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1
Panicucci, Chiara, Lizzia Raffaghello, Santina Bruzzone, Serena Baratto, Elisa Principi, Carlo Minetti, Elisabetta Gazzerro et Claudio Bruno. « eATP/P2X7R Axis : An Orchestrated Pathway Triggering Inflammasome Activation in Muscle Diseases ». International Journal of Molecular Sciences 21, no 17 (19 août 2020) : 5963. http://dx.doi.org/10.3390/ijms21175963.
Texte intégralRésumé :
In muscle ATP is primarily known for its function as an energy source and as a mediator of the “excitation-transcription” process, which guarantees muscle plasticity in response to environmental stimuli. When quickly released in massive concentrations in the extracellular space as in presence of muscle membrane damage, ATP acts as a damage-associated molecular pattern molecule (DAMP). In experimental murine models of muscular dystrophies characterized by membrane instability, blockade of eATP/P2X7 receptor (R) purinergic signaling delayed the progression of the dystrophic phenotype dampening the local inflammatory response and inducing Foxp3+ T Regulatory lymphocytes. These discoveries highlighted the relevance of ATP as a harbinger of immune-tissue damage in muscular genetic diseases. Given the interactions between the immune system and muscle regeneration, the comprehension of ATP/purinerigic pathway articulated organization in muscle cells has become of extreme interest. This review explores ATP release, metabolism, feedback control and cross-talk with members of muscle inflammasome in the context of muscular dystrophies.
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Buchanan, Kelly L., Laura E. Rupprecht, M. Maya Kaelberer, Atharva Sahasrabudhe, Marguerita E. Klein, Jorge A. Villalobos, Winston W. Liu et al. « The preference for sugar over sweetener depends on a gut sensor cell ». Nature Neuroscience 25, no 2 (13 janvier 2022) : 191–200. http://dx.doi.org/10.1038/s41593-021-00982-7.
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AbstractGuided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices.
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Shirai, Y., K. Kashiwagi, N. Sakai et N. Saito. « Phospholipase A(2) and its products are involved in the purinergic receptor-mediated translocation of protein kinase C in CHO-K1 cells ». Journal of Cell Science 113, no 8 (15 avril 2000) : 1335–43. http://dx.doi.org/10.1242/jcs.113.8.1335.
Texte intégralRésumé :
The signal transduction involved in the purinergic stimuli-induced activation of protein kinase C (PKC) in CHO-K1 cells was investigated. Purinergic stimuli such as adenosine triphosphate and uridine triphosphate induced a transient translocation of PKC epsilon, gamma, and delta from the cytoplasm to the plasma membrane. These translocations were blocked by an inhibitor of phosphatidylinositol-specific phospholipase C (PLC), but not by an inhibitor of phosphatidylcholine-specific PLC. A diacylglycerol (DAG) analogue also induced reversible translocations of PKC gamma, epsilon, and delta from the cytoplasm to the plasma membrane, while the calcium ionophore A23187 caused a similar translocation of only the gamma subtype. These results confirm that the hydrolysis of phosphatidylinositol-2-phosphate by PLC and the subsequent generation of DAG and increase in Ca(2+)are involved in the purinergic stimuli-induced translocation of PKC. A DAG antagonist, 1-o-hexadecyl-2-o-acetyl-glycerol, blocked the DAG analogue-induced translocations of all PKC subtypes tested but failed to inhibit the purinergic stimuli-induced translocations of PKC epsilon and gamma. The DAG antagonist could not block the ATP- and UTP-induced translocation of PKC epsilon even in the absence of extracellular Ca(2+). Co-application of the DAG antagonist and a phospholipase A(2) (PLA(2)) inhibitor such as aristolochic acid, arachidonyltrifluoromethyl ketone, or bromoenol lactone inhibited the purinergic receptor-mediated translocation of PKC epsilon although each PLA(2) inhibitor alone did not block the translocation. In contrast to the epsilon subtype, ATP-induced translocation of PKC gamma was observed in the presence of both the PLA(2) inhibitor and the DAG antagonist. However, it is noteworthy that re-translocation of PKC gamma was hastened by the PLA(2) inhibitor. Furthermore products of PLA(2), such as lysophospholipids and fatty acids, induced the translocation of PKC gamma and epsilon in a dose dependent manner, but not delta. These results indicate that, in addition to PLC and DAG, PLA(2) and its products are involved in the purinergic stimuli-induced translocation of PKC epsilon and gamma in CHO-K1 cells. Each subtype of PKC in CHO-K1 cell is individually activated in response to a purinergic stimulation.
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Matsuyama, Hayato, AbuBakr El-Mahmoudy, Yasutake Shimizu et Tadashi Takewaki. « Nitrergic Prejunctional Inhibition of Purinergic Neuromuscular Transmission in the Hamster Proximal Colon ». Journal of Neurophysiology 89, no 5 (1 mai 2003) : 2346–53. http://dx.doi.org/10.1152/jn.00686.2002.
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Neurogenic ATP and nitric oxide (NO) may play important roles in the physiological control of gastrointestinal motility. However, the interplay between purinergic and nitrergic neurons in mediating the inhibitory neurotransmission remains uncertain. This study investigated whether neurogenic NO modulates the purinergic transmission to circular smooth muscles of the hamster proximal colon. Electrical activity was recorded from circular muscle cells of the hamster proximal colon by using the microelectrode technique. Intramural nerve stimulation with a single pulse evoked a fast purinergic inhibitory junction potential (IJP) followed by a slow nitrergic IJP. The purinergic component of the second IJP evoked by paired stimulus pulses at pulse intervals between 1 and 3 s became smaller than that of the first IJP. This purinergic IJP depression could be observed at pulse intervals <3 s, but not at longer ones, and failed to occur in the presence of NO synthase inhibitor. Exogenous NO (0.3–1 μM), at which no hyperpolarization is produced, inhibited purinergic IJPs, without altering the nitrergic IJP and exogenously applied ATP-induced hyperpolarization. In the presence of both purinoceptor antagonist and nitric oxide synthase (NOS) inhibitor, intramural nerve stimulation with 5 pulses at 20 Hz evoked vasoactive intestinal peptide (VIP)-associated IJPs, suggesting that VIP component may be masked in the IJPs of the hamster proximal colon. Our results suggest that neurogenic NO may modulate the purinergic transmission to circular smooth muscles of the hamster proximal colon via a prejunctional mechanism. In addition, VIP may be involved in the neurotransmitter in the hamster proximal colon.
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Spek, Annabel, Bingsheng Li, Beata Rutz, Anna Ciotkowska, Ru Huang, Yuhan Liu, Ruixiao Wang et al. « Purinergic smooth muscle contractions in the human prostate : estimation of relevance and characterization of different agonists ». Naunyn-Schmiedeberg's Archives of Pharmacology 394, no 6 (11 janvier 2021) : 1113–31. http://dx.doi.org/10.1007/s00210-020-02044-4.
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AbstractNon-adrenergic prostate smooth muscle contractions may account for the limited effectiveness of α1-adrenoceptor antagonists, which are the first-line option for medical treatment of voiding symptoms suggestive of benign prostatic hyperplasia. In non-human prostates, purinergic agonists induce contractions reaching similar magnitudes as α1-adrenergic contractions. However, evidence for the human prostate is highly limited, and pointed to much weaker purinergic contractions. Here, we examined contractions of different purinergic agonists in human prostate tissues. Tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath, and expression of purinergic receptors was studied by RT-PCR. Electric field stimulation (EFS)–induced contractions amounted to 104% of KCl-induced contractions (95% CI: 84–124%). From all tested agonists, only ATP induced concentration-dependent contractions, reaching an average maximum of 18% (12–24%) of KCl. Maximum tensions following application of other agonists averaged to 7.1% of KCl for α,β-methylene-ATP (1.8–12.4%), 3.9% for β,γ-methylene-ATP (2.0–5.4%), 3.1% for 2-methylthio-ATP (− 0.1–6.3%), and 5.1% for ATPγS (1.0–9.2%). Responses were not affected by the P2X antagonist NF023 or the P2Y antagonist PPADS. mRNA expression of P2X1-4 correlated with expression of a marker for catecholaminergic nerves, although neither ATP, NF023, nor PPADS changed EFS-induced contractions. Correlation between expression of receptors and the smooth muscle marker calponin was not observed. Our findings point to a low relevance of purinergic contractions in the human prostate, compared to other contractile stimuli in the human prostate and compared to purinergic contractions in non-human prostates. Purinergic contractions in the human prostate are not sensitive to NF023 or PPADS.
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Oyasu, Miho, Mineko Fujimiya, Kaori Kashiwagi, Shiho Ohmori, Hirotsugu Imaeda et Naoaki Saito. « Immunogold Electron Microscopic Demonstration of Distinct Submembranous Localization of the Activated γPKC Depending on the Stimulation ». Journal of Histochemistry & ; Cytochemistry 56, no 3 (12 novembre 2007) : 253–65. http://dx.doi.org/10.1369/jhc.7a7291.2007.
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We examined the precise intracellular translocation of γ subtype of protein kinase C (γPKC) after various extracellular stimuli using confocal laser-scanning fluorescent microscopy (CLSM) and immunogold electron microscopy. By CLSM, treatment with 12- O-tetradecanoylphorbol-13-acetate (TPA) resulted in a slow and irreversible accumulation of green fluorescent protein (GFP)-tagged γPKC (γPKC–GFP) on the plasma membrane. In contrast, treatment with Ca2+ ionophore and activation of purinergic or NMDA receptors induced a rapid and transient membrane translocation of γPKC–GFP. Although each stimulus resulted in PKC localization at the plasma membrane, electron microscopy revealed that γPKC showed a subtle but significantly different localization depending on stimulation. Whereas TPA and UTP induced a sustained localization of γPKC–GFP on the plasma membrane, Ca2+ ionophore and NMDA rapidly translocated γPKC–GFP to the plasma membrane and then restricted γPKC–GFP in submembranous area (<500 nm from the plasma membrane). These results suggest that Ca2+ influx alone induced the association of γPKC with the plasma membrane for only a moment and then located this enzyme at a proper distance in a touch-and-go manner, whereas diacylglycerol or TPA tightly anchored this enzyme on the plasma membrane. The distinct subcellular targeting of γPKC in response to various stimuli suggests a novel mechanism for PKC activation.
