scholarly journals Poly-arginine-18 (R18) Confers Neuroprotection through Glutamate Receptor Modulation, Intracellular Calcium Reduction, and Preservation of Mitochondrial Function

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 2977
Author(s):  
Gabriella MacDougall ◽  
Ryan S. Anderton ◽  
Amy Trimble ◽  
Frank L. Mastaglia ◽  
Neville W. Knuckey ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Glutamate Receptor ◽  
Cortical Neurons ◽  
Calcium Influx ◽  
Ros Generation ◽  
Neuronal Cultures ◽  
Atp Production ◽  
Endoplasmic Reticulum Calcium ◽  
Receptor Modulation ◽  
Insight Into

Recent studies have highlighted that a novel class of neuroprotective peptide, known as cationic arginine-rich peptides (CARPs), have intrinsic neuroprotective properties and are particularly effective anti-excitotoxic agents. As such, the present study investigated the mechanisms underlying the anti-excitotoxic properties of CARPs, using poly-arginine-18 (R18; 18-mer of arginine) as a representative peptide. Cortical neuronal cultures subjected to glutamic acid excitotoxicity were used to assess the effects of R18 on ionotropic glutamate receptor (iGluR)-mediated intracellular calcium influx, and its ability to reduce neuronal injury from raised intracellular calcium levels after inhibition of endoplasmic reticulum calcium uptake by thapsigargin. The results indicate that R18 significantly reduces calcium influx by suppressing iGluR overactivation, and results in preservation of mitochondrial membrane potential (ΔΨm) and ATP production, and reduced ROS generation. R18 also protected cortical neurons against thapsigargin-induced neurotoxicity, which indicates that the peptide helps maintain neuronal survival when intracellular calcium levels are elevated. Taken together, these findings provide important insight into the mechanisms of action of R18, supporting its potential application as a neuroprotective therapeutic for acute and chronic neurological disorders.

Glutamate Receptor Modulation of [3H]GABA Release and Intracellular Calcium in Chick Retina Cellsa

1995 ◽  
Vol 757 (1) ◽  
pp. 439-456 ◽  
Author(s):  
ARSÉLIO P. CARVALHO ◽  
ILDETE L. FERREIRA ◽  
ANA L. CARVALHO ◽  
CARLOS B. DUARTE
Keyword(s):  
Intracellular Calcium ◽  
Glutamate Receptor ◽  
Gaba Release ◽  
Chick Retina ◽  
Receptor Modulation

scholarly journals Lysophosphatidylcholine induces oxidative stress in  human endothelial cells via NOX5 activation - implications in atherosclerosis

2021 ◽  
Author(s):  
Josiane Fernandes da Silva ◽  
Juliano V Alves ◽  
Julio A Silva-Neto ◽  
Rafael Menezes Costa ◽  
Karla Bianca Neves ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Intracellular Calcium ◽  
Calcium Influx ◽  
Ros Generation ◽  
Ros Production ◽  
Aortic Endothelial Cells ◽  
Cell Dysfunction ◽  
Inflammatory Processes ◽  
Electron Paramagnetic Spectroscopy

Objective: The mechanisms involved in NOX5 activation in atherosclerotic processes are not completely understood.  This study tested the hypothesis that lysophosphatidylcholine (LPC), a proatherogenic component of oxLDL, induces endothelial calcium influx, which drives NOX5-dependent reactive oxygen species (ROS) production, oxidative stress, and endothelial cell dysfunction.  Approach: Human aortic endothelial cells (HAEC) were stimulated with LPC (10-5 M, for different time points).  Pharmacological inhibition of NOX5 (Melittin, 10-7 M) and NOX5 gene silencing (siRNA) were used to determine the role of NOX5-dependent ROS production in endothelial oxidative stress induced by LPC.  ROS production was determined by lucigenin assay and electron paramagnetic spectroscopy (EPR), calcium transients by Fluo4 fluorimetry, and NOX5 activity and protein expression by pharmacological assays and immunoblotting, respectively. Results: LPC increased ROS generation in endothelial cells at short (15 min) and long (4 h) stimulation times.  LPC-induced ROS was abolished by a selective NOX5 inhibitor and by NOX5 siRNA. NOX1/4 dual inhibition and selective NOX1 inhibition only decreased ROS generation at 4 h.  LPC increased HAEC intracellular calcium, important for NOX5 activation, and this was blocked by nifedipine and thapsigargin.  Bapta-AM, selective Ca2+ chelator, prevented LPC-induced ROS production.  NOX5 knockdown decreased LPC-induced ICAM-1 mRNA expression and monocyte adhesion to endothelial cells. Conclusion: These results suggest that NOX5, by mechanisms linked to increased intracellular calcium, is key to early LPC-induced endothelial oxidative stress and pro-inflammatory processes.  Since these are essential events in the formation and progression of atherosclerotic lesions, this study highlights an important role for NOX5 in atherosclerosis.

