scholarly journals Structure and Lateral Organization of Phosphatidylinositol 4,5-bisphosphate

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3885
Author(s):  
Luís Borges-Araújo ◽  
Fabio Fernandes
Keyword(s):  
Membrane Dynamics ◽  
Eukaryotic Cells ◽  
Signaling Proteins ◽  
Steady State Concentration ◽  
Biophysical Properties ◽  
Cellular Functions ◽  
Downstream Signaling ◽  
A Minor ◽  
State Concentration ◽  
Lateral Organization

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a minor but ubiquitous component of the inner leaflet of the plasma membrane of eukaryotic cells. However, due to its particular complex biophysical properties, it stands out from its neighboring lipids as one of the most important regulators of membrane-associated signaling events. Despite its very low steady-state concentration, PI(4,5)P2 is able to engage in a multitude of simultaneous cellular functions that are temporally and spatially regulated through the presence of localized transient pools of PI(4,5)P2 in the membrane. These pools are crucial for the recruitment, activation, and organization of signaling proteins and consequent regulation of downstream signaling. The present review showcases some of the most important PI(4,5)P2 molecular and biophysical properties as well as their impact on its membrane dynamics, lateral organization, and interactions with other biochemical partners.

scholarly journals Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 332
Author(s):  
Valentina Brillo ◽  
Leonardo Chieregato ◽  
Luigi Leanza ◽  
Silvia Muccioli ◽  
Roberto Costa
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Eukaryotic Cells ◽  
Therapeutic Approaches ◽  
Cellular Functions ◽  
Lipid Trafficking ◽  
Mitochondrial Ros ◽  
Intracellular Organelles ◽  
Proliferation Regulation ◽  
Dynamic Plasticity

Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute to the dynamic plasticity of their network, also strongly influenced by mitochondrial contacts with other subcellular organelles. Nevertheless, mitochondria release a major amount of reactive oxygen species (ROS) inside eukaryotic cells, which are reported to mediate a plethora of both physiological and pathological cellular functions, such as growth and proliferation, regulation of autophagy, apoptosis, and metastasis. Therefore, targeting mitochondrial ROS could be a promising strategy to overcome and hinder the development of diseases such as cancer, where malignant cells, possessing a higher amount of ROS with respect to healthy ones, could be specifically targeted by therapeutic treatments. In this review, we collected the ultimate findings on the blended interplay among mitochondrial shaping, mitochondrial ROS, and several signaling pathways, in order to contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology of eukaryotic cells, possibly improving future therapeutic approaches.

Divergent effects of intravenous GSH and cysteine on renal and hepatic GSH

1992 ◽  
Vol 263 (2) ◽  
pp. R348-R352 ◽  
Author(s):  
S. Aebi ◽  
B. H. Lauterburg
Keyword(s):  
Steady State ◽  
De Novo ◽  
Feedback Inhibition ◽  
Therapeutic Use ◽  
Steady State Concentration ◽  
De Novo Synthesis ◽  
State Concentration ◽  
Cellular Thiol

There is a growing interest in the therapeutic use of sulfhydryls. To assess the effect of glutathione (GSH) and cysteine on the cellular thiol status, thiols were administered intravenously to rats in doses ranging from 1.67 to 8.35 mmol/kg with and without pretreatment with 4 mmol/kg buthionine-[S,R]-sulfoximine (BSO), an inhibitor of GSH synthesis. One hour after administration of 1.67 mmol/kg GSH, the concentration of GSH rose from 5.2 +/- 1.0 to 8.4 +/- 0.9 mumol/g and from 2.5 +/- 0.5 to 3.7 +/- 0.7 mumol/g in liver and kidneys, respectively. After 8.35 mmol/kg, hepatic GSH did not increase further, but renal GSH rose to 6.7 +/- 1.8 mumol/g. Infusion of cysteine increased hepatic GSH to the same extent as intravenous GSH, but renal GSH did not increase after 1.67 mmol/kg and even significantly decreased to 0.6 +/- 0.2 mumol/g after 8.35 mmol/kg. In the presence of BSO, GSH resulted in a significant increase in renal but not hepatic GSH, suggesting that the kidneys take up intact GSH and indicating that the increment in hepatic GSH was due to de novo synthesis. The present data show that hepatic GSH can be markedly increased in vivo by increasing the supply of cysteine. Measurements of hepatic cysteine indicate that up to a concentration of approximately 0.5 mumol/g cysteine is a key determinant of hepatic GSH, such that the physiological steady-state concentration of GSH in the liver appears to be mainly determined by the availability of cysteine. At higher concentrations GSH does not increase further, possibly due to feedback inhibition of GSH synthesis or increased efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals On demand MyD88 oligomerization is controlled by IRAK4 during Myddosome signaling

2020 ◽  
Author(s):  
Rafael Deliz-Aguirre ◽  
Fakun Cao ◽  
Fenja H. U. Gerpott ◽  
Nichanok Auevechanichkul ◽  
Mariam Chupanova ◽  
...  
Keyword(s):  
Self Assembly ◽  
Intracellular Signaling ◽  
Innate Immune ◽  
Live Cells ◽  
Signaling Proteins ◽  
Protein Oligomerization ◽  
Downstream Signaling ◽  
Oligomeric Complex ◽  
Mechanistic Basis ◽  
Cell Signaling Pathways