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Klausen, Polina, Daria Semenova, Daria Kostina, Vladimir Uspenskiy et Anna Malashicheva. « Purinergic Signaling in Pathologic Osteogenic Differentiation of Aortic Valve Interstitial Cells from Patients with Aortic Valve Calcification ». Biomedicines 11, no 2 (21 janvier 2023) : 307. http://dx.doi.org/10.3390/biomedicines11020307.
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Purinergic signaling is associated with a vast spectrum of physiological processes, including cardiovascular system function and, in particular, its pathological calcifications, such as aortic valve stenosis. Aortic valve stenosis (AS) is a degenerative disease for which there is no cure other than surgical replacement of the affected valve. Purinergic signaling is known to be involved in the pathologic osteogenic differentiation of valve interstitial cells (VIC) into osteoblast-like cells, which underlies the pathogenesis of AS. ATP, its metabolites and related nucleotides also act as signaling molecules in normal osteogenic differentiation, which is observed in pro-osteoblasts and leads to bone tissue development. We show that stenotic and non-stenotic valve interstitial cells significantly differ from each other, especially under osteogenic stimuli. In osteogenic conditions, the expression of the ecto-nucleotidases ENTPD1 and ENPP1, as well as ADORA2b, is increased in AS VICs compared to normal VICs. In addition, AS VICs after osteogenic stimulation look more similar to osteoblasts than non-stenotic VICs in terms of purinergic signaling, which suggests the stronger osteogenic differentiation potential of AS VICs. Thus, purinergic signaling is impaired in stenotic aortic valves and might be used as a potential target in the search for an anti-calcification therapy.
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Zhang, Yong, et William G. Paterson. « Characterization of the peristaltic reflex in murine distal colon ». Canadian Journal of Physiology and Pharmacology 94, no 2 (février 2016) : 190–98. http://dx.doi.org/10.1139/cjpp-2015-0086.
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Ascending and descending neuromuscular reflexes play an important role in gastrointestinal motility. However, the underlying mechanisms in colon are incompletely understood. Nerve stimulation (NS)- and balloon distention (BD)-mediated reflexes in distal colonic circular smooth muscle (CSM) and longitudinal smooth muscle (LSM) of mice were investigated using conventional intracellular recordings. In the CSM, NS evoked ascending purinergic inhibitory junction potentials (IJPs), whereas BD induced atropine-sensitive ascending depolarization with superimposed action potentials (APs). The ascending depolarization reached a peak ∼4–7 s after the onset of distention and gradually returned to baseline after termination of the distention. In the LSM, NS produced an ascending biphasic IJP followed by a train of atropine-sensitive APs. Both stimuli produced similar descending IJPs in CSM and LSM, which were blocked by MRS-2500 and MRS-2179, putative purinergic receptor blockers. These data indicate that in the murine distal colon, descending purinergic inhibition in both CSM and LSM occurs. Ascending responses are more complex, with NS producing both inhibition and excitation to CSM and LSM, and BD evoking only cholinergic excitation.
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Guzman-Aranguez, Ana, Xavier Gasull, Yolanda Diebold et Jesús Pintor. « Purinergic Receptors in Ocular Inflammation ». Mediators of Inflammation 2014 (2014) : 1–11. http://dx.doi.org/10.1155/2014/320906.
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Inflammation is a complex process that implies the interaction between cells and molecular mediators, which, when not properly “tuned,” can lead to disease. When inflammation affects the eye, it can produce severe disorders affecting the superficial and internal parts of the visual organ. The nucleoside adenosine and nucleotides including adenine mononucleotides like ADP and ATP and dinucleotides such as P1,P4-diadenosine tetraphosphate (Ap4A), and P1,P5-diadenosine pentaphosphate (Ap5A) are present in different ocular locations and therefore they may contribute/modulate inflammatory processes. Adenosine receptors, in particularA2Aadenosine receptors, present anti-inflammatory action in acute and chronic retinal inflammation. Regarding the A3receptor, selective agonists like N6-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine (CF101) have been used for the treatment of inflammatory ophthalmic diseases such as dry eye and uveoretinitis. Sideways, diverse stimuli (sensory stimulation, large intraocular pressure increases) can produce a release of ATP from ocular sensory innervation or after injury to ocular tissues. Then, ATP will activate purinergic P2 receptors present in sensory nerve endings, the iris, the ciliary body, or other tissues surrounding the anterior chamber of the eye to produce uveitis/endophthalmitis. In summary, adenosine and nucleotides can activate receptors in ocular structures susceptible to suffer from inflammatory processes. This involvement suggests the possible use of purinergic agonists and antagonists as therapeutic targets for ocular inflammation.
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Chen, Zhiyong, Chi Zhang, Xiaodan Song, Xiang Cui, Jing Liu, Neil C. Ford, Shaoqiu He et al. « BzATP Activates Satellite Glial Cells and Increases the Excitability of Dorsal Root Ganglia Neurons In Vivo ». Cells 11, no 15 (23 juillet 2022) : 2280. http://dx.doi.org/10.3390/cells11152280.
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The purinergic system plays an important role in pain transmission. Recent studies have suggested that activation of P2-purinergic receptors (P2Rs) may be involved in neuron-satellite glial cell (SGC) interactions in the dorsal root ganglia (DRG), but the details remain unclear. In DRG, P2X7R is selectively expressed in SGCs, which closely surround neurons, and is highly sensitive to 3’-O-(4-Benzoyl) benzoyl-ATP (BzATP). Using calcium imaging in intact mice to survey a large number of DRG neurons and SGCs, we examined how intra-ganglionic purinergic signaling initiated by BzATP affects neuronal activities in vivo. We developed GFAP-GCaMP6s and Pirt-GCaMP6s mice to express the genetically encoded calcium indicator GGCaM6s in SGCs and DRG neurons, respectively. The application of BzATP to the ganglion induced concentration-dependent activation of SGCs in GFAP-GCaMP6s mice. In Pirt-GCaMP6s mice, BzATP initially activated more large-size neurons than small-size ones. Both glial and neuronal responses to BzATP were blocked by A438079, a P2X7R-selective antagonist. Moreover, blockers to pannexin1 channels (probenecid) and P2X3R (A317491) also reduced the actions of BzATP, suggesting that P2X7R stimulation may induce the opening of pannexin1 channels, leading to paracrine ATP release, which could further excite neurons by acting on P2X3Rs. Importantly, BzATP increased the responses of small-size DRG neurons and wide-dynamic range spinal neurons to subsequent peripheral stimuli. Our findings suggest that intra-ganglionic purinergic signaling initiated by P2X7R activation could trigger SGC-neuron interaction in vivo and increase DRG neuron excitability.
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Muñoz, Manuel F., Theanne N. Griffith et Jorge E. Contreras. « Mechanisms of ATP release in pain : role of pannexin and connexin channels ». Purinergic Signalling 17, no 4 (18 novembre 2021) : 549–61. http://dx.doi.org/10.1007/s11302-021-09822-6.
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AbstractPain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.
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Scarpellino, Giorgia, Tullio Genova, Elisa Quarta, Carla Distasi, Marianna Dionisi, Alessandra Fiorio Pla et Luca Munaron. « P2X Purinergic Receptors Are Multisensory Detectors for Micro-Environmental Stimuli That Control Migration of Tumoral Endothelium ». Cancers 14, no 11 (31 mai 2022) : 2743. http://dx.doi.org/10.3390/cancers14112743.
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The tumoral microenvironment often displays peculiar features, including accumulation of extracellular ATP, hypoxia, low pH-acidosis, as well as an imbalance in zinc (Zn2+) and calcium (Ca2+). We previously reported the ability of some purinergic agonists to exert an anti-migratory activity on tumor-derived human endothelial cells (TEC) only when applied at a high concentration. They also trigger calcium signals associated with release from intracellular stores and calcium entry from the external medium. Here, we provide evidence that high concentrations of BzATP (100 µM), a potent agonist of P2X receptors, decrease migration in TEC from different tumors, but not in normal microvascular ECs (HMEC). The same agonist evokes a calcium increase in TEC from the breast and kidney, as well as in HMEC, but not in TEC from the prostate, suggesting that the intracellular pathways responsible for the P2X-induced impairment of TEC migration could vary among different tumors. The calcium signal is mainly due to a long-lasting calcium entry from outside and is strictly dependent on the presence of the receptor occupancy. Low pH, as well as high extracellular Zn2+ and Ca2+, interfere with the response, a distinctive feature typically found in some P2X purinergic receptors. This study reveals that a BzATP-sensitive pathway impairs the migration of endothelial cells from different tumors through mechanisms finely tuned by environmental factors.
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Scarpellino, Giorgia, Tullio Genova, Daniele Avanzato, Michela Bernardini, Serena Bianco, Sara Petrillo, Emanuela Tolosano et al. « Purinergic Calcium Signals in Tumor-Derived Endothelium ». Cancers 11, no 6 (1 juin 2019) : 766. http://dx.doi.org/10.3390/cancers11060766.
