Статті в журналах: "P2X3 antagonist"

1

Coutinho-Silva, Robson, Lynn Stahl, Kwok-Kuen Cheung, Nathalia Enes de Campos, Carolina de Oliveira Souza, David M. Ojcius, and Geoffrey Burnstock. "P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 5 (May 2005): G1024—G1035. http://dx.doi.org/10.1152/ajpgi.00211.2004.

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Extracellular nucleotides interact with purinergic receptors, which regulate ion transport in a variety of epithelia. With the use of two different human epithelial carcinoma cell lines (HCT8 and Caco-2), we have shown by RT-PCR that the cells express mRNA for P2X1, P2X3, P2X4, P2X5, P2X6, P2X7, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, and P2Y12 receptors. Protein expression for P2Y1 and P2Y2 receptors was also demonstrated immunohistochemically, and P2X receptor subtype protein was present in the following decreasing order: P2X4 > P2X7 > P2X1 > P2X3 > P2X6 > P2X5 >> P2X2. The functional presence of P2X7, P2Y1, P2Y2, and P2Y4 receptors was shown based on the effect of extracellular nucleotides on apoptosis or cell proliferation, and measurement of nucleotide-dependent calcium fluxes using a fluorometric imaging plate reader in the presence of different selective agonists and antagonists. ATP, at high concentrations, induced apoptosis through ligation of P2X7 and P2Y1 receptors; conversely, ATP, at lower concentrations, and UTP stimulated proliferation, probably acting via P2Y2 receptors. We therefore propose that stimulation or dysfunction of purinergic receptors may contribute at least partially to modulation of epithelial carcinoma cell proliferation and apoptosis.

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2

Nakamura, Ei'Ichiro, Yasuhito Uezono, Ken'Ichiro Narusawa, Izumi Shibuya, Yosuke Oishi, Masahiro Tanaka, Nobuyuki Yanagihara, Toshitaka Nakamura, and Futoshi Izumi. "ATP activates DNA synthesis by acting on P2X receptors in human osteoblast-like MG-63 cells." American Journal of Physiology-Cell Physiology 279, no. 2 (August 1, 2000): C510—C519. http://dx.doi.org/10.1152/ajpcell.2000.279.2.c510.

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In human osteoblast-like MG-63 cells, extracellular ATP increased [3H]thymidine incorporation and cell proliferation and synergistically enhanced platelet-derived growth factor- or insulin-like growth factor I-induced [3H]thymidine incorporation. ATP-induced [3H]thymidine incorporation was mimicked by the nonhydrolyzable ATP analogs adenosine 5′- O-(3-thiotriphosphate) and adenosine 5′-adenylylimidodiphosphate and was inhibited by the P2 purinoceptor antagonist suramin, suggesting involvement of P2 purinoceptors. The P2Y receptor agonist UTP and UDP and a P2Y receptor antagonist reactive blue 2 did not affect [3H]thymidine incorporation, whereas the P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2′,4-disulfonic acid inhibited ATP-induced [3H]thymidine incorporation, suggesting that ATP-induced DNA synthesis was mediated by P2X receptors. RT-PCR analysis revealed that MG-63 cells expressed P2X4, P2X5, P2X6, and P2X7, but not P2X1, P2X2, and P2X3, receptors. In fura 2-loaded cells, not only ATP, but also UTP, increased intracellular Ca2+concentration, and inhibitors for several Ca2+-activated protein kinases had no effect on ATP-induced DNA synthesis, suggesting that an increase in intracellular Ca2+concentration is not indispensable for ATP-induced DNA synthesis. ATP increased mitogen-activated protein kinase activity in a Ca2+-independent manner and synergistically enhanced platelet-derived growth factor- or insulin-like growth factor I-induced kinase activity. Furthermore, the mitogen-activated protein kinase kinase inhibitor PD-98059 totally abolished ATP-induced DNA synthesis. We conclude that ATP increases DNA synthesis and enhances the proliferative effects of growth factors through P2X receptors by activating a mitogen-activated protein kinase pathway.

