scholarly journals Dissection of P2X4 and P2X7 Receptor Current Components in BV-2 Microglia

2020 ◽  
Vol 21 (22) ◽  
pp. 8489
Author(s):  
Mira Trang ◽  
Günther Schmalzing ◽  
Christa E. Müller ◽  
Fritz Markwardt
Keyword(s):  
P2x7 Receptor ◽  
Purinergic Receptors ◽  
Cell Voltage ◽  
P2x Receptors ◽  
Interferon Γ ◽  
Pain Sensation ◽  
P2x7 Receptors ◽  
Receptor Blockers ◽  
The Central Nervous System ◽  
Inflamed Tissue

Microglia cells represent the immune system of the central nervous system. They become activated by ATP released from damaged and inflamed tissue via purinergic receptors. Ionotropic purinergic P2X4 and P2X7 receptors have been shown to be involved in neurological inflammation and pain sensation. Whether the two receptors assemble exclusively as homotrimers or also as heterotrimers is still a matter of debate. We investigated the expression of P2X receptors in BV-2 microglia cells applying the whole-cell voltage-clamp technique. We dissected P2X4 and P2X7 receptor-mediated current components by using specific P2X4 and P2X7 receptor blockers and by their characteristic current kinetics. We found that P2X4 and P2X7 receptors are activated independently from each other, indicating that P2X4/P2X7 heteromers are not of functional significance in these cells. The pro-inflammatory mediators lipopolysaccharide and interferon γ, if applied in combination, upregulated P2X4, but not P2X7 receptor-dependent current components also arguing against phenotypically relevant heteromerization of P2X4 and P2X7 receptor subunits.

scholarly journals Astroglial and Microglial Purinergic P2X7 Receptor as a Major Contributor to Neuroinflammation during the Course of Multiple Sclerosis

2021 ◽  
Vol 22 (16) ◽  
pp. 8404
Author(s):  
Marta Sidoryk-Węgrzynowicz ◽  
Lidia Strużyńska
Keyword(s):  
Multiple Sclerosis ◽  
Inflammatory Reaction ◽  
P2x7 Receptor ◽  
Purinergic Signaling ◽  
Causative Factor ◽  
P2x7 Receptors ◽  
Autoimmune Inflammatory Disease ◽  
Demyelinating Lesions ◽  
Purinergic P2x7 Receptor ◽  
The Central Nervous System

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that leads to the progressive disability of patients. A characteristic feature of the disease is the presence of focal demyelinating lesions accompanied by an inflammatory reaction. Interactions between autoreactive immune cells and glia cells are considered as a central mechanism underlying the pathology of MS. A glia-mediated inflammatory reaction followed by overproduction of free radicals and generation of glutamate-induced excitotoxicity promotes oligodendrocyte injury, contributing to demyelination and subsequent neurodegeneration. Activation of purinergic signaling, in particular P2X7 receptor-mediated signaling, in astrocytes and microglia is an important causative factor in these pathological processes. This review discusses the role of astroglial and microglial cells, and in particular glial P2X7 receptors, in inducing MS-related neuroinflammatory events, highlighting the importance of P2X7R-mediated molecular pathways in MS pathology and identifying these receptors as a potential therapeutic target.

scholarly journals Role of P2X7 Receptors in Immune Responses During Neurodegeneration

2021 ◽  
Vol 15 ◽  
Author(s):  
Ágatha Oliveira-Giacomelli ◽  
Lyvia Lintzmaier Petiz ◽  
Roberta Andrejew ◽  
Natalia Turrini ◽  
Jean Bezerra Silva ◽  
...  
Keyword(s):  
Immune Cells ◽  
P2x7 Receptor ◽  
Receptor Activation ◽  
Brain Parenchyma ◽  
Cytokine Release ◽  
P2x7 Receptors ◽  
Inflammatory Conditions ◽  
The Central Nervous System ◽  
Peripheral Immune Cells ◽  
P2x7 Receptor Activation

P2X7 receptors are ion-gated channels activated by ATP. Under pathological conditions, the extensive release of ATP induces sustained P2X7 receptor activation, culminating in induction of proinflammatory pathways with inflammasome assembly and cytokine release. These inflammatory conditions, whether occurring peripherally or in the central nervous system (CNS), increase blood-brain-barrier (BBB) permeability. Besides its well-known involvement in neurodegeneration and neuroinflammation, the P2X7 receptor may induce BBB disruption and chemotaxis of peripheral immune cells to the CNS, resulting in brain parenchyma infiltration. For instance, despite common effects on cytokine release, P2X7 receptor signaling is also associated with metalloproteinase secretion and activation, as well as migration and differentiation of T lymphocytes, monocytes and dendritic cells. Here we highlight that peripheral immune cells mediate the pathogenesis of Multiple Sclerosis and Parkinson’s and Alzheimer’s disease, mainly through T lymphocyte, neutrophil and monocyte infiltration. We propose that P2X7 receptor activation contributes to neurodegenerative disease progression beyond its known effects on the CNS. This review discusses how P2X7 receptor activation mediates responses of peripheral immune cells within the inflamed CNS, as occurring in the aforementioned diseases.

