Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age

Biomedicines, Journal Year: 2024, Volume and Issue: 12(4), P. 880 - 880

Published: April 16, 2024

Glutamate is the major excitatory neurotransmitter in central nervous system. Glutamatergic transmission can be mediated by ionotropic glutamate receptors (iGluRs), which mediate rapid synaptic depolarization that associated with Ca2+ entry and activity-dependent change strength of transmission, as well metabotropic (mGluRs), slower postsynaptic responses through recruitment second messenger systems. A wealth evidence reported over last three decades has shown this dogmatic subdivision between iGluRs mGluRs may not reflect actual physiological signaling mode iGluRs, i.e., α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) (AMPAR), kainate (KARs), N-methyl-D-aspartate (NMDA) (NMDARs). Herein, we review available supporting notion canonical recruit flux-independent pathways only neurons, but also brain astrocytes cerebrovascular endothelial cells. Understanding versatility exert a profound impact on our understanding glutamatergic synapses. Furthermore, it shed light novel neuroprotective strategies against disorders.

Language: Английский

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The Unexpected Role of the Endothelial Nitric Oxide Synthase at the Neurovascular Unit: Beyond the Regulation of Cerebral Blood Flow

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 9071 - 9071

Published: Aug. 21, 2024

Nitric oxide (NO) is a highly versatile gasotransmitter that has first been shown to regulate cardiovascular function and then exert tight control over much broader range of processes, including neurotransmitter release, neuronal excitability, synaptic plasticity. Endothelial NO synthase (eNOS) usually far from the mind neurophysiologists, who have focused most their attention on (nNOS) as primary source at neurovascular unit (NVU). Nevertheless, available evidence suggests eNOS could also contribute generating burst that, serving volume intercellular messenger, produced in response activity brain parenchyma. Herein, we review role both regulation cerebral blood flow plasticity discuss mechanisms by which cerebrovascular endothelial cells may transduce inputs into signal. We further suggest play critical vascular-to-neuronal communication integrating signals converging onto streaming active neurons.

Language: Английский

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Klebsiella pneumoniae disrupts vasodilation by targeting eNOS post translational modifications via the type VI secretion system and the capsule polysaccharide

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

SUMMARY Vasodilation is a crucial protective response to inflammation and infection. Endothelial cells control vasodilation through the bioavailability of eNOS-produced nitric oxide (NO), generation endothelium-dependent hyperpolarization (EDH). Here, we demonstrate that Klebsiella pneumoniae , one most prevalent blood stream infection pathogens, inhibits agonist-induced by blunting NO-dependent pathway attenuating EDH pathway. The type VI secretion system (T6SS) effector VgrG4 licences kinase PKCβ in an NLRX1-controlled mitochondria reactive oxygen species (mtROS)-dependent manner phosphorylate eNOS inhibitory site Thr 495 effectively dampening activity. capsule polysaccharide, on other hand, limits phosphorylation activation Ser 1177 inducing phosphatase PP2Ac upon EGF receptor-dependent VgrG4-induced mtROS attenuates Overall, this work reveals new anti-host activity T6SS illustrates how pathogens can vascular biology targeting post translational modifications.

Language: Английский

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Ca2+ Signaling in Cardiac Fibroblasts: An Emerging Signaling Pathway Driving Fibrotic Remodeling in Cardiac Disorders

Biomedicines, Journal Year: 2025, Volume and Issue: 13(3), P. 734 - 734

Published: March 17, 2025

Cardiac fibrosis is a scarring event that occurs in the myocardium response to multiple cardiovascular disorders, such as acute myocardial infarction (AMI), ischemic cardiomyopathy, dilated hypertensive heart disease, inflammatory diabetic and aortic stenosis. Fibrotic remodeling mainly sustained by differentiation of fibroblasts into myofibroblasts, which synthesize secrete most extracellular matrix (ECM) proteins. An increase intracellular Ca2+ concentration ([Ca2+]i) cardiac emerging critical mediator fibrogenic signaling cascade. Herein, we review mechanisms may shape signals involved fibroblast transdifferentiation myofibroblasts. We focus our attention on functional interplay between inositol-1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) store-operated entry (SOCE). In accordance with this, InsP3Rs SOCE drive elicited Gq-protein coupled (GqPCRs) promote fibrotic remodeling. Then, describe additional sustain entry, including receptor-operated (ROCE), P2X receptors, Transient Receptor Potential (TRP) channels, Piezo1 channels. parallel, discuss pharmacological manipulation handling machinery promising approach mitigate or reverse disorders.