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3

Nunes, Ana R., Raul Chavez-Valdez, Tarrah Ezell, David F. Donnelly, Joel C. Glover, and Estelle B. Gauda. "Effect of development on [Ca2+]i transients to ATP in petrosal ganglion neurons: a pharmacological approach using optical recording." Journal of Applied Physiology 112, no. 8 (April 15, 2012): 1393–402. http://dx.doi.org/10.1152/japplphysiol.00511.2011.

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ATP, acting through P2X2/P2X3 receptor-channel complexes, plays an important role in carotid body chemoexcitation in response to natural stimuli in the rat. Since the channels are permeable to calcium, P2X activation by ATP should induce changes in intracellular calcium ([Ca2+]i). Here, we describe a novel ex vivo approach using fluorescence [Ca2+]i imaging that allows screening of retrogradely labeled chemoafferent neurons in the petrosal ganglion of the rat. ATP-induced [Ca2+]i responses were characterized at postnatal days (P) 5–8 and P19–25. While all labeled cells showed a brisk increase in [Ca2+]i in response to depolarization by high KCl (60 mM), only a subpopulation exhibited [Ca2+]i responses to ATP. ATP (250–1,000 μM) elicited one of three temporal response patterns: fast (R1), slow (R2), and intermediate (R3). At P5–8, R2 predominated and its magnitude was attenuated 44% by the P2X1 antagonist, NF449 (10 μM), and 95% by the P2X1/P2X3/P2X2/3 antagonist, TNP-ATP (10 μM). At P19–25, R1 and R3 predominated and their magnitudes were attenuated 15% by NF449, 66% by TNP-ATP, and 100% by suramin (100 μM), a nonspecific P2 purinergic receptor antagonist. P2X1 and P2X2 protein levels in the petrosal ganglion decreased with development, while P2X3 protein levels did not change significantly. We conclude that the profile of ATP-induced P2X-mediated [Ca2+]i responses changes in the postnatal period, corresponding with changes in receptor isoform expression. We speculate that these changes may participate in the postnatal maturation of chemosensitivity.

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4

Gui, Yu, ZengYong Wang, XiaoRui Sun, Michael P. Walsh, Jing-Jing Li, Jie Gao, and Xi-Long Zheng. "Uridine adenosine tetraphosphate induces contraction of airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 5 (November 2011): L789—L794. http://dx.doi.org/10.1152/ajplung.00203.2011.

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Contraction of airway smooth muscle (ASM) plays an important role in the regulation of air flow and is potentially involved in the pathophysiology of certain respiratory diseases. Extracellular nucleotides regulate ASM contraction via purinergic receptors, but the signaling mechanisms involved are not fully understood. Uridine adenosine tetraphosphate (Up4A) contains both pyrimidine and purine moieties, which are known to potentially activate P2X and P2Y receptors. Both P2X and P2Y receptors have been identified in the lung, including airway epithelial cells and ASM. We report here a study of purinergic signaling in the respiratory system, with a focus on the effect of Up4A on ASM contraction. Up4A induced contraction of rat isolated trachea and extrapulmonary bronchi as well as human intrapulmonary bronchioles. Up4A-induced contraction was blocked by di-inosine pentaphosphate, a P2X antagonist, but not by suramin, a nonselective P2 antagonist. Up4A-induced contraction was also attenuated by α,β-methylene-ATP-mediated P2X receptor desensitization. Several P2X receptors were detected at the mRNA level: P2X1, P2X4, P2X6, and P2X7, and to a lesser extent P2X3. Furthermore, the Up4A response was inhibited by removal of extracellular Ca2+ and by the presence of the L-type Ca2+ channel blocker, nifedipine, or the Rho-associated kinase inhibitor, H1152. We conclude that Up4A stimulates ASM contraction, and the underlying signaling mechanism appears to involve P2X (most likely P2X1) receptors, extracellular Ca2+ entry via L-type Ca2+ channels, and Ca2+ sensitization through the RhoA/Rho-associated kinase pathway. This study will add to our understanding of the pathophysiological roles of extracellular nucleotides in the lung.