scholarly journals Functional Coupling between the P2X7 Receptor and Pannexin-1 Channel in Rat Trigeminal Ganglion Neurons

2021 ◽  
Vol 22 (11) ◽  
pp. 5978
Author(s):  
Hiroyuki Inoue ◽  
Hidetaka Kuroda ◽  
Wataru Ofusa ◽  
Sadao Oyama ◽  
Maki Kimura ◽  
...  
Keyword(s):  
Trigeminal Ganglion ◽  
P2x7 Receptor ◽  
P2x Receptor ◽  
Functional Coupling ◽  
Dependent Manner ◽  
High Concentration ◽  
Receptor Antagonists ◽  
P2x7 Receptors ◽  
Pannexin 1 ◽  
Ganglion Neurons

The ionotropic P2X receptor, P2X7, is believed to regulate and/or generate nociceptive pain, and pain in several neuropathological diseases. Although there is a known relationship between P2X7 receptor activity and pain sensing, its detailed functional properties in trigeminal ganglion (TG) neurons remains unclear. We examined the electrophysiological and pharmacological characteristics of the P2X7 receptor and its functional coupling with other P2X receptors and pannexin-1 (PANX1) channels in primary cultured rat TG neurons, using whole-cell patch-clamp recordings. Application of ATP and Bz-ATP induced long-lasting biphasic inward currents that were more sensitive to extracellular Bz-ATP than ATP, indicating that the current was carried by P2X7 receptors. While the biphasic current densities of the first and second components were increased by Bz-ATP in a concentration dependent manner; current duration was only affected in the second component. These currents were significantly inhibited by P2X7 receptor antagonists, while only the second component was inhibited by P2X1, 3, and 4 receptor antagonists, PANX1 channel inhibitors, and extracellular ATPase. Taken together, our data suggests that autocrine or paracrine signaling via the P2X7-PANX1-P2X receptor/channel complex may play important roles in several pain sensing pathways via long-lasting neuronal activity driven by extracellular high-concentration ATP following tissue damage in the orofacial area.

scholarly journals Immune system markers of neuroinflammation in patients with clinical diagnose of neuromyelitis optica

2008 ◽  
Vol 66 (3b) ◽  
pp. 678-684 ◽  
Author(s):  
Soniza Vieira Alves-Leon ◽  
Maria Lucia Vellutini Pimentel ◽  
Gabrielle Sant'Anna ◽  
Fabíola Rachid Malfetano ◽  
Cláudio Duque Estrada ◽  
...  
Keyword(s):  
Neuromyelitis Optica ◽  
B Lymphocyte ◽  
Demyelinating Disease ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Control Group ◽  
Regulatory Cells ◽  
Immunological Parameters ◽  
Healthy Control ◽  
The Central Nervous System

Neuromyelitis optica (NMO) is an inflammatory, demyelinating disease of the central nervous system characterized by the association of a serious myelitis and unilateral or bilateral optic neuritis. The present study aimed to analyze the immunological parameters of NMO patients with diagnosis established based on Wingerchuck et al. (1999) criteria. Production of IgG and IgA antibodies to antigens of MBP, PLP 95-116, MOG 92-106, and the cytokines interleukin-4 (IL-4) and interferon-γ (INF-γ) were assessed by Elisa assay. The cohort was formed by 28 NMO patients and a matched healthy control group. NMO patients had significant high levels of IgG to MOG (p<0.0001), PLP (p=0.0002) and MBP (p<0.0001), and solely IgA to MBP (p<0.0001). INF-γ (p=0.61) levels were similar to healthy controls. Increased production of IL-4 (p=0.0084) indicates an important role for this cytokine in the activation of Th2 regulatory cells and of the IgA producers B lymphocyte indicating activation of humoral immunity.

scholarly journals Vaccination with DNA Encoding an Immunodominant Myelin Basic Protein Peptide Targeted to Fc of Immunoglobulin G Suppresses Experimental Autoimmune Encephalomyelitis

1998 ◽  
Vol 187 (9) ◽  
pp. 1543-1548 ◽  
Author(s):  
Anna Lobell ◽  
Robert Weissert ◽  
Maria K. Storch ◽  
Cecilia Svanholm ◽  
Katrien L. de Graaf ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Cell Epitope ◽  
Interferon Γ ◽  
Dna Encoding ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