Language: Английский

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Cognitive Impairment and Synaptic Dysfunction in Cardiovascular Disorders: The New Frontiers of the Heart–Brain Axis

Biomedicines, Journal Year: 2024, Volume and Issue: 12(10), P. 2387 - 2387

Published: Oct. 18, 2024

Within the central nervous system, synaptic plasticity, fundamental to processes like learning and memory, is largely driven by activity-dependent changes in strength. This plasticity often manifests as long-term potentiation (LTP) depression (LTD), which are bidirectional modulations of efficacy. Strong epidemiological experimental evidence show that heart-brain axis could be severely compromised both neurological cardiovascular disorders. Particularly, disorders, such heart failure, hypertension, obesity, diabetes insulin resistance, arrhythmias, may lead cognitive impairment, a condition known cardiogenic dementia. Herein, we review available knowledge on molecular mechanisms dementia arise describe how LTP and/or LTD induction maintenance CA1 region hippocampus metabolic syndrome, arrhythmias. We also discuss emerging endothelial dysfunction contribute directly altering hippocampal impairing synaptically induced activation nitric oxide synthase. A better understanding CV disorders impact proper function synapses will shed novel light underpinnings dementia, thereby providing new perspective for more specific pharmacological treatments.

Language: Английский

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Chromogranin B Protects Human Umbilical Endothelial Cells against Oxidative Stress

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10296 - 10296

Published: Sept. 25, 2024

Chromogranin B (CgB) is involved in the control of cardiovascular system through regulation catecholamine release. Whether CgB can exert direct actions on endothelium has not yet been clarified. Here, we aimed to investigate effects cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), glutathione (GSH), nitric oxide (NO) release, and cytosolic calcium concentration ([Ca2+]c) human vascular endothelial cells (HUVECs) cultured under both physiological peroxidative conditions. In HUVECs, experiments were conducted establish proper timing stimulation. Thereafter, specific assays used evaluate response HUVECs physiologic or oxidative stress conditions presence absence β-adrenergic receptor agonists antagonists intracellular pathways blockers. Analysis NO release revealed that was able cause increased Additionally, same analyses performed with H2O2, showed protective exerted by CgB, which also counteract ROS maintain GSH levels. Furthermore, played a dual role [Ca2+]c depending culturing conclusion, our data provide new information about function highlight its potential as agent against conditions, such those found diseases.

Language: Английский

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Lysosomal TRPML1 triggers global Ca2+ signals and nitric oxide release in human cerebrovascular endothelial cells

Frontiers in Physiology, Journal Year: 2024, Volume and Issue: 15

Published: June 21, 2024

Lysosomal Ca

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An automated planar patch-clamp approach to measure the membrane potential and resting membrane currents in a human cerebrovascular endothelial cell line

Journal of Neuroscience Methods, Journal Year: 2024, Volume and Issue: 410, P. 110248 - 110248

Published: Aug. 6, 2024

Language: Английский

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Increased TRPV4 channel expression enhances and impairs blood vessel function in hypertension

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 29, 2024

Abstract Background Endothelial cell TRPV4 channels provide a control point that is pivotal in regulating blood vessel diameter by mediating the Ca 2+ -dependent release of endothelial-derived vasoactive factors. In hypertension, TRPV4-mediated vascular function disrupted but underlying mechanisms, and precise physiological consequences remain controversial. Methods Here, using comprehensive array methodologies, endothelial channel was examined intact arteries from normotensive WKY hypertensive SHR rats. Results Our results show there notable shift reactivity characterized enhanced endothelium-dependent vasodilation at low levels activation. However, higher activity, this vasodilatory response reversed, contributing to aberrant tone observed hypertension. The change response, dilation constriction, accompanied intracellular signaling modalities arising activity. Oscillatory TRPV4-evoked IP 3 -mediated release, which underlies dilation, decreased, while contraction inducing sustained rise, influx, increased. findings also reveal sensitivity activation unchanged, expression upregulated receptors are downregulated Conclusions These data highlight intricate interplay between expression, dynamics, reactivity. Moreover, support new unifying hypothesis for impairment accompanies Specifically, play dual role modulating

Language: Английский

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Distinct Patterns of Endothelial Cell Activation Produced by Extracellular Histones and Bacterial Lipopolysaccharide

Shock, Journal Year: 2024, Volume and Issue: 62(5), P. 728 - 735

Published: Aug. 28, 2024

Objective : Vascular endothelial cells (ECs) sense and respond to both trauma factors (histone proteins) sepsis signals (bacterial lipopolysaccharide, LPS) with elevations in calcium (Ca 2+ ), but it is not clear if the patterns of activation are similar or different. We hypothesized that within seconds exposure, histones LPS would produce a large EC Ca response. also different spatio-temporal events veins than arteries. Methods studied cultured ECs (EA.hy926) native from surgically opened murine blood vessels. High-speed live cell imaging were acquired for 5 min before after stimulation alone combination. Histone-induced compared resistance-sized arteries veins. activity was quantified as "Ca prevalence" using custom spatiotemporal analysis. Additionally, collected 6 h exposure RNA sequencing. Results ECs-both culture vessels-rapidly increased histone exposure. In contrast, produced only slight increase no effect on vessels over 5-min recording periods. Histones evoked aberrant (>30 s duration) arteries, patterns. arterial often appeared "rosettes", propagated one all adjacent surrounding cells. veins, responded individually without spreading. Surprisingly, potentiated by an order magnitude. Exposure gene expression, mRNAs induced. Conclusions activate through mechanisms distinct additive; events. display responses histones.

Language: Английский

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