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5

Hu, Bo, Chen Yu Chiang, James W. Hu, Jonathan O. Dostrovsky, and Barry J. Sessle. "P2X Receptors in Trigeminal Subnucleus Caudalis Modulate Central Sensitization in Trigeminal Subnucleus Oralis." Journal of Neurophysiology 88, no. 4 (October 1, 2002): 1614–24. http://dx.doi.org/10.1152/jn.2002.88.4.1614.

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This study investigated the role of trigeminal subnucleus caudalis (Vc) P2X receptors in the mediation of central sensitization induced in nociceptive neurons in subnucleus oralis (Vo) by mustard oil (MO) application to the tooth pulp in anesthetized rats. MO application produced a long-lasting central sensitization reflected in neuroplastic changes (i.e., increases in neuronal mechanoreceptive field size and responses to innocuous and noxious mechanical stimuli) in Vo nociceptive neurons. Twenty minutes after MO application, the intrathecal (i.t.) administration to the rostral Vc of the selective P2X1, P2X3, and P2X2/3 receptor antagonist, 2′-(or 3′-) O-trinitrophenyl-ATP (TNP-ATP), significantly and reversibly attenuated the MO-induced central sensitization for more than 15 min; saline administration had no effect. Administration to the rostral Vc of the selective P2X1, P2X3, and P2X2/3 receptor agonist, α,β-methylene ATP (α,β-meATP, i.t.) produced abrupt and significant neuroplastic changes in Vo nociceptive neurons, followed by neuronal desensitization as evidenced by the ineffectiveness of a second i.t. application of α,β-meATP and subsequent MO application to the pulp. Administration to the rostral Vc of the selective P2X1 receptor agonist β,γ-methylene ATP (β,γ-meATP, i.t.) produced no significant neuroplastic changes per se and did not affect the subsequent MO-induced neuroplastic changes in Vo nociceptive neurons. These results suggest that P2X3 and possibly also the P2X2/3 receptor subtypes in Vc may play a role in the initiation and maintenance of central sensitization in Vo nociceptive neurons induced by MO application to the pulp.

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6

Gomes, Dayane A., Zhilin Song, Wanida Stevens, and Celia D. Sladek. "Sustained stimulation of vasopressin and oxytocin release by ATP and phenylephrine requires recruitment of desensitization-resistant P2X purinergic receptors." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 297, no. 4 (October 2009): R940—R949. http://dx.doi.org/10.1152/ajpregu.00358.2009.

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Coexposure of hypothalamo-neurohypophyseal system explants to ATP and phenylephrine [PE; an α1-adrenergic receptor (α1-AR) agonist] induces an extended elevation in vasopressin and oxytocin (VP/OT) release. New evidence is presented that this extended response is mediated by recruitment of desensitization-resistant ionotropic purinergic receptor subtypes (P2X-Rs): 1) Antagonists of the P2X2/3 and P2X7-Rs truncated the sustained VP/OT release induced by ATP+PE but did not alter the transient response to ATP alone. 2) The P2X2/3 and P2X7-R antagonists did not alter either ATP or ATP+PE-induced increases in [Ca2+]i. 3) P2X2/3 and P2X7-R agonists failed to elevate [Ca2+]i, while ATP-γ-S, an agonist for P2X2-Rs increased [Ca2+]iand induced a transient increase in VP/OT release. 4) A P2Y1-R antagonist did not prevent initiation of the synergistic, sustained stimulation of VP/OT release by ATP+PE but did reduce its duration. Thus, the desensitization-resistant P2X2/3 and P2X7-R subtypes are required for the sustained, synergistic hormone response to ATP+PE, while P2X2-Rs are responsible for the initial activation of Ca2+-influx by ATP and ATP stimulation of VP/OT release. Immunohistochemistry, coimmunoprecipitation, and Western blot analysis confirmed the presence of P2X2 and P2X3, P2X2/3, and P2X7-R protein, respectively in SON. These findings support the hypothesis that concurrent activation of P2X2-R and α1-AR induces calcium-driven recruitment of P2X2/3 and 7-Rs, allowing sustained activation of a homeostatic circuit. Recruitment of these receptors may provide sustained release of VP during dehydration and may be important