Calcium entry, mobilization, and extrusion in postcapillary venular endothelium exposed to bradykinin

1993 ◽  
Vol 265 (2) ◽  
pp. H569-H580 ◽  
Author(s):  
M. Ziche ◽  
D. Zawieja ◽  
R. K. Hester ◽  
H. Granger
Keyword(s):  
Endoplasmic Reticulum ◽  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Calcium Influx ◽  
Cytosolic Calcium ◽  
Calcium Pump ◽  
Endoplasmic Reticulum Calcium ◽  
Calcium Indicator ◽  
Subsequent Exposure ◽  
Calcium Extrusion

The effect of bradykinin (BK) on cytosolic calcium in coronary venular endothelial cells (CVEC) was studied using the intracellular calcium indicator indo 1. At normal extracellular calcium levels, CVEC responded to BK at concentrations as low as 0.1 pM; maximum cytosolic calcium spikes occurred at 10 nM. In calcium-free medium, poststimulation cytosolic calcium concentration returned to levels below prestimulation values, implying that BK modulates calcium extrusion mechanisms that are normally masked by calcium influx into the cell. To test this hypothesis, we depleted internal stores of calcium using two approaches: preconditioning or blockade of the endoplasmic reticulum calcium pump with the sesquiterpene lactone, thapsigargin. Depletion by preconditioning consisted of two prior doses of BK followed by a third stimulus of the agonist. Under these conditions, the final dose of BK caused a fall, rather than rise, in cytosolic calcium. Thapsigargin blocked the endoplasmic reticulum calcium pump, leading to a steady-state rise in intracellular calcium concentration. Subsequent exposure of these cells to BK also led to a fall in cytosolic calcium. The preconditioning and thapsigargin studies are consistent with a modulation of calcium extrusion processes by BK in CVEC. The signals responsible for this modulation are unknown.

scholarly journals Humanin Attenuates NMDA-Induced Excitotoxicity by Inhibiting ROS-dependent JNK/p38 MAPK Pathway

2018 ◽  
Vol 19 (10) ◽  
pp. 2982 ◽  
Author(s):  
Xiaorong Yang ◽  
Hongmei Zhang ◽  
Jinzi Wu ◽  
Litian Yin ◽  
Liang-Jun Yan ◽  
...  
Keyword(s):  
Cell Survival ◽  
Intracellular Calcium ◽  
P38 Mapk ◽  
Cortical Neurons ◽  
Mapk Pathway ◽  
Neurological Diseases ◽  
Mapk Signaling ◽  
Ros Generation ◽  
Mapk Activation

Humanin (HN) is a novel 24-amino acid peptide that protects neurons against N-methyl-d-aspartate (NMDA)-induced toxicity. However, the contribution of the different mitogen-activated protein kinases (MAPKs) signals to HN neuroprotection against NMDA neurotoxicity remains unclear. The present study was therefore aimed to investigate neuroprotective mechanisms of HN. We analyzed intracellular Ca2+ levels, reactive oxygen species (ROS) production, and the MAPKs signal transduction cascade using an in vitro NMDA-mediated excitotoxicity of cortical neurons model. Results showed that: (1) HN attenuated NMDA-induced neuronal insults by increasing cell viability, decreasing lactate dehydrogenase (LDH) release, and increasing cell survival; (2) HN reversed NMDA-induced increase in intracellular calcium; (3) pretreatment by HN or 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, decreased ROS generation after NMDA exposure; (4) administration of HN or N-Acetyl-l-cysteine (NAC), a ROS scavenger, inhibited NMDA-induced JNK and p38 MAPK activation. These results indicated that HN reduced intracellular elevation of Ca2+ levels, which, in turn, inhibited ROS generation and subsequent JNK and p38 MAPK activation that are involved in promoting cell survival in NMDA-induced excitotoxicity. Therefore, the present study suggests that inhibition of ROS-dependent JNK/p38 MAPK signaling pathway serves an effective strategy for HN neuroprotection against certain neurological diseases.

Presence of P2X1 Purinoceptors in Human Platelets and Megakaryoblastic Cell Lines

1997 ◽  
Vol 78 (06) ◽  
pp. 1500-1504 ◽  
Author(s):  
Catherine Vial ◽  
Béatrice Hechier ◽  
Catherine Léon ◽  
Jean-Pierre Cazenave ◽  
Christian Gachet
Keyword(s):  
Intracellular Calcium ◽  
G Proteins ◽  
Cell Lines ◽  
Calcium Influx ◽  
Human Platelets ◽  
P2y1 Receptor ◽  
Calcium Response ◽  
Ionotropic Receptors ◽  
External Calcium

SummaryHuman platelets are thought to possess at least two subtypes of purinoceptor, one of which, coupled to G-proteins, could be the P2Y1 receptor (Léon et al. 1997). However, it has been suggested that the unique rapid calcium influx induced by ADP in platelets could involve P2X1 ionotropic receptors (MacKenzie et al. 1996) and the aim of this study was thus to investigate the presence of P2X purinoceptors in platelets and megakaryoblastic cells. Using PCR experiments, we found P2X1 mRNA to be present in human platelets and megakaryoblastic cell lines. In platelets, the selective P2X1 agonist αβMeATP induced a rise in intracellular calcium only in the presence of external calcium and this effect was antagonized by suramin and PPADS. Repeated addition of a�MeATP desensitized the P2X1 purinoceptor but only slightly affected the ADP response, while no calcium response to αβMeATP was observed in megakaryoblastic cells. These results support the existence of functional P2X1 purinoceptors on human platelets and the presence of P2X1 transcripts in megakaryoblastic cell lines.

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