scholarly journals Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1267
Author(s):  
Stefania Merighi ◽  
Tino Emanuele Poloni ◽  
Anna Terrazzan ◽  
Eva Moretti ◽  
Stefania Gessi ◽  
...  
Keyword(s):  
Purinergic Signaling ◽  
Scientific Evidence ◽  
Membrane Receptors ◽  
Extracellular Nucleotides ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Neurological Damage ◽  
Promising Target ◽  
G Protein Coupled ◽  
The Brain

Alzheimer’s disease (AD) is a widespread neurodegenerative pathology responsible for about 70% of all cases of dementia. Adenosine is an endogenous nucleoside that affects neurodegeneration by activating four membrane G protein-coupled receptor subtypes, namely P1 receptors. One of them, the A2A subtype, is particularly expressed in the brain at the striatal and hippocampal levels and appears as the most promising target to counteract neurological damage and adenosine-dependent neuroinflammation. Extracellular nucleotides (ATP, ADP, UTP, UDP, etc.) are also released from the cell or are synthesized extracellularly. They activate P2X and P2Y membrane receptors, eliciting a variety of physiological but also pathological responses. Among the latter, the chronic inflammation underlying AD is mainly caused by the P2X7 receptor subtype. In this review we offer an overview of the scientific evidence linking P1 and P2 mediated purinergic signaling to AD development. We will also discuss potential strategies to exploit this knowledge for drug development.

scholarly journals GRKs as Modulators of Neurotransmitter Receptors

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 52
Author(s):  
Eugenia V. Gurevich ◽  
Vsevolod V. Gurevich
Keyword(s):  
G Protein ◽  
General Model ◽  
G Protein Coupled Receptors ◽  
Receptor Internalization ◽  
Neurotransmitter Receptors ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Receptor Kinase ◽  
G Protein Coupled ◽  
Homologous Desensitization

Many receptors for neurotransmitters, such as dopamine, norepinephrine, acetylcholine, and neuropeptides, belong to the superfamily of G protein-coupled receptors (GPCRs). A general model posits that GPCRs undergo two-step homologous desensitization: the active receptor is phosphorylated by kinases of the G protein-coupled receptor kinase (GRK) family, whereupon arrestin proteins specifically bind active phosphorylated receptors, shutting down G protein-mediated signaling, facilitating receptor internalization, and initiating distinct signaling pathways via arrestin-based scaffolding. Here, we review the mechanisms of GRK-dependent regulation of neurotransmitter receptors, focusing on the diverse modes of GRK-mediated phosphorylation of receptor subtypes. The immediate signaling consequences of GRK-mediated receptor phosphorylation, such as arrestin recruitment, desensitization, and internalization/resensitization, are equally diverse, depending not only on the receptor subtype but also on phosphorylation by GRKs of select receptor residues. We discuss the signaling outcome as well as the biological and behavioral consequences of the GRK-dependent phosphorylation of neurotransmitter receptors where known.

Recent progress on the role of GABAergic neurotransmission in the pathogenesis of Alzheimer’s disease

2016 ◽  
Vol 27 (4) ◽  
pp. 449-455 ◽  
Author(s):  
Ghulam Abbas ◽  
Wajahat Mahmood ◽  
Nurul Kabir
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gaba Receptor ◽  
Amyloid Β ◽  
Receptor Subtypes ◽  
Causative Role ◽  
Gabaergic Neurotransmission ◽  
Promising Target ◽  
The Brain

AbstractDespite their possible causative role, targeting amyloidosis, tau phosphorylation, acetylcholine esterase, glutamate, oxidative stress and mitochondrial metabolism have not yet led to the development of drugs to cure Alzheimer’s disease (AD). Recent preclinical and clinical reports exhibit a surge in interest in the role of GABAergic neurotransmission in the pathogenesis of AD. The interaction among GABAergic signaling, amyloid-β and acetylcholine is shown to affect the homeostasis between excitation (glutamate) and inhibition (GABA) in the brain. As a consequence, over-excitation leads to neurodegeneration (excitotoxicity) and impairment in the higher level functions. Previously, the glutamate arm of this balance received the most attention. Recent literature suggests that over-excitation is primarily mediated by dysfunctional GABA signaling and can possibly be restored by rectifying anomalous metabolism observed in the GABAergic neurons during AD. Additionally, neurogenesis and synaptogenesis have also been linked with GABAergic signaling. This association may provide a basis for the needed repair mechanism. Furthermore, several preclinical interventional studies revealed that targeting various GABA receptor subtypes holds potential in overcoming the memory deficits associated with AD. In conclusion, the recent scientific literature suggests that GABAergic signaling presents itself as a promising target for anti-AD drug development.

