luciferase reporter assay were performed to determine the relationship between miR-383 and Wnt2. Ethological analysis was evaluated by sugar preference test, refuge island test and open field tests. Rescue experiments including knockdown of miR-383, overexpression and silencing of Wnt2 were performed to determine the role of miR-383. High expression levels of miR-383 were observed in the hippocampus of rats submitted to CUMS model. Downregulation of miR-383 significantly inhibited the apoptosis and inflammatory response of hippocampal neurons, and increased the expression levels of GFAP, BDNF and CREB which were impacted in depression, as well as neurotransmitters, then attenuated neural injury in rats induced by CUMS. Furthermore, Wnt family member 2 (Wnt2) was identified as a target of miR-383, and silencing of Wnt2 obviously attenuated the protective effect of miR-383 inhibitor on the apoptosis and inflammatory response in hippocampal neurons, as well as neural injury in CUMS-induced rats. Downregulation of miR-383 ameliorated the behavioral and neurochemical changes induced by chronic stress in rats by directly targeting Wnt2, indicating that the miR-383/Wnt2 axis might be a potential therapeutic target for MDD.

scholarly journals Diazepam-induced changes in sleep: Role of the  1 GABAA receptor subtype

2001 ◽  
Vol 98 (11) ◽  
pp. 6464-6469 ◽  
Author(s):  
I. Tobler ◽  
C. Kopp ◽  
T. Deboer ◽  
U. Rudolph
Keyword(s):  
Gabaa Receptor ◽  
Receptor Subtype ◽  
Induced Changes

scholarly journals Retrograde Transport from the Pre-Golgi Intermediate Compartment and the Golgi Complex Is Affected by the Vacuolar H+-ATPase Inhibitor Bafilomycin A1

1998 ◽  
Vol 9 (12) ◽  
pp. 3561-3578 ◽  
Author(s):  
Harri Palokangas ◽  
Ming Ying ◽  
Kalervo Väänänen ◽  
Jaakko Saraste
Keyword(s):  
Brefeldin A ◽  
Retrograde Transport ◽  
Small Gtpase ◽  
Bafilomycin A1 ◽  
Atpase Inhibitor ◽  
Marker Proteins ◽  
Golgi Region ◽  
Intermediate Compartment ◽  
Acidic Compartments

The effect of the vacuolar H+-ATPase inhibitor bafilomycin A1 (Baf A1) on the localization of pre-Golgi intermediate compartment (IC) and Golgi marker proteins was used to study the role of acidification in the function of early secretory compartments. Baf A1 inhibited both brefeldin A- and nocodazole-induced retrograde transport of Golgi proteins to the endoplasmic reticulum (ER), whereas anterograde ER-to-Golgi transport remained largely unaffected. Furthermore, p58/ERGIC-53, which normally cycles between the ER, IC, and cis-Golgi, was arrested in pre-Golgi tubules and vacuoles, and the number of p58-positive ∼80-nm Golgi (coatomer protein I) vesicles was reduced, suggesting that the drug inhibits the retrieval of the protein from post-ER compartments. In parallel, redistribution of β-coatomer protein from the Golgi to peripheral pre-Golgi structures took place. The small GTPase rab1p was detected in short pre-Golgi tubules in control cells and was efficiently recruited to the tubules accumulating in the presence of Baf A1. In contrast, these tubules showed no enrichment of newly synthesized, anterogradely transported proteins, indicating that they participate in retrograde transport. These results suggest that the pre-Golgi structures contain an active H+-ATPase that regulates retrograde transport at the ER–Golgi boundary. Interestingly, although Baf A1 had distinct effects on peripheral pre-Golgi structures, only more central, p58-containing elements accumulated detectable amounts of 3-(2,4-dinitroanilino)-3′-amino-N-methyldipropylamine (DAMP), a marker for acidic compartments, raising the possibility that the lumenal pH of the pre-Golgi structures gradually changes in parallel with their translocation to the Golgi region.

scholarly journals Deletion of the Actin-Associated Tropomyosin Tpm3 Leads to Reduced Cell Complexity in Cultured Hippocampal Neurons—New Insights into the Role of the C-Terminal Region of Tpm3.1

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 715
Author(s):  
Tamara Tomanić ◽  
Claire Martin ◽  
Holly Stefen ◽  
Esmeralda Parić ◽  
Peter Gunning ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Growth Cones ◽  
Amino Acid Residues ◽  
Terminal Amino Acid ◽  
C Terminus ◽  
Primary Mouse ◽  
Terminal Amino

Tropomyosins (Tpms) have been described as master regulators of actin, with Tpm3 products shown to be involved in early developmental processes, and the Tpm3 isoform Tpm3.1 controlling changes in the size of neuronal growth cones and neurite growth. Here, we used primary mouse hippocampal neurons of C57/Bl6 wild type and Bl6Tpm3flox transgenic mice to carry out morphometric analyses in response to the absence of Tpm3 products, as well as to investigate the effect of C-terminal truncation on the ability of Tpm3.1 to modulate neuronal morphogenesis. We found that the knock-out of Tpm3 leads to decreased neurite length and complexity, and that the deletion of two amino acid residues at the C-terminus of Tpm3.1 leads to more detrimental changes in neurite morphology than the deletion of six amino acid residues. We also found that Tpm3.1 that lacks the 6 C-terminal amino acid residues does not associate with stress fibres, does not segregate to the tips of neurites, and does not impact the amount of the filamentous actin pool at the axonal growth cones, as opposed to Tpm3.1, which lacks the two C-terminal amino acid residues. Our study provides further insight into the role of both Tpm3 products and the C-terminus of Tpm3.1, and it forms the basis for future studies that aim to identify the molecular mechanisms underlying Tpm3.1 targeting to different subcellular compartments.

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