AbstractA recurring feature of innate immune receptor signaling is the self-assembly of signaling proteins into oligomeric complexes. The Myddosome is an oligomeric complex that is required to transmit inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for how Myddosome proteins self-assemble and regulate intracellular signaling remains poorly understood. Here, we developed a novel assay to analyze the spatiotemporal dynamics of IL1R and Myddosome signaling in live cells. We found that MyD88 oligomerization is inducible and initially reversible. Moreover, the formation of larger, stable oligomers consisting of more than 4 MyD88s triggers the sequential recruitment of IRAK4 and IRAK1. Notably, genetic knockout of IRAK4 enhanced MyD88 oligomerization, indicating that IRAK4 controls MyD88 oligomer size and growth. MyD88 oligomer size thus functions as a physical threshold to trigger downstream signaling. These results provide a mechanistic basis for how protein oligomerization might function in cell signaling pathways.

scholarly journals Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins

2016 ◽  
Vol 291 (11) ◽  
pp. 5528-5540 ◽  
Author(s):  
Tom Ronan ◽  
Jennifer L. Macdonald-Obermann ◽  
Lorel Huelsmann ◽  
Nicholas J. Bessman ◽  
Kristen M. Naegle ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Signaling Proteins ◽  
Downstream Signaling ◽  
Epidermal Growth

Effect of oxidative stress during imbibition of soybean embryonic axes

1994 ◽  
Vol 102 ◽  
pp. 279-286 ◽  
Author(s):  
Susana Puntarulo
Keyword(s):  
Oxidative Stress ◽  
Steady State ◽  
External Medium ◽  
Tocopherol Content ◽  
Active Species ◽  
Oxygen Species ◽  
Steady State Concentration ◽  
Embryonic Axes ◽  
State Concentration

SynopsisBoth respiration and generation by soybean embryonic axes showed a sharp increase upon germination, leading to a significant increase in the steady-state concentration of and H2O2 after 6 h of imbibition. An assay was developed to assess in vivo generation of reactive oxygen species, based upon DCFH-DA oxidation. Fluorescence of the external medium was dependent on reaction time and axes number and was inhibited by catalase.α-Tocopherol content declined significantly after 24 h of incubation, as compared to the content at the onset of germination. Incubation in the presence of redox cycling agent paraquat (4 mM) for 24 h increased α-tocopherol content to 1.9±0.2 nmol per axis from 1.0 ± 0.1 nmol per axis in the absence of paraquat. Supplementation of the incubation medium with 500 μM Fe-EDTA increased α-tocopherol content to 1.8±0.1 nmol/axis and DCFH-DA oxidation by two-fold.The data presented here showed that active metabolism at the onset of germination increased steady-state concentration of oxygen active species and suggest that cellular content of α-tocopherol is physiologically adjusted as a response to conditions of oxidative stress.

scholarly journals ClC-3: biophysical properties clarify cellular functions

2018 ◽  
Vol 596 (17) ◽  
pp. 3823-3824
Author(s):  
Raul E. Guzman ◽  
Christoph Fahlke
Keyword(s):  
Biophysical Properties ◽  
Cellular Functions

8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine

2019 ◽  
Vol 52 (05) ◽  
pp. 237-244
Author(s):  
Masataka Shinozaki ◽  
Jason Pierce ◽  
Yuki Hayashi ◽  
Takashi Watanabe ◽  
Taro Sasaki ◽  
...  
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Plasma Levels ◽  
High Performance ◽  
Psychiatric Patients ◽  
Plasma Concentrations ◽  
Steady State Concentration ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
State Concentration

Abstract Introduction  To investigate the metabolism of mirtazapine (MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N-desmethylmirtazapine (DMIR), 8-hydroxy-mirtazapine (8-OH-MIR), mirtazapine glucuronide (MIR-G), and 8-hydroxy-mirtazapine glucuronide (8-OH-MIR-G). Methods  Seventy-nine Japanese psychiatric patients were treated with MIR for 1–8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH-MIR were determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH-MIR-G were determined by total MIR and total 8-OH-MIR (i. e., concentrations after hydrolysis) minus unconjugated MIR and unconjugated 8-OH-MIR, respectively. Polymerase chain reaction was used to determine CYP2D6 genotypes. Results  Plasma levels of 8-OH-MIR were lower than those of MIR and DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH-MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/MIR and 8-OH-MIR-G/8-OH-MIR ratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIR concentration (dose- and body weight–corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight–corrected, p=0.018). The steady-state plasma concentrations of MIR and its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles. Discussion  The plasma concentration of 8-OH-MIR was as low as 1.42 nmol/L, whereas 8-OH-MIR-G had an approximate 59.50 times higher concentration than 8-OH-MIR, suggesting a significant role for hydroxylation of MIR and its glucuronidation in the Japanese population.

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