Distribution of α1-adrenoceptor subtype proteins in different tissues of neonatal and adult rats

2000 ◽  
Vol 78 (3) ◽  
pp. 237-243 ◽  
Author(s):  
Hao Shen ◽  
Krishna G Peri ◽  
Xing-Fei Deng ◽  
Sylvain Chemtob ◽  
Daya R Varma
Keyword(s):  
Vas Deferens ◽  
Polyclonal Antibodies ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Rat Tissues ◽  
Adult Rats ◽  
Adult Rat ◽  
Old Rats ◽  
Kidney Liver ◽  
The Brain

Distribution of α1-adrenoceptor (α1AR) subtype (α1A, α1B, α1D) proteins in brain, heart, kidney, and liver of 1-week-old rats and in brain, heart, aorta, kidney, liver, vas deferens, prostate, and adrenal glands of adult rats was investigated by Western analysis, using receptor subtype specific polyclonal antibodies. High levels of immunoreactive α1AAR and α1DAR in brain and heart and of α1BAR in liver and heart of neonatal rats were detected. In adult rat tissues, the abundance of α1AAR protein was most marked in the brain, intermediate in heart, aorta, liver, vas deferens, and adrenals, and minimal in the kidney and prostate; relative to other tissues, the expression of α1BAR was higher in brain and heart and that of α1DAR in brain. All the three receptor subtypes increased with age in the brain cortex, whereas the abundance of α1BAR increased in the heart but decreased in the liver; α1AAR and α1DAR in liver, kidney, and heart were not affected by age. It is concluded that α1AR subtypes are widely expressed in different neonatal and adult rat tissues.Key words: α1A-adrenoceptors, α1B-adrenoceptors, α1D-adrenoceptors, α1-adrenoceptor proteins.

P2 receptors in the regulation of renal transport mechanisms

2008 ◽  
Vol 294 (1) ◽  
pp. F10-F27 ◽  
Author(s):  
Volker Vallon
Keyword(s):  
Collecting Duct ◽  
P2 Receptors ◽  
Extracellular Nucleotides ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Inhibitory Influence ◽  
P2 Receptor ◽  
Transport Mechanisms ◽  
Renal Epithelia ◽  
Regulation Of Transport

Extracellular nucleotides (e.g., ATP) regulate physiological and pathophysiological processes through activation of nucleotide P2 receptors in the plasma membrane. Examples include such diverse processes as communication from taste buds to gustatory nerves, platelet aggregation, nociception, or neutrophil chemotaxis. Over approximately the last 15 years, evidence has also accumulated that cells in renal epithelia release nucleotides in response to physiological stimuli and that these nucleotides act in a paracrine and autocrine way to activate P2 receptors and play a significant role in the regulation of transport mechanisms and cell volume regulation. This review discusses potential stimuli and mechanisms involved in nucleotide release in renal epithelia and summarizes the available data on the expression and function of nucleotide P2 receptors along the native mammalian tubular and collecting duct system. Using established agonist profiles for P2 receptor subtypes, significant insights have been gained particularly into a potential role for P2Y2-like receptors in the regulation of transport mechanisms in the collecting duct. Due to the lack of receptor subtype-specific antagonists, however, the in vivo relevance of P2 receptor subtypes is unclear. Studies in gene knockout mice provided first insights including an antihypertensive activity of P2Y2receptors that is linked to an inhibitory influence on renal Na+and water reabsorption. We are only beginning to unravel the important roles of extracellular nucleotides and P2 receptors in the regulation of the diverse transport mechanisms of the kidney.

scholarly journals Melatonin

2002 ◽  
Vol 4 (1) ◽  
pp. 57-72 ◽  
Keyword(s):  
Seasonal Affective Disorder ◽  
Physiological Role ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Receptor Subtypes ◽  
Seasonal Breeding ◽  
Livestock Management ◽  
G Protein Coupled ◽  
The Brain ◽  
Melatonin Production