We explore here if vaccination with DNA encoding an autoantigenic peptide can suppress autoimmune disease. For this purpose we used experimental autoimmune encephalomyelitis (EAE), which is an autoaggressive disease in the central nervous system and an animal model for multiple sclerosis. Lewis rats were vaccinated with DNA encoding an encephalitogenic T cell epitope, guinea pig myelin basic protein peptide 68–85 (MBP68–85), before induction of EAE with MBP68–85 in complete Freund's adjuvant. Compared to vaccination with a control DNA construct, the vaccination suppressed clinical and histopathological signs of EAE, and reduced the interferon γ production after challenge with MBP68–85. Targeting of the gene product to Fc of IgG was essential for this effect. There were no signs of a Th2 cytokine bias. Our data suggest that DNA vaccines encoding autoantigenic peptides may be useful tools in controlling autoimmune disease.

scholarly journals m6A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity

2021 ◽  
Vol 7 (25) ◽  
pp. eabg0470
Author(s):  
Jing Zhou ◽  
Xingli Zhang ◽  
Jiajia Hu ◽  
Rihao Qu ◽  
Zhibin Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Messenger Rna ◽  
Interferon Γ ◽  
Autoimmune Encephalomyelitis ◽  
Cell Responses ◽  
Chemokine Ligand ◽  
The Central Nervous System ◽  
Chemokine Ligand 2

N6-methyladenosine (m6A) modification is dynamically regulated by “writer” and “eraser” enzymes. m6A “writers” have been shown to ensure the homeostasis of CD4+ T cells, but the “erasers” functioning in T cells is poorly understood. Here, we reported that m6A eraser AlkB homolog 5 (ALKBH5), but not FTO, maintains the ability of naïve CD4+ T cells to induce adoptive transfer colitis. In addition, T cell–specific ablation of ALKBH5 confers protection against experimental autoimmune encephalomyelitis. During the induced neuroinflammation, ALKBH5 deficiency increased m6A modification on interferon-γ and C-X-C motif chemokine ligand 2 messenger RNA (mRNA), thus decreasing their mRNA stability and protein expression in CD4+ T cells. These modifications resulted in attenuated CD4+ T cell responses and diminished recruitment of neutrophils into the central nervous system. Our findings reveal an unexpected specific role of ALKBH5 as an m6A eraser in controlling the pathogenicity of CD4+ T cells during autoimmunity.

scholarly journals The Tyrosine Phosphatase hPTPRβ Controls the Early Signals and Dopaminergic Cells Viability via the P2X7 Receptor

2021 ◽  
Vol 22 (23) ◽  
pp. 12936
Author(s):  
Francisco Llavero Bernal ◽  
Miriam Luque Montoro ◽  
Alazne Arrazola Sastre ◽  
Hadriano M. Lacerda ◽  
José Luis Zugaza
Keyword(s):  
Cell Death ◽  
Dopaminergic Neurons ◽  
P2x7 Receptor ◽  
Purinergic Receptors ◽  
Neuronal Response ◽  
Tyrosine Phosphatase ◽  
Neuronal Cell ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Dopaminergic Cells

ATP, one of the signaling molecules most commonly secreted in the nervous system and capable of stimulating multiple pathways, binds to the ionotropic purinergic receptors, in particular, the P2X7 receptor (P2X7R) and stimulates neuronal cell death. Given this effect of purinergic receptors on the viability of dopaminergic neurons model cells and that Ras GTPases control Erk1/2-regulated mitogen-activated cell proliferation and survival, we have investigated the role of the small GTPases of the Ras superfamily, together with their regulatory and effector molecules as the potential molecular intermediates in the P2X7R-regulated cell death of SN4741 dopaminergic neurons model cells. Here, we demonstrate that the neuronal response to purinergic stimulation involves the Calmodulin/RasGRF1 activation of the small GTPase Ras and Erk1/2. We also demonstrate that tyrosine phosphatase PTPRβ and other tyrosine phosphatases regulate the small GTPase activation pathway and neuronal viability. Our work expands the knowledge on the intracellular responses of dopaminergic cells by identifying new participating molecules and signaling pathways. In this sense, the study of the molecular circuitry of these neurons is key to understanding the functional effects of ATP, as well as considering the importance of these cells in Parkinson’s Disease.

scholarly journals Performance of P2x7 and P2Y Purinergic Receptors as an Inhibiting Factor in the Progression of Pulmonary Neoplastic Cells