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Tumor microenvironment is particularly enriched with extracellular ATP (eATP), but conflicting evidence has been provided on its functional effects on tumor growth and vascular remodeling. We have previously shown that high eATP concentrations exert a strong anti-migratory, antiangiogenic and normalizing activity on human tumor-derived endothelial cells (TECs). Since both metabotropic and ionotropic purinergic receptors trigger cytosolic calcium increase ([Ca2+]c), the present work investigated the properties of [Ca2+]c events elicited by high eATP in TECs and their role in anti-migratory activity. In particular, the quantitative and kinetic properties of purinergic-induced Ca2+ release from intracellular stores and Ca2+ entry from extracellular medium were investigated. The main conclusions are: (1) stimulation of TECs with high eATP triggers [Ca2+]c signals which include Ca2+ mobilization from intracellular stores (mainly ER) and Ca2+ entry through the plasma membrane; (2) the long-lasting Ca2+ influx phase requires both store-operated Ca2+ entry (SOCE) and non-SOCE components; (3) SOCE is not significantly involved in the antimigratory effect of high ATP stimulation; (4) ER is the main source for intracellular Ca2+ release by eATP: it is required for the constitutive migratory potential of TECs but is not the only determinant for the inhibitory effect of high eATP; (5) a complex interplay occurs among ER, mitochondria and lysosomes upon purinergic stimulation; (6) high eUTP is unable to inhibit TEC migration and evokes [Ca2+]c signals very similar to those described for eATP. The potential role played by store-independent Ca2+ entry and Ca2+-independent events in the regulation of TEC migration by high purinergic stimula deserves future investigation.
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Dahl, Gerhard. « ATP release through pannexon channels ». Philosophical Transactions of the Royal Society B : Biological Sciences 370, no 1672 (5 juillet 2015) : 20140191. http://dx.doi.org/10.1098/rstb.2014.0191.
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Extracellular adenosine triphosphate (ATP) serves as a signal for diverse physiological functions, including spread of calcium waves between astrocytes, control of vascular oxygen supply and control of ciliary beat in the airways. ATP can be released from cells by various mechanisms. This review focuses on channel-mediated ATP release and its main enabler, Pannexin1 (Panx1). Six subunits of Panx1 form a plasma membrane channel termed ‘pannexon’. Depending on the mode of stimulation, the pannexon has large conductance (500 pS) and unselective permeability to molecules less than 1.5 kD or is a small (50 pS), chloride-selective channel. Most physiological and pathological stimuli induce the large channel conformation, whereas the small conformation so far has only been observed with exclusive voltage activation of the channel. The interaction between pannexons and ATP is intimate. The pannexon is not only the conduit for ATP, permitting ATP efflux from cells down its concentration gradient, but the pannexon is also modulated by ATP. The channel can be activated by ATP through both ionotropic P2X as well as metabotropic P2Y purinergic receptors. In the absence of a control mechanism, this positive feedback loop would lead to cell death owing to the linkage of purinergic receptors with apoptotic processes. A control mechanism preventing excessive activation of the purinergic receptors is provided by ATP binding (with low affinity) to the Panx1 protein and gating the channel shut.
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Boncoeur, Émilie, Guillaume F. Bouvet, Francis Migneault, Valérie Tardif, Pasquale Ferraro, Danuta Radzioch, Juan B. de Sanctis et al. « Induction of nitric oxide synthase expression by lipopolysaccharide is mediated by calcium-dependent PKCα-β1 in alveolar epithelial cells ». American Journal of Physiology-Lung Cellular and Molecular Physiology 305, no 2 (15 juillet 2013) : L175—L184. http://dx.doi.org/10.1152/ajplung.00295.2012.
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Nitric oxide (NO) plays an important role in innate host defense and inflammation. In response to infection, NO is generated by inducible nitric oxide synthase (iNOS), a gene product whose expression is highly modulated by different stimuli, including lipopolysaccharide (LPS) from gram-negative bacteria. We reported recently that LPS from Pseudomonas aeruginosa altered Na+ transport in alveolar epithelial cells via a suramin-dependent process, indicating that LPS activated a purinergic response in these cells. To further study this question, in the present work, we tested whether iNOS mRNA and protein expression were modulated in response to LPS in alveolar epithelial cells. We found that LPS induced a 12-fold increase in iNOS mRNA expression via a transcription-dependent process in these cells. iNOS protein, NO, and nitrotyrosine were also significantly elevated in LPS-treated cells. Ca2+ chelation and protein kinase C (PKCα-β1) inhibition suppressed iNOS mRNA induction by LPS, implicating Ca2+-dependent PKC signaling in this process. LPS evoked a significant increase of extracellular ATP. Because PKC activation is one of the signaling pathways known to mediate purinergic signaling, we evaluated the hypothesis that iNOS induction was ATP dependent. Although high suramin concentration inhibited iNOS mRNA induction, the process was not ATP dependent, since specific purinergic receptor antagonists could not inhibit the process. Altogether, these findings demonstrate that iNOS expression is highly modulated in alveolar epithelial cells by LPS via a Ca2+/PKCα-β1 pathway independent of ATP signaling.
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Ferrari, D., P. Chiozzi, S. Falzoni, M. Dal Susino, L. Melchiorri, O. R. Baricordi et F. Di Virgilio. « Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. » Journal of Immunology 159, no 3 (1 août 1997) : 1451–58. http://dx.doi.org/10.4049/jimmunol.159.3.1451.
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Abstract Extracellular ATP (ATPe) is known to cause release of processed IL-1 beta from LPS-treated macrophages and microglial cells. IL-1 beta release is fast and thought to be associated with cell death. We have reinvestigated this process to identify 1) the purinergic receptor involved; 2) the relationship to cell death; and 3) pharmacologic agonists or antagonists able to modulate IL-1 beta release. Our data confirm that ATPe is a powerful stimulus for IL-1 beta release from LPS-treated human macrophages; however, we also show that IL-1 beta release is not necessarily associated with cell death, as it occurs at lower ATP concentrations and much earlier than leakage of cytoplasmic markers. The selective purinergic P2Z receptor agonist benzoylbenzoyl ATP was at least one order of magnitude more powerful than ATP, but also had a strong cytotoxic effect. 2-Methylthio-ATP was equipotent as ATPe at the optimal concentration of 1 mM, but markedly inhibitory at higher concentrations. The irreversible P2Z blocker-oxidized ATP completely inhibited ATPe-induced IL-1 beta release. IL-1 beta release also was inhibited by increasing the K+ concentration of the incubation medium. These data suggest that ATPe triggers IL-1 beta via the purinergic P2Z receptor recently shown to be expressed by human macrophages and identified as a new member of the P2X family (P2X7), and provide pharmacologic tools for the modulation of IL-1 beta release in vitro and, possibly, in vivo.
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Rohn, T. T., A. Sauvadet, C. Pavoine et F. Pecker. « Xanthine affects [Ca2+]i and contractile responses of ventricular cardiocytes to electrical stimulation ». American Journal of Physiology-Cell Physiology 273, no 3 (1 septembre 1997) : C909—C917. http://dx.doi.org/10.1152/ajpcell.1997.273.3.c909.
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Xanthine, a major purine by-product of ATP, accumulates during myocardial ischemia. In the present study, we show that xanthine (0.5-1 mM) impaired the occurrence of cytosolic Ca2+ concentration ([Ca2+]i) transients, visualized in fura 2-loaded cells, and twitches of contraction in ventricular cardiocytes in response to electrical stimulation. This effect of xanthine was independent of superoxide anion production. That it was a result of decreased membrane excitability was supported by the following: 1) it was reversed by increasing either the amplitude of the stimulus voltage required to stimulate cardiocytes or the extracellular concentration of NaCl; and 2) xanthine reversed the depolarization following electrical stimulation in cardiocytes loaded with the voltage-sensitive dye bis-oxonol. P2 purinergic-agonists, including ATP (10 microM), but not P1 purinergic agonists reproduced the effects seen with xanthine. In addition, a lack of additivity between xanthine and ATP at maximal concentrations was observed. We conclude that xanthine, through activation of a P2 purinoceptor, may contribute to myocardial arrhythmia occurring during ischemia-reperfusion injury.
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Fleck, David, Nadine Mundt, Felicitas Bruentgens, Petra Geilenkirchen, Patricia A. Machado, Thomas Veitinger, Sophie Veitinger et al. « Distinct purinergic signaling pathways in prepubescent mouse spermatogonia ». Journal of General Physiology 148, no 3 (29 août 2016) : 253–71. http://dx.doi.org/10.1085/jgp.201611636.
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Spermatogenesis ranks among the most complex, yet least understood, developmental processes. The physiological principles that control male germ cell development in mammals are notoriously difficult to unravel, given the intricate anatomy and complex endo- and paracrinology of the testis. Accordingly, we lack a conceptual understanding of the basic signaling mechanisms within the testis, which control the seminiferous epithelial cycle and thus govern spermatogenesis. Here, we address paracrine signal transduction in undifferentiated male germ cells from an electrophysiological perspective. We identify distinct purinergic signaling pathways in prepubescent mouse spermatogonia, both in vitro and in situ. ATP—a dynamic, widespread, and evolutionary conserved mediator of cell to cell communication in various developmental contexts—activates at least two different spermatogonial purinoceptor isoforms. Both receptors operate within nonoverlapping stimulus concentration ranges, display distinct response kinetics and, in the juvenile seminiferous cord, are uniquely expressed in spermatogonia. We further find that spermatogonia express Ca2+-activated large-conductance K+ channels that appear to function as a safeguard against prolonged ATP-dependent depolarization. Quantitative purine measurements additionally suggest testicular ATP-induced ATP release, a mechanism that could increase the paracrine radius of initially localized signaling events. Moreover, we establish a novel seminiferous tubule slice preparation that allows targeted electrophysiological recordings from identified testicular cell types in an intact epithelial environment. This unique approach not only confirms our in vitro findings, but also supports the notion of purinergic signaling during the early stages of spermatogenesis.