Melatonin (MEL) is a hormone synthesized and secreted by the pineal gland deep within the brain in response to photoperiodic cues relayed from the retina via an endogenous circadian oscillator within the suprachiasmatic nucleus in the hypothalamus. The circadian rhythm of melatonin production and release, characterized by nocturnal activity and daytime quiescence, is an important temporal signal to the body structures that can read it. Melatonin acts through high-affinity receptors located centrally and in numerous peripheral organs. Different receptor subtypes have been cloned and characterized: MT(1) and MT(2) (transmembrane G-protein-coupled receptors), and MT(3). However, their physiological role remains unelucidated, although livestock management applications already include the control of seasonal breeding and milk production. As for potential therapeutic applications, exogenous melatonin or a melatonin agonist and selective 5-hydroxytrypiamine receptor (5-HT(2c)) antagonist, eg, S 20098, can be used to manipulate circadian processes such as the sleep-vake cycle, which are frequently disrupted in many conditions, most notably seasonal affective disorder.

scholarly journals The Contribution of Formyl Peptide Receptor Dysfunction to the Course of Neuroinflammation: A Potential Role in the Brain Pathology

2020 ◽  
Vol 18 (3) ◽  
pp. 229-249 ◽  
Author(s):  
Ewa Trojan ◽  
Natalia Bryniarska ◽  
Monika Leśkiewicz ◽  
Magdalena Regulska ◽  
Katarzyna Chamera ◽  
...  
Keyword(s):  
Potential Role ◽  
Membrane Receptors ◽  
Formyl Peptide Receptor ◽  
Proinflammatory Response ◽  
Formyl Peptide ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
G Protein Coupled ◽  
The Brain

: Chronic inflammatory processes within the central nervous system (CNS) are in part responsible for the development of neurodegenerative and psychiatric diseases. These processes are associated with, among other things, the increased and disturbed activation of microglia and the elevated production of proinflammatory factors. Recent studies indicated that the disruption of the process of resolution of inflammation (RoI) may be the cause of CNS disorders. It is shown that the RoI is regulated by endogenous molecules called specialized pro-resolving mediators (SPMs), which interact with specific membrane receptors. Some SPMs activate formyl peptide receptors (FPRs), which belong to the family of seven-transmembrane G protein-coupled receptors. These receptors take part not only in the proinflammatory response but also in the resolution of the inflammation process. Therefore, the activation of FPRs might have complex consequences. : This review discusses the potential role of FPRs, and in particular the role of FPR2 subtype, in the brain under physiological and pathological conditions and their involvement in processes underlying neurodegenerative and psychiatric disorders as well as ischemia, the pathogenesis of which involves the dysfunction of inflammatory processes.

Purinergic Signaling Modulates Human Bone Marrow-Derived Mesenchymal Stem Cells Function.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1441-1441
Author(s):  
Valentina Salvestrini ◽  
Davide Ferrari ◽  
Sara Gulinelli ◽  
Luisa Caione ◽  
Wanda Piacibello ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Purinergic Signaling ◽  
Human Mesenchymal Stem Cells ◽  
Membrane Receptors ◽  
Extracellular Nucleotides ◽  
P2 Receptor ◽  
Murine Bone Marrow

Abstract Abstract 1441 Poster Board I-464 Nucleotides triphosphates are extracellular messengers binding to specific plasma membrane receptors (P2Rs) modulating a wide variety of biological responses in several cell types. In this study, we show that bone marrow-derived human mesenchymal stem cells (hMSCs) express several functional P2R subtypes at the molecular and protein level. hMSCs are very resistant to the cytotoxic effects of high concentrations of extracellular ATP, as demonstrated by the lack of morphological and mitochondrial changes or release of intracellular markers of cell death. Gene expression profiling revealed that hMSCs stimulated with ATP underwent a down-regulation of genes involved in cell proliferation, whereas those involved in cell migration were strongly up-regulated. Functional studies confirmed the inhibitory activity of ATP on proliferation of hMSCs and clonogenic stromal progenitors. Furthermore, ATP potentiated the chemotactic response of hMSCs to the chemokine CXCL12, and increased their spontaneous migration. In vivo, xenotransplant experiments demonstrated that the homing capacity of hMSCs to murine bone marrow was significantly increased by pre-treatment with ATP. Moreover ATP increased the production of the pro-inflammatory cytokines IL-2, IFN-gamma, and IL-12p70, while decreasing the anti-inflammatory cytokine IL-10. Thus, our data show that purinergic signaling modulates hMSCs functions and highlight a role for extracellular nucleotides in hMSCs biology. Disclosures Di Virgilio: F. Di Virgilio serves as a consultant for Cordex Pharma Inc. (USA) involved in the development of “P2 receptor-based drugs”. : Consultancy; F. Di Virgilio serves as a consultant for Affectis Pharmaceuticals AG (Germany), involved in the development of “P2 receptor-based drugs”. : Consultancy.