2020 ◽  
pp. 56-62
Author(s):  
Matheus Ribeiro Bizuti ◽  
Laura Nyland Jostl ◽  
Emanuely Scramim ◽  
Keroli Eloiza Tessaro da Silva ◽  
Luana Paula Schio ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Adenosine Receptors ◽  
Purinergic Receptors ◽  
Cell Permeability ◽  
Lung Cells ◽  
Nucleotide Receptors ◽  
Toxic Substances ◽  
P2x7 Receptors ◽  
Specific Targeting ◽  
Inhibiting Factor

Different pathological processes are considered in lung cancer, such as nicotine deposition, oxidative stress, deregulation of metal ions and chronic inflammation. Purine signaling is involved in all processes, suggesting the importance of nucleotide receptors (P2X7 and P2Y) and adenosine receptors present in lung cells. The accumulation of toxic substances promotes chronic inflammation and cellular alteration, which induces the release of Adenosine Triphosphate (ATP) in the extracellular space, thus stimulating P2X7 receptors. The activation of P2X7 promotes an increase in the synthesis and release of some pro-inflammatory mediators. P2Y works by promoting the increase of intracellular calcium levels and, P2X7, changing cell permeability. Thus, drugs can be developed with a specific targeting for such recipients, thus provid additional therapeutic options to those existing.

scholarly journals Intrathecal injection of brilliant blue G, a P2X7 antagonist, attenuates the exercise pressor reflex in rats

2020 ◽  
Vol 319 (2) ◽  
pp. R223-R232
Author(s):  
Juan A. Estrada ◽  
Guillaume P. Ducrocq ◽  
Joyce S. Kim ◽  
Marc P. Kaufman
Keyword(s):  
Spinal Cord ◽  
Pressor Response ◽  
Intrathecal Injection ◽  
P2x Receptors ◽  
Brilliant Blue ◽  
Brilliant Blue G ◽  
P2x7 Receptors ◽  
P2x3 Receptors ◽  
Exercise Pressor Reflex ◽  
Pressor Reflex

Purinergic 2X (P2X) receptors on the endings of group III and IV afferents play a role in evoking the exercise pressor reflex. Particular attention has been paid to P2X3 receptors because their blockade in the periphery attenuated this reflex. In contrast, nothing is known about the role played by P2X receptors in the spinal cord in evoking the exercise pressor reflex in rats. P2X7 receptors, in particular, may be especially important in this regard because they are found in abundance on spinal glial cells and may communicate with neurons to effect reflexes controlling cardiovascular function. Consequently, we investigated the role played by spinal P2X7 receptors in evoking the exercise pressor reflex in decerebrated rats. We found that intrathecal injection of the P2X7 antagonist brilliant blue G (BBG) attenuated the exercise pressor reflex (blood pressure index: 294 ± 112 mmHg·s before vs. 7 ± 32 mmHg·s after; P < 0.05). Likewise, intrathecal injection of minocycline, which inhibits microglial cell output, attenuated the reflex. In contrast, intrathecal injection of BBG did not attenuate the pressor response evoked by intracarotid injection of sodium cyanide, a maneuver that stimulated carotid chemoreceptors. Moreover, injections of BBG either into the arterial supply of the contracting hindlimb muscles or into the jugular vein did not attenuate the exercise pressor reflex. Our findings support the hypothesis that P2X7 receptors on microglial cells within the spinal cord play a role in evoking the exercise pressor reflex.

Pain, Painrelieving Mechanisms and Trauma

1987 ◽  
Vol 3 (1) ◽  
pp. 12-13
Author(s):  
B. Sjolund
Keyword(s):  
Spinal Cord ◽  
Great Britain ◽  
Nerve Fibers ◽  
Point Of View ◽  
Pain Sensation ◽  
Small Peptides ◽  
Periaqueductal Gray Matter ◽  
Nociceptive Afferents ◽  
The Central Nervous System ◽  
Areas Of Interest

Activity in nociceptive nerve fibers does not only trigger the sensation of pain but it also starts a variety of nocifensive reflexes to protect the organism from the noxious agent. Some of these reflexes may, if active long enough, be harmful themselves, causing ischemia in visceral organs or other inadvertent reactions. Recently, several endogenous mechanisms have been discovered that can inhibit the transmission of nerve impulses from nociceptive afferents to other nerve cells, thus not only preventing the pain sensation but also modulating the nocifensive reflex responses. Several such mechanisms may involve the release of endorphins. These are small peptides, with opiate-like activity that were first discovered in 1975 by Hughes and Kosterlitz in Great Britain and by Terenius in Sweden. The distribution of such endorphins in the central nervous system was first investigated by Hökfelt and his coworkers. They found terminals and cell bodies containing endorphins in several areas of interest from the point of view of nociception. Thus the dorsal horn of the spinal cord, the corresponding area of the fifth cranial nerve and the periaqueductal gray matter contained such material.

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