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Brayden, Joseph E., Yao Li et Matthew J. Tavares. « Purinergic Receptors Regulate Myogenic Tone in Cerebral Parenchymal Arterioles ». Journal of Cerebral Blood Flow & ; Metabolism 33, no 2 (21 novembre 2012) : 293–99. http://dx.doi.org/10.1038/jcbfm.2012.169.
Texte intégralRésumé :
Myogenic tone is a fundamental aspect of vascular behavior in resistance arteries. This contractile response to changes in intravascular pressure is critically involved in blood flow autoregulation in tissues such as the brain, kidneys, and heart. Myogenic tone also helps regulate precapillary pressure and provides a level of background tone upon which vasodilator stimuli act to increase tissue perfusion when appropriate. Despite the importance of these processes in the brain, little is known about the mechanisms involved in control of myogenic tone in the cerebral microcirculation. Here, we report that pharmacological inhibition of P2Y4 and P2Y6 pyrimidine receptors nearly abolished myogenic tone in cerebral parenchymal arterioles (PAs). Molecular suppression of either P2Y4 or P2Y6 receptors using antisense oligodeoxynucleotides reduced myogenic tone by 44% ± 8% and 45% ± 7%, respectively. These results indicate that both receptor isoforms are activated by increased intravascular pressure, which enhances the activity of voltage-dependent calcium channels and increases myogenic tone in PAs. Enhancement or inhibition of ectonucleotidase activity had no effect on parenchymal arteriolar myogenic tone, indicating that this response is not mediated by local release of nucleotides, but rather may involve direct mechanical activation of P2Y receptors in the smooth muscle cells.
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Yang, Lijing, Mengjia Hu, Yukai Lu, Songling Han et Junping Wang. « Inflammasomes and the Maintenance of Hematopoietic Homeostasis : New Perspectives and Opportunities ». Molecules 26, no 2 (9 janvier 2021) : 309. http://dx.doi.org/10.3390/molecules26020309.
Texte intégralRésumé :
Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.
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Yang, Lijing, Mengjia Hu, Yukai Lu, Songling Han et Junping Wang. « Inflammasomes and the Maintenance of Hematopoietic Homeostasis : New Perspectives and Opportunities ». Molecules 26, no 2 (9 janvier 2021) : 309. http://dx.doi.org/10.3390/molecules26020309.
Texte intégralRésumé :
Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.
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Mulkey, Daniel K., Ian C. Wenker et Orsolya Kréneisz. « Current ideas on central chemoreception by neurons and glial cells in the retrotrapezoid nucleus ». Journal of Applied Physiology 108, no 5 (mai 2010) : 1433–39. http://dx.doi.org/10.1152/japplphysiol.01240.2009.
Texte intégralRésumé :
Central chemoreception is the mechanism by which CO2/pH-sensitive neurons (i.e., chemoreceptors) regulate breathing in response to changes in tissue pH. A region of the brain stem called the retrotrapezoid nucleus (RTN) is thought to be an important site of chemoreception ( 23 ), and recent evidence suggests that RTN chemoreception involves two interrelated mechanisms: H+-mediated activation of pH-sensitive neurons ( 38 ) and purinergic signaling ( 19 ), possibly from pH-sensitive glial cells. A third, potentially important, aspect of RTN chemoreception is the regulation of blood flow, which is an important determinate of tissue pH and consequently chemoreceptor activity. It is well established in vivo that changes in cerebral blood flow can profoundly affect the chemoreflex ( 2 ); e.g., limiting blood flow by vasoconstriction acidifies tissue pH and increases the ventilatory response to CO2, whereas vasodilation can wash out metabolically produced CO2 from tissue to increase tissue pH and decrease the stimulus at chemoreceptors. In this review, we will summarize the defining characteristics of pH-sensitive neurons and discuss potential contributions of pH-sensitive glial cells as both a source of purinergic drive to pH-sensitive neurons and a modulator of vasculature tone.
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Wong, Adrian Y. C., Brian Billups, Jamie Johnston, Richard J. Evans et Ian D. Forsythe. « Endogenous Activation of Adenosine A1 Receptors, but Not P2X Receptors, During High-Frequency Synaptic Transmission at the Calyx of Held ». Journal of Neurophysiology 95, no 6 (juin 2006) : 3336–42. http://dx.doi.org/10.1152/jn.00694.2005.
Texte intégralRésumé :
Activation of presynaptic receptors plays an important role in modulation of transmission at many synapses, particularly during high-frequency trains of stimulation. Adenosine-triphosphate (ATP) is coreleased with several neurotransmitters and acts at presynaptic sites to reduce transmitter release; such presynaptic P2X receptors occur at inhibitory and excitatory terminals in the medial nucleus of the trapezoid body (MNTB). We have investigated the mechanism of purinergic modulation during high-frequency repetitive stimulation at the calyx of Held synapse. Suppression of calyceal excitatory postsynaptic currents (EPSCs) by ATP and ATPγS (100 μM) was mimicked by adenosine application and was blocked by DPCPX (10 μM), indicating mediation by adenosine A1 receptors. DPCPX enhanced EPSC amplitudes during high-frequency synaptic stimulation, suggesting that adenosine has a physiological role in modulating transmission at the calyx. The Luciferin-Luciferase method was used to probe for endogenous ATP release (at 37°C), but no release was detected. Blockers of ectonucleotidases also had no effect on endogenous synaptic depression, suggesting that it is adenosine acting on A1 receptors, rather than degradation of released ATP, which accounts for presynaptic purinergic suppression of synaptic transmission during physiological stimulus trains at this glutamatergic synapse.
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He, Jin-Rong, Shu-Guang Yu, Yong Tang et Peter Illes. « Purinergic signaling as a basis of acupuncture-induced analgesia ». Purinergic Signalling 16, no 3 (23 juin 2020) : 297–304. http://dx.doi.org/10.1007/s11302-020-09708-z.
Texte intégralRésumé :
Abstract This review summarizes experimental evidence indicating that purinergic mechanisms are causally involved in acupuncture (AP)-induced analgesia. Electroacupuncture (EAP) and manual AP release at pain-relevant acupoints ATP which may activate purinergic P2X receptors (Rs) especially of the P2X3 type situated at local sensory nerve endings (peripheral terminals of dorsal root ganglion [DRG] neurons); the central processes of these neurons are thought to inhibit via collaterals of ascending dorsal horn spinal cord neurons, pain-relevant pathways projecting to higher centers of the brain. In addition, during AP/EAP non-neuronal P2X4 and/or P2X7Rs localized at microglial cells of the CNS become activated at the spinal or supraspinal levels. In consequence, these microglia secrete bioactive compounds such as growth factors, cytokines, chemokines, reactive oxygen, and nitrogen species, which modulate the ascending neuronal pathways conducting painful stimuli. Alternatively, ATP released at acupoints by AP/EAP may be enzymatically degraded to adenosine, stimulating in loco presynaptic A1Rs exerting an inhibitory influence on the primary afferent fibers (the above mentioned pain-sensing peripheral terminals of DRG neurons) which thereby fail to conduct action potentials to the spinal cord dorsal horn. The net effect of the stimulation of P2X3, P2X4, P2X7, and A1Rs by the AP/EAP-induced release of ATP/adenosine at certain acupoints will be analgesia.
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Iwanaga, Koichi, Takahisa Murata, Masatoshi Hori et Hiroshi Ozaki. « Purinergic P2Y1 receptor signaling mediates wound stimuli-induced cyclooxygenase-2 expression in intestinal subepithelial myofibroblasts ». European Journal of Pharmacology 702, no 1-3 (février 2013) : 158–64. http://dx.doi.org/10.1016/j.ejphar.2013.01.025.
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Sangsiri, Sutheera, Hui Xu, Roxanne Fernandes, Greg D. Fink, Heidi L. Lujan, Stephen E. DiCarlo et James J. Galligan. « Spinal cord injury alters purinergic neurotransmission to mesenteric arteries in rats ». American Journal of Physiology-Heart and Circulatory Physiology 318, no 2 (1 février 2020) : H223—H237. http://dx.doi.org/10.1152/ajpheart.00525.2019.
Texte intégralRésumé :
Complications associated with spinal cord injury (SCI) result from unregulated reflexes below the lesion level. Understanding neurotransmission distal to the SCI could improve quality of life by mitigating complications. The long-term impact of SCI on neurovascular transmission is poorly understood, but reduced sympathetic activity below the site of SCI enhances arterial neurotransmission (1). We studied sympathetic neurovascular transmission using a rat model of long-term paraplegia (T2–3) and tetraplegia (C6–7). Sixteen weeks after SCI, T2–3 and C6–7 rats had lower blood pressure (BP) than sham rats (103 ± 2 and 97 ± 4 vs. 117 ± 6 mmHg, P < 0.05). T2–3 rats had tachycardia (410 ± 6 beats/min), and C6–7 rats had bradycardia (299 ± 10 beats/min) compared with intact rats (321 ± 4 beats/min, P < 0.05). Purinergic excitatory junction potentials (EJPs) were measured in mesenteric arteries (MA) using microlectrodes, and norepinephrine (NE) release was measured using amperometry. NE release was similar in all groups, while EJP frequency-response curves from T2–3 and C6–7 rats were left-shifted vs. sham rats. EJPs in T2–3 and C6–7 rats showed facilitation followed by run-down during stimulation trains (10 Hz, 50 stimuli). MA reactivity to exogenous NE and ATP was similar in all rats. In T2–3 and C6–7 rats, NE content was increased in left cardiac ventricles compared with intact rats, but was not changed in MA, kidney, or spleen. Our data indicate that peripheral purinergic, but not adrenergic, neurotransmission increases following SCI via enhanced ATP release from periarterial nerves. Sympathetic BP support is reduced after SCI, but improving neurotransmitter release might maintain cardiovascular stability in individuals living with SCI. NEW & NOTEWORTHY This study revealed increased purinergic, but not noradrenergic, neurotransmission to mesenteric arteries in rats with spinal cord injury (SCI). An increased releasable pool of ATP in periarterial sympathetic nerves may contribute to autonomic dysreflexia following SCI, suggesting that purinergic neurotransmission may be a therapeutic target for maintaining stable blood pressure in individuals living with SCI. The selective increase in ATP release suggests that ATP and norepinephrine may be stored in separate synaptic vesicles in periarterial sympathetic varicosities.
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Hanna, Ramy L., et Marc P. Kaufman. « Role played by purinergic receptors on muscle afferents in evoking the exercise pressor reflex ». Journal of Applied Physiology 94, no 4 (1 avril 2003) : 1437–45. http://dx.doi.org/10.1152/japplphysiol.01011.2002.
Texte intégralRésumé :
The exercise pressor reflex is believed to be evoked, in part, by multiple metabolic stimuli that are generated when blood supply to exercising muscles is inadequate to meet metabolic demand. Recently, ATP, which is a P2 receptor agonist, has been suggested to be one of the metabolic stimuli evoking this reflex. We therefore tested the hypothesis that blockade of P2 receptors within contracting skeletal muscle attenuated the exercise pressor reflex in decerebrate cats. We found that popliteal arterial injection of pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 10 mg/kg), a P2 receptor antagonist, attenuated the pressor response to static contraction of the triceps surae muscles. Specifically, the pressor response to contraction before PPADS averaged 36 ± 3 mmHg, whereas afterward it averaged 14 ± 3 mmHg ( P < 0.001; n = 19). In addition, PPADS attenuated the pressor response to postcontraction circulatory occlusion ( P < 0.01; n = 11). In contrast, popliteal arterial injection of CGS-15943 (250 μg/kg), a P1 receptor antagonist, had no effect on the pressor response to static contraction of the triceps surae muscles. In addition, popliteal arterial injection of PPADS but not CGS-15943 attenuated the pressor response to stretch of the calcaneal (Achilles) tendon. We conclude that P2 receptors on the endings of thin fiber muscle afferents play a role in evoking both the metabolic and mechanoreceptor components of the exercise pressor reflex.
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Bradley, Eamonn, Andrea Law, David Bell et Christopher D. Johnson. « Effects of varying impulse number on cotransmitter contributions to sympathetic vasoconstriction in rat tail artery ». American Journal of Physiology-Heart and Circulatory Physiology 284, no 6 (1 juin 2003) : H2007—H2014. http://dx.doi.org/10.1152/ajpheart.01061.2002.
Texte intégralRésumé :
We examined the contributions of the cotransmitters norepinephrine (NE), ATP, and neuropeptide Y (NPY) to sympathetically evoked vasoconstriction in the rat tail artery in isolated vascular rings by using 1–100 stimulation impulses at 20 Hz. Phentolamine (2 μM), the α-adrenoceptor antagonist, markedly reduced responses to all stimuli, although responses to lower impulse numbers were reduced less than responses to longer trains. The purinergic receptor antagonist suramin (100 μM) reduced all responses, but to a much greater extent with few impulse trains. Responses were further reduced or abolished by addition of the second antagonist. Any remaining responses were abolished by the NPY-Y1 receptor antagonist BIBP-3226 (75 nM). NPY had a direct agonist action and potentiated sympathetically mediated responses. NPY (75 nM) potentiated responses and BIBP-3226 decreased responses to 2- and 20-impulse trains. Both affected responses from 2 impulses to >20 impulses, but there was no preferential effect on purinergic contributions to responses because neurally released NPY potentiated both “pure” NE and ATP responses equally. We conclude that all three cotransmitters contribute significantly to vascular responses and their contribution varies markedly with impulse numbers. There is considerable synergy between cotransmitters, especially with lower impulse numbers where NPY contributions are greater than expected.
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LIGHT, ALAN R., YING WU, RONALD W. HUGHEN et PETER B. GUTHRIE. « Purinergic receptors activating rapid intracellular Ca2+ increases in microglia ». Neuron Glia Biology 2, no 2 (1 décembre 2005) : 125–38. http://dx.doi.org/10.1017/s1740925x05000323.
Texte intégralRésumé :
We provide both molecular and pharmacological evidence that the metabotropic, purinergic, P2Y6, P2Y12 and P2Y13 receptors and the ionotropic P2X4 receptor contribute strongly to the rapid calcium response caused by ATP and its analogues in mouse microglia. Real-time PCR demonstrates that the most prevalent P2 receptor in microglia is P2Y6 followed, in order, by P2X4, P2Y12, and P2X7 = P2Y13. Only very small quantities of mRNA for P2Y1, P2Y2, P2Y4, P2Y14, P2X3 and P2X5 were found. Dose-response curves of the rapid calcium response gave a potency order of: 2MeSADP>ADP=UDP=IDP=UTP>ATP>BzATP, whereas A2P4 had little effect. Pertussis toxin partially blocked responses to 2MeSADP, ADP and UDP. The P2X4 antagonist suramin, but not PPADS, significantly blocked responses to ATP. These data indicate that P2Y6, P2Y12, P2Y13 and P2X receptors mediate much of the rapid calcium responses and shape changes in microglia to low concentrations of ATP, presumably at least partly because ATP is rapidly hydrolyzed to ADP. Expression of P2Y6, P2Y12 and P2Y13 receptors appears to be largely glial in the brain, so that peripheral immune cells and CNS microglia share these receptors. Thus, purinergic, metabotropic, P2Y6, P2Y12, P2Y13 and P2X4 receptors might share a role in the activation and recruitment of microglia in the brain and spinal cord by widely varying stimuli that cause the release of ATP, including infection, injury and degeneration in the CNS, and peripheral tissue injury and inflammation which is signaled via nerve signaling to the spinal cord.
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McDonnell, Bronagh, Ross Hamilton, Miranda Fong, Sean M. Ward et Kathleen D. Keef. « Functional evidence for purinergic inhibitory neuromuscular transmission in the mouse internal anal sphincter ». American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no 4 (avril 2008) : G1041—G1051. http://dx.doi.org/10.1152/ajpgi.00356.2007.
Texte intégralRésumé :
The neurotransmitter(s) underlying nitric oxide synthase (NOS)-independent neural inhibition in the internal anal sphincter (IAS) is still uncertain. The present study investigated the role of purinergic transmission. Contractile and electrical responses to electrical field stimulation of nerves (0.1–5 Hz for 10–60 s) were recorded in strips of mouse IAS. A single stimulus generated a 28-mV fast inhibitory junction potential (IJP) and relaxation. The NOS inhibitor Nω-nitro-l-arginine (l-NNA) reduced the fast IJP duration by 20%. Repetitive stimulation at 2.5–5 Hz caused a more sustained IJP and sustained relaxation. l-NNA reduced relaxation at 1 Hz and the sustained IJP at 2.5–5 Hz. All other experiments were carried out in the presence of NOS blockade. IJPs and relaxation were significantly reduced by the P2 receptor antagonists 4-[[4-formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-2-pyridinyl]azo]-1,3-benzenedisulfonic acid (PPADS) (100 μM), by desensitization of P2Y receptors with adenosine 5′-[β-thio]diphosphate (ADP-βS) (10 μM), and by the selective P2Y1 receptor blocker 2′-deoxy- N6-methyl adenosine 3′,5′-diphosphate (MRS2179) (10 μM). Relaxation and IJPs were also significantly reduced by the K+ channel blocker apamin (1 μM). Removal of extracellular potassium (Ko) increased IJP amplitude to 205% of control, whereas return of Ko 30 min later hyperpolarized cells by 19 mV and reduced IJP amplitude to 50% of control. Exogenous ATP (3 mM) relaxed muscles in the presence of TTX (1 μM) and hyperpolarized cells by 15 mV. In conclusion, these data suggest that purinergic transmission significantly contributes to NOS-independent neural inhibition in the mouse IAS. P2Y1 receptors, as well as at least one other P2 receptor subtype, contribute to this pathway. Purinergic receptors activate apamin-sensitive K+ channels as well as other apamin-insensitive conductances leading to hyperpolarization and relaxation.
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Yu, Yongbei, et William C. de Groat. « Sensitization of pelvic afferent nerves in the in vitro rat urinary bladder-pelvic nerve preparation by purinergic agonists and cyclophosphamide pretreatment ». American Journal of Physiology-Renal Physiology 294, no 5 (mai 2008) : F1146—F1156. http://dx.doi.org/10.1152/ajprenal.00592.2007.
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Effects of purinergic agonists (α,β-meATP and ATP) and cyclophosphamide-induced cystitis on bladder afferent nerve (BAN) activity were studied in an in vitro bladder-pelvic nerve preparation. Distension of the bladder induced spontaneous bladder contractions that were accompanied by multiunit afferent firing. Intravesical administration of 40 and 130 μM α,β-meATP increased afferent firing from 27 ± 3 to 53 ± 6 and 61 ± 2 spikes/s, respectively, but did not change the maximum amplitude of spontaneous bladder contractions. Electrical stimulation on the surface of the bladder elicited action potentials (AP) in BAN. α,β-meATP decreased the voltage threshold from 9.0 ± 1.2 to 3.5 ± 0.5 V (0.15-ms pulse duration) and increased the area of the APs (82% at 80-V stimulus intensity). These effects were blocked by TNP-ATP (30 μM). ATP (2 mM) applied in the bath produced similar changes in BAN activity. These effects were blocked by bath application of PPADS (30 μM). Neither TNP-ATP nor PPADS affected BAN activity induced by distension of the bladder. Cystitis induced by pretreatment of the rats with cyclophosphamide (100 mg/kg ip) increased afferent firing in response to isotonic bladder distension (10–40 cmH2O), decreased the threshold, and increased the area of evoked APs. The increase in afferent firing at 10 cmH2O intravesical pressure was reduced 52% by PPADS. These results indicate that purinergic agonists acting on P2X receptors and cystitis induced by cyclophosphamide can increase excitability of the BANs.
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Henriques, Tiago, Emilio Agostinelli, Andres Hernandez-Clavijo, Devendra Kumar Maurya, Jason R. Rock, Brian D. Harfe, Anna Menini et Simone Pifferi. « TMEM16A calcium-activated chloride currents in supporting cells of the mouse olfactory epithelium ». Journal of General Physiology 151, no 7 (2 mai 2019) : 954–66. http://dx.doi.org/10.1085/jgp.201812310.
Texte intégralRésumé :
Glial-like supporting (or sustentacular) cells are important constituents of the olfactory epithelium that are involved in several physiological processes such as production of endocannabinoids, insulin, and ATP and regulation of the ionic composition of the mucus layer that covers the apical surface of the olfactory epithelium. Supporting cells express metabotropic P2Y purinergic receptors that generate ATP-induced Ca2+ signaling through the activation of a PLC-mediated cascade. Recently, we reported that a subpopulation of supporting cells expresses also the Ca2+-activated Cl− channel TMEM16A. Here, we sought to extend our understanding of a possible physiological role of this channel in the olfactory system by asking whether Ca2+ can activate Cl− currents mediated by TMEM16A. We use whole-cell patch-clamp analysis in slices of the olfactory epithelium to measure dose–response relations in the presence of various intracellular Ca2+ concentrations, ion selectivity, and blockage. We find that knockout of TMEM16A abolishes Ca2+-activated Cl− currents, demonstrating that TMEM16A is essential for these currents in supporting cells. Also, by using extracellular ATP as physiological stimuli, we found that the stimulation of purinergic receptors activates a large TMEM16A-dependent Cl− current, indicating a possible role of TMEM16A in ATP-mediated signaling. Altogether, our results establish that TMEM16A-mediated currents are functional in olfactory supporting cells and provide a foundation for future work investigating the precise physiological role of TMEM16A in the olfactory system.
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Furuya, Kishio, Ju Jing Tan, Francis Boudreault, Masahiro Sokabe, Yves Berthiaume et Ryszard Grygorczyk. « Real-time imaging of inflation-induced ATP release in the ex vivo rat lung ». American Journal of Physiology-Lung Cellular and Molecular Physiology 311, no 5 (1 novembre 2016) : L956—L969. http://dx.doi.org/10.1152/ajplung.00425.2015.
Texte intégralRésumé :
Extracellular ATP and other nucleotides are important autocrine/paracrine mediators that regulate diverse processes critical for lung function, including mucociliary clearance, surfactant secretion, and local blood flow. Cellular ATP release is mechanosensitive; however, the impact of physical stimuli on ATP release during breathing has never been tested in intact lungs in real time and remains elusive. In this pilot study, we investigated inflation-induced ATP release in rat lungs ex vivo by real-time luciferin-luciferase (LL) bioluminescence imaging coupled with simultaneous infrared tissue imaging to identify ATP-releasing sites. With LL solution introduced into air spaces, brief inflation of such edematous lung (1 s, ∼20 cmH2O) induced transient (<30 s) ATP release in a limited number of air-inflated alveolar sacs during their recruitment/opening. Released ATP reached concentrations of ∼10−6 M, relevant for autocrine/paracrine signaling, but it remained spatially restricted to single alveolar sacs or their clusters. ATP release was stimulus dependent: prolonged (100 s) inflation evoked long-lasting ATP release that terminated upon alveoli deflation/derecruitment while cyclic inflation/suction produced cyclic ATP release. With LL introduced into blood vessels, inflation induced transient ATP release in many small patchlike areas the size of alveolar sacs. Findings suggest that inflation induces ATP release in both alveoli and the surrounding blood capillary network; the functional units of ATP release presumably consist of alveolar sacs or their clusters. Our study demonstrates the feasibility of real-time ATP release imaging in ex vivo lungs and provides the first direct evidence of inflation-induced ATP release in lung air spaces and in pulmonary blood capillaries, highlighting the importance of purinergic signaling in lung function.
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Giannantoni, Antonella, Silvia Proietti, Silvia Giovannozzi et Massimo Porena. « Vesical Urothelium and New Concepts ». Urologia Journal 79, no 1 (janvier 2012) : 14–18. http://dx.doi.org/10.5301/ru.2012.9021.
Texte intégralRésumé :
Vesical urothelium was long considered to simply be a protection barrier, which passively separates the urinary content from the underlying smooth muscle and the blood stream. Recent observations, though, have pointed out that vesical urothelium cells have clear active and sensory functions, in response to various physical and chemical stimuli. Among these characteristics are the expression of several neurotransmitters and receptors: Acetylcholine, Nitric Oxide, VIP, CGRP, NKA, SP and cholinergic, vanilloid, purinergic, and tachykinin receptors. Urothelium-produced neurotransmitters are likely supposed to act through a receptor stimulation of the afferent nerve fibers within the sub-urothelial spaces. Sub-urothelial myofibroblasts are considered to play a mediation role between urothelium-produced neurotransmitters and the underlying receptors. According to these observations, a pharmacologic modulation, directly affecting the urothelium, can be hypothesized.
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Amorim, Mateus Ramos, et Júnia Lara de Deus. « Purinergic signalling and TRPV1 receptors are associated with the carotid body plasticity induced by an apnoea-like stimulus ». Journal of Physiology 596, no 15 (26 mars 2018) : 2961–62. http://dx.doi.org/10.1113/jp275889.
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Moschetta, Donato, Enrico Di Maria, Vincenza Valerio, Ilaria Massaiu, Michele Bozzi, Paola Songia, Yuri D’alessandra, Veronika A. Myasoedova et Paolo Poggio. « Purinergic Receptor P2Y2 Stimulation Averts Aortic Valve Interstitial Cell Calcification and Myofibroblastic Activation ». Biomedicines 10, no 2 (16 février 2022) : 457. http://dx.doi.org/10.3390/biomedicines10020457.
Texte intégralRésumé :
Rationale—Calcific aortic valve stenosis (CAVS) is a pathological condition of the aortic valve with a prevalence of 3% in the general population. It is characterized by massive rearrangement of the extracellular matrix, mostly due to the accumulation of fibro-calcific deposits driven by valve interstitial cells (VIC), and no pharmacological treatment is currently available. The aim of this study was to evaluate the effects of P2Y2 receptor (P2RY2) activation on fibro-calcific remodeling of CAVS. Methods—We employed human primary VICs isolated from CAVS leaflets treated with 2-thiouridine-5′-triphosphate (2ThioUTP, 10 µM), an agonist of P2RY2. The calcification was induced by inorganic phosphate (2 mM) and ascorbic acid (50 µg/mL) for 7 or 14 days, while the 2ThioUTP was administered starting from the seventh day. 2ThioUTP was chronically administered for 5 days to evaluate myofibroblastic activation. Results—P2RY2 activation, under continuous or interrupted pro-calcific stimuli, led to a significant inhibition of VIC calcification potential (p < 0.01). Moreover, 2ThioUTP treatment was able to significantly reduce pro-fibrotic gene expression (p < 0.05), as well as that of protein α-smooth muscle actin (p = 0.004). Conclusions—Our data suggest that P2RY2 activation should be further investigated as a pharmacological target for the prevention of CAVS progression, acting on both calcification and myofibroblastic activation.
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Khan, Amna, Salman Khan et Yeong Shik Kim. « Insight into Pain Modulation : Nociceptors Sensitization and Therapeutic Targets ». Current Drug Targets 20, no 7 (9 mai 2019) : 775–88. http://dx.doi.org/10.2174/1389450120666190131114244.
Texte intégralRésumé :
Pain is a complex multidimensional concept that facilitates the initiation of the signaling cascade in response to any noxious stimuli. Action potential generation in the peripheral nociceptor terminal and its transmission through various types of nociceptors corresponding to mechanical, chemical or thermal stimuli lead to the activation of receptors and further neuronal processing produces the sensation of pain. Numerous types of receptors are activated in pain sensation which vary in their signaling pathway. These signaling pathways can be regarded as a site for modulation of pain by targeting the pain transduction molecules to produce analgesia. On the basis of their anatomic location, transient receptor potential ion channels (TRPV1, TRPV2 and TRPM8), Piezo 2, acid-sensing ion channels (ASICs), purinergic (P2X and P2Y), bradykinin (B1 and B2), α-amino-3-hydroxy-5- methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), metabotropic glutamate (mGlu), neurokinin 1 (NK1) and calcitonin gene-related peptide (CGRP) receptors are activated during pain sensitization. Various inhibitors of TRPV1, TRPV2, TRPM8, Piezo 2, ASICs, P2X, P2Y, B1, B2, AMPA, NMDA, mGlu, NK1 and CGRP receptors have shown high therapeutic value in experimental models of pain. Similarly, local inhibitory regulation by the activation of opioid, adrenergic, serotonergic and cannabinoid receptors has shown analgesic properties by modulating the central and peripheral perception of painful stimuli. This review mainly focused on various classes of nociceptors involved in pain transduction, transmission and modulation, site of action of the nociceptors in modulating pain transmission pathways and the drugs (both clinical and preclinical data, relevant to targets) alleviating the painful stimuli by exploiting nociceptor-specific channels and receptors.
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Speirs, Lynne, Aisling Donnelly, Joanne Lynch, C. Norman Scholfield et Christopher Johnson. « ATP and norepinephrine contributions to sympathetic vasoconstriction of tail artery are altered in streptozotocin-diabetic rats ». American Journal of Physiology-Heart and Circulatory Physiology 291, no 5 (novembre 2006) : H2327—H2333. http://dx.doi.org/10.1152/ajpheart.01298.2005.
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Sympathetic vasoconstriction is susceptible to diabetes, but contributions made by purinergic neurotransmission in this state have not been investigated. We aimed to evaluate sympathetic vasoconstriction contributions by ATP and norepinephrine in the tail artery from streptozotocin-diabetic rats by using isometric vascular rings. Tail arteries were isolated from rats made diabetic 3 mo earlier with streptozotocin (diabetic group), age-matched nondiabetic rats (nondiabetic injected), age-matched untreated animals (noninjected normal), and age-matched untreated animals in high glucose control Krebs solution (high glucose control). Responses to KCl (60 mM) or nerve stimulus trains of 1–100 impulses were identical in all groups. Electrical stimulation produced progressively greater contractions with increasing impulse numbers. These were partially reduced by suramin (100 μM, P2 antagonist), NF-279 (1 μM, P2X blocker), and phentolamine (2 μM, α-blocker). For purinergic antagonists, blockade was greater in diabetic vessels compared with that in others. No differential effect could be detected for phentolamine between groups. Bath-applied ATP (1 nM–1 mM) and norepinephrine (0.1 nM–100 μM) showed increased potency with diabetic group vessels. Desipramine (1 μM, norepinephrine reuptake inhibitor) potentiated neurally evoked responses in all groups equally and increased sensitivity to exogenous norepinephrine in a similar fashion. Histochemical labeling of sympathetic nerves with neuronal marker protein PGP-9.5 and a sympathetic nerve-specific antibody for tyrosine hydroxylase showed no reduction in diabetic innervation density. We demonstrate, for the first time, changes in contributions of ATP and norepinephrine in sympathetic responses of rat tail artery in diabetes, which cannot be accounted for by axonal degeneration or by changes in norepinephrine reuptake.
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Murakami, Makoto, Yasuyuki Furukawa et Shigetoshi Chiba. « Effects of Glibenclamide on Negative Cardiac Responses to Cholinergic and Purinergic Stimuli and Cromakalim in the Isolated Dog Heart ». Japanese Journal of Pharmacology 65, no 3 (1994) : 215–22. http://dx.doi.org/10.1016/s0021-5198(19)35752-x.
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Murakami, Makoto, Yasuyuki Furukawa et Shigetoshi Chiba. « Effects of Glibenclamide on Negative Cardiac Responses to Cholinerg and Purinergic Stimuli and Cromakalim in the Isolated Dog Heart. » Japanese Journal of Pharmacology 65, no 3 (1994) : 215–22. http://dx.doi.org/10.1254/jjp.65.215.
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Sikora, Andrew, Judy Liu, Celia Brosnan, Gary Buell, Iain Chessel et Barry R. Bloom. « Cutting Edge : Purinergic Signaling Regulates Radical-Mediated Bacterial Killing Mechanisms in Macrophages Through a P2X7-Independent Mechanism ». Journal of Immunology 163, no 2 (15 juillet 1999) : 558–61. http://dx.doi.org/10.4049/jimmunol.163.2.558.
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Abstract Signaling by extracellular nucleotides through P2 purinergic receptors affects diverse macrophage functions; however, its role in regulating antimicrobial radicals during bacterial infection has not been investigated. Mycobacterium tuberculosis-infected macrophages released ATP in a dose-dependent manner, which correlated with nitrite accumulation. P2 receptor inhibitors, including oxidized ATP, blocked NO synthase (NOSII) up-regulation and NO production induced by infection with M. tuberculosis or bacille Calmette-Guérin, or treatment with LPS or TNF-α. Oxidized ATP also inhibited oxygen radical production and activation of NF-κB and AP-1 in response to infection and inhibited NO-dependent killing of bacille Calmette-Guérin by macrophages. Experiments using macrophages derived from P2X7 gene-disrupted mice ruled out an essential role for P2X7 in NOSII regulation. These data demonstrate that P2 receptors regulate macrophage activation in response to bacteria and proinflammatory stimuli, and suggest that extracellular nucleotides released from infected macrophages may enhance production of oxygen radicals and NO at sites of infection.
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Kindig, Angela E., Shawn G. Hayes et Marc P. Kaufman. « Blockade of purinergic 2 receptors attenuates the mechanoreceptor component of the exercise pressor reflex ». American Journal of Physiology-Heart and Circulatory Physiology 293, no 5 (novembre 2007) : H2995—H3000. http://dx.doi.org/10.1152/ajpheart.00743.2007.
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The finding that pyridoxalphosphate-6-azophenyl-2,4-disulfonic acid (PPADS), a P2 antagonist, attenuated the pressor response to calcaneal tendon stretch, a purely mechanical stimulus, raises the possibility that P2 receptors sensitize mechanoreceptors to static contraction of the triceps surae muscles. The mechanical component of the exercise pressor reflex, which is evoked by static contraction, can be assessed by measuring renal sympathetic nerve activity during the first 2–5 s of this maneuver. During this period of time, group III mechanoreceptors often discharge explosively in response to the sudden tension developed at the onset of contraction. In decerebrated cats, we, therefore, examined the effect of PPADS (10 mg/kg) injected into the popliteal artery on the renal sympathetic and pressor responses to contraction and stretch. We found that PPADS significantly attenuated the renal sympathetic response to contraction, with the effect starting 2 s after its onset and continuing throughout its 60-s period. PPADS also significantly attenuated the renal sympathetic nerve response to stretch, but did so after a latency of 10 s. Our findings lead us to conclude that P2 receptors sensitize group III muscle afferents to contraction. The difference in the onset latency between the PPADS-induced attenuation of the renal sympathetic response to contraction and the renal sympathetic response to stretch is probably due to the sensitivities of different populations of group III afferents to ATP released during contraction and stretch.
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Rogers, Richard C., David H. McDougal, Sue Ritter, Emily Qualls-Creekmore et Gerlinda E. Hermann. « Response of catecholaminergic neurons in the mouse hindbrain to glucoprivic stimuli is astrocyte dependent ». American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 315, no 1 (1 juillet 2018) : R153—R164. http://dx.doi.org/10.1152/ajpregu.00368.2017.
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Hindbrain catecholaminergic (CA) neurons are required for critical autonomic, endocrine, and behavioral counterregulatory responses (CRRs) to hypoglycemia. Recent studies suggest that CRR initiation depends on hindbrain astrocyte glucose sensors (McDougal DH, Hermann GE, Rogers RC. Front Neurosci 7: 249, 2013; Rogers RC, Ritter S, Hermann GE. Am J Physiol Regul Integr Comp Physiol 310: R1102–R1108, 2016). To test the proposition that hindbrain CA responses to glucoprivation are astrocyte dependent, we utilized transgenic mice in which the calcium reporter construct (GCaMP5) was expressed selectively in tyrosine hydroxylase neurons (TH-GCaMP5). We conducted live cell calcium-imaging studies on tissue slices containing the nucleus of the solitary tract (NST) or the ventrolateral medulla, critical CRR initiation sites. Results show that TH-GCaMP5 neurons are robustly activated by a glucoprivic challenge and that this response is dependent on functional astrocytes. Pretreatment of hindbrain slices with fluorocitrate (an astrocytic metabolic suppressor) abolished TH-GCaMP5 neuronal responses to glucoprivation, but not to glutamate. Pharmacologic results suggest that the astrocytic connection with hindbrain CA neurons is purinergic via P2 receptors. Parallel imaging studies on hindbrain slices of NST from wild-type C57BL/6J mice, in which astrocytes and neurons were prelabeled with a calcium reporter dye and an astrocytic vital dye, show that both cell types are activated by glucoprivation but astrocytes responded significantly sooner than neurons. Pretreatment of these hindbrain slices with P2 antagonists abolished neuronal responses to glucoprivation without interruption of astrocyte responses; pretreatment with fluorocitrate eliminated both astrocytic and neuronal responses. These results support earlier work suggesting that the primary detection of glucoprivic signals by the hindbrain is mediated by astrocytes.
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Johnson, Christopher D., Andrew M. Coney et Janice M. Marshall. « Roles of norepinephrine and ATP in sympathetically evoked vasoconstriction in rat tail and hindlimb in vivo ». American Journal of Physiology-Heart and Circulatory Physiology 281, no 6 (1 décembre 2001) : H2432—H2440. http://dx.doi.org/10.1152/ajpheart.2001.281.6.h2432.
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In anesthetized rats, we characterized the contributions of norepinephrine (NE) and ATP to changes in tail and hindlimb (femoral) vascular resistances (TVR and FVR, respectively) evoked by three patterns of sympathetic stimulation: 1) couplets (2 impulses at 20 Hz), 2) short trains (20 impulses at 20 Hz), and 3) a natural irregular pattern previously recorded from a sympathetic fiber innervating the rat tail artery. All stimuli evoked greater changes in TVR than FVR. Judging from the effects of the α-adrenoceptor antagonist phentolamine, the purinergic receptor antagonist suramin, or α,β-methylene ATP (which desensitizes P2X receptors), we propose that NE has a major role in the constriction evoked by the couplet, as well as by the short train and by the low- and high-frequency components of the natural pattern, but that considerable synergy occurred between the actions of ATP and NE. This contrasts with previous in vitro studies that indicated that ATP dominates vascular responses evoked by sympathetic stimulation with a few impulses at low frequency and that NE dominates responses to longer trains or at high frequencies.
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Moore, B. A., et S. Vanner. « Properties of synaptic inputs from myenteric neurons innervating submucosal S neurons in guinea pig ileum ». American Journal of Physiology-Gastrointestinal and Liver Physiology 278, no 2 (1 février 2000) : G273—G280. http://dx.doi.org/10.1152/ajpgi.2000.278.2.g273.
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This study examined synaptic inputs from myenteric neurons innervating submucosal neurons. Intracellular recordings were obtained from submucosal S neurons in guinea pig ileal preparations in vitro, and synaptic inputs were recorded in response to electrical stimulation of exposed myenteric plexus. Most S neurons received synaptic inputs [>80% fast (f) excitatory postsynaptic potentials (EPSP), >30% slow (s) EPSPs] from the myenteric plexus. Synaptic potentials were recorded significant distances aboral (fEPSPs, 25 mm; sEPSPs, 10 mm) but not oral to the stimulating site. When preparations were studied in a double-chamber bath that chemically isolated the stimulating “myenteric chamber” from the recording side “submucosal chamber,” all fEPSPs were blocked by hexamethonium in the submucosal chamber, but not by a combination of nicotinic, purinergic, and 5-hydroxytryptamine-3 receptor antagonists in the myenteric chamber. In 15% of cells, a stimulus train elicited prolonged bursts of fEPSPs (>30 s duration) that were blocked by hexamethonium. These findings suggest that most submucosal S neurons receive synaptic inputs from predominantly anally projecting myenteric neurons. These inputs are poised to coordinate intestinal motility and secretion.
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Palikova, Yuliya A., Viktor A. Palikov et Igor A. Dyachenko. « Maximum tolerant dose and analgesic activity of PT1 peptide ». Research Results in Pharmacology 5, no 3 (30 septembre 2019) : 37–42. http://dx.doi.org/10.3897/rrpharmacology.5.38520.
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Introduction: The article presents the results of the study of the maximum tolerant dose (MTD) and the analgesic activity of peptide PT1 isolated from Alopecosa marikovskyi spider venom. PT1 is the first compound of polypeptide nature, capable of exerting a selective modulating effect on purinergic P2X3 receptors. Materials and methods: The study was conducted on 174 ICR mice. The analgesic activity of the peptide was evaluated in a thermal hypersensitivity test triggered by CFA and in a model of chemical irritation. Results and discussion: The determined MTD for the peptide PT1 when administered intravenously provides evidence to attribute it to low-toxic compounds. The maximum analgesic activity of PT1 using the biomodel of hypersensitivity induced by CFA when tested 15 minutes after the administration was recorded at doses of 0.1 and 0.5 mg/kg. In the visceral pain test, the maximum analgesic activity 15 minutes after the administration of the chemical stimulus was observed at a dose of 0.01 mg/kg. Conclusions: According to the results of testing peptide PT1, it is shown that it belongs to low-toxic compounds, has a pronounced analgesic activity in a wide range of doses of 0.0001–10 mg/kg.
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Leiva-Salcedo, Elias, Claudio Coddou, Felipe E. Rodríguez, Antonello Penna, Ximena Lopez, Tanya Neira, Ricardo Fernández et al. « Lipopolysaccharide Inhibits the Channel Activity of the P2X7 Receptor ». Mediators of Inflammation 2011 (2011) : 1–12. http://dx.doi.org/10.1155/2011/152625.
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The purinergic P2X7 receptor (P2X7R) plays an important role during the immune response, participating in several events such as cytokine release, apoptosis, and necrosis. The bacterial endotoxin lipopolysaccharide (LPS) is one of the strongest stimuli of the immune response, and it has been shown that P2X7R activation can modulate LPS-induced responses. Moreover, a C-terminal binding site for LPS has been proposed. In order to evaluate if LPS can directly modulate the activity of the P2X7R, we tested several signaling pathways associated with P2X7R activation in HEK293 cells that do not express the TLR-4 receptor. We found that LPS alone was unable to induce any P2X7R-related activity, suggesting that the P2X7R is not directly activated by the endotoxin. On the other hand, preapplication of LPS inhibited ATP-induced currents, intracellular calcium increase, and ethidium bromide uptake and had no effect on ERK activation in HEK293 cells. In splenocytes-derived T-regulatory cells, in which ATP-induced apoptosis is driven by the P2X7R, LPS inhibited ATP-induced apoptosis. Altogether, these results demonstrate that LPS modulates the activity of the P2X7R and suggest that this effect could be of physiological relevance.
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Pettengill, Matthew A., Camila Marques-da-Silva, Maria Luisa Avila, Suellen d'Arc dos Santos Oliveira, Verissa W. Lam, Ikechukwu Ollawa, Ali A. Abdul Sater, Robson Coutinho-Silva, Georg Häcker et David M. Ojcius. « Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X4Receptors ». Infection and Immunity 80, no 12 (17 septembre 2012) : 4232–38. http://dx.doi.org/10.1128/iai.00441-12.
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ABSTRACTBacterial infections of the mucosal epithelium are a major cause of human disease. The prolonged presence of microbial pathogens stimulates inflammation of the local tissues, which leads to changes in the molecular composition of the extracellular milieu. A well-characterized molecule that is released to the extracellular milieu by stressed or infected cells is extracellular ATP and its ecto-enzymatic degradation products, which function as signaling molecules through ligation of purinergic receptors. There has been little information, however, on the effects of the extracellular metabolites on bacterial growth in inflamed tissues. Millimolar concentrations of ATP have been previously shown to inhibit irreversibly bacterial infection through ligation of P2X7receptors. We show here that the proinflammatory mediator, ATP, is released fromChlamydia trachomatis-infected epithelial cells. Moreover, further stimulation of the infected cells with micromolar extracellular ADP or ATP significantly impairs the growth of the bacteria, with a profile characteristic of the involvement of P2X4receptors. A specific role for P2X4was confirmed using cells overexpressing P2X4. The chlamydiae remain viable and return to normal growth kinetics after removal of the extracellular stimulus, similar to responses previously described for persistence of chlamydial infection.
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Birder, Lori, et Karl-Erik Andersson. « Urothelial Signaling ». Physiological Reviews 93, no 2 (avril 2013) : 653–80. http://dx.doi.org/10.1152/physrev.00030.2012.
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The urothelium, which lines the inner surface of the renal pelvis, the ureters, and the urinary bladder, not only forms a high-resistance barrier to ion, solute and water flux, and pathogens, but also functions as an integral part of a sensory web which receives, amplifies, and transmits information about its external milieu. Urothelial cells have the ability to sense changes in their extracellular environment, and respond to chemical, mechanical and thermal stimuli by releasing various factors such as ATP, nitric oxide, and acetylcholine. They express a variety of receptors and ion channels, including P2X3 purinergic receptors, nicotinic and muscarinic receptors, and TRP channels, which all have been implicated in urothelial-neuronal interactions, and involved in signals that via components in the underlying lamina propria, such as interstitial cells, can be amplified and conveyed to nerves, detrusor muscle cells, and ultimately the central nervous system. The specialized anatomy of the urothelium and underlying structures, and the possible communication mechanisms from urothelial cells to various cell types within the bladder wall are described. Changes in the urothelium/lamina propria (“mucosa”) produced by different bladder disorders are discussed, as well as the mucosa as a target for therapeutic interventions.
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Lapel, Martin, Philip Weston, Derek Strassheim, Vijaya Karoor, Nana Burns, Taras Lyubchenko, Petr Paucek, Kurt R. Stenmark et Evgenia V. Gerasimovskaya. « Glycolysis and oxidative phosphorylation are essential for purinergic receptor-mediated angiogenic responses in vasa vasorum endothelial cells ». American Journal of Physiology-Cell Physiology 312, no 1 (1 janvier 2017) : C56—C70. http://dx.doi.org/10.1152/ajpcell.00250.2016.
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Angiogenesis is an energy-demanding process; however, the role of cellular energy pathways and their regulation by extracellular stimuli, especially extracellular nucleotides, remain largely unexplored. Using metabolic inhibitors of glycolysis (2-deoxyglucose) and oxidative phosphorylation (OXPHOS) (oligomycin, rotenone, and FCCP), we demonstrate that glycolysis and OXPHOS are both essential for angiogenic responses of vasa vasorum endothelial cell (VVEC). Treatment with P2R agonists, ATP, and 2-methylthioadenosine diphosphate trisodium salt (MeSADP), but not P1 receptor agonist, adenosine, increased glycolytic activity in VVEC (measured by extracellular acidification rate and lactate production). Stimulation of glycolysis was accompanied by increased levels of phospho-phosphofructokinase B3, hexokinase (HK), and GLUT-1, but not lactate dehydrogenase. Moreover, extracellular ATP and MeSADP, and to a lesser extent adenosine, increased basal and maximal oxygen consumption rates in VVEC. These effects were potentiated when the cells were cultured in 20 mM galactose and 5 mM glucose compared with 25 mM glucose. Treatment with P2R agonists decreased phosphorylation of pyruvate dehydrogenase (PDH)-E1α and increased succinate dehydrogenase (SDH), cytochrome oxidase IV, and β-subunit of F1F0 ATP synthase expression. In addition, P2R stimulation transiently elevated mitochondrial Ca2+ concentration, implying involvement of mitochondria in VVEC angiogenic activation. We also demonstrated a critical role of phosphatidylinositol 3-kinase and Akt pathways in lactate production, PDH-E1α phosphorylation, and the expression of HK, SDH, and GLUT-1 in ATP-stimulated VVEC. Together, our findings suggest that purinergic and metabolic regulation of VVEC energy pathways is essential for VV angiogenesis and may contribute to pathologic vascular remodeling in pulmonary hypertension.