scholarly journals Immunohistochemical Localization ofAT1a,AT1b, andAT2Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

2013 ◽  
Vol 2013 ◽  
pp. 1-22 ◽  
Author(s):  
Courtney Premer ◽  
Courtney Lamondin ◽  
Ann Mitzey ◽  
Robert C. Speth ◽  
Mark S. Brownfield
Keyword(s):  
Angiotensin Ii ◽  
Area Postrema ◽  
Zona Glomerulosa ◽  
Immunohistochemical Localization ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Multivesicular Bodies ◽  
Sodium Appetite ◽  
Endocytic Vesicles ◽  
The Brain

Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors:AT1a,AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealedAT1aand AT2receptors in adrenal zona glomerulosa and medulla.AT1bimmunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for theAT1areceptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus.AT1band AT2, but notAT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells wereAT1bpositive while ovoid cells were AT2positive. In the brain, neurons wereAT1a,AT1b, and AT2positive, but glia was onlyAT1bpositive. Highest levels ofAT1a,AT1b, and AT2receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors.

scholarly journals The Galanin and Galanin Receptor Subtypes, its Regulatory Role in the Biological and Pathological Functions

2017 ◽  
pp. 729-740 ◽  
Author(s):  
J. ŠÍPKOVÁ ◽  
I. KRAMÁRIKOVÁ ◽  
S. HYNIE ◽  
V. KLENEROVÁ
Keyword(s):  
G Protein Coupled Receptors ◽  
Receptor Subtypes ◽  
Galanin Receptor ◽  
Peripheral Tissues ◽  
Important Target ◽  
Galanin Receptors ◽  
The Relationship ◽  
G Protein Coupled ◽  
The Brain ◽  
Stimulation Of

The multitalented neuropeptide galanin was first discovered 30 years ago but initially no biologic activity was found. Further research studies discovered the presence of galanin in the brain and some peripheral tissues, and galanin was identified as a modulator of neurotransmission in the central and peripheral nervous system. Over the last decade there were performed very intensive studies of the neuronal actions and also of nonneuronal actions of galanin. Other galanin family peptides have been described, namely galanin, galanin-like peptide, galanin-message associated peptide and alarin. The effect of these peptides is mediated through three galanin receptors subtypes, GalR1, GalR2 and GalR3 belonging to G protein coupled receptors, and signaling via multiple transduction pathways, including inhibition of cyclic AMP/protein kinase A (GalR1, GalR3) and stimulation of phospholipase C (GalR2). This also explains why one specific molecule of galanin can be responsible for different roles in different tissues. The present review summarizes the information currently available on the relationship between the galaninergic system and known pathological states. The research of novel galanin receptor specific agonists and antagonists is also very promising for its future role in pharmacological treatment. The galaninergic system is important target for current and future biomedical research.

Stimulation of P2 receptors causes release of IL-1β–loaded microvesicles from human dendritic cells

Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 3856-3864 ◽  
Author(s):  
Cinzia Pizzirani ◽  
Davide Ferrari ◽  
Paola Chiozzi ◽  
Elena Adinolfi ◽  
Dorianna Sandonà ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Plasma Membrane ◽  
Ionic Strength ◽  
Membrane Vesicle ◽  
P2 Receptors ◽  
Membrane Receptors ◽  
Extracellular Nucleotides ◽  
Receptor Subtype ◽  
Plasma Membrane Vesicle ◽  
Stimulation Of

Abstract Dendritic cells (DCs) are professional antigen-presenting cells that initiate the immune response by activating T lymphocytes. DCs express plasma membrane receptors for extracellular nucleotides named P2 receptors (P2Rs). Stimulation of P2Rs in these cells is known to cause chemotaxis, cytokine release, and cell death and to modulate LPS-dependent differentiation. Here we show that stimulation of the P2X7 receptor subtype (P2X7R) causes fast microvesicle shedding from DC plasma membrane. Vesicle release occurs from both immature and mature DCs; however, only vesicles from mature DCs, due to their previous exposure to LPS, contain IL-1β. Microvesicles, whether from immature or mature DCs, also contain caspase-1 and -3 and cathepsin D. They also express the P2X7R in addition to other P2Rs and known markers of immune cells such as major histocompatibility complex II (MHC II) and CD39. Activation of the P2X7R by extracellular ATP causes IL-1β release from the vesicle lumen. Previous studies demonstrated that high extracellular K+ inhibits IL-1β processing and release; here we show that high ionic strength reduces microvesicle shedding when compared with a low ionic strength medium but strongly increases microvesicle IL-1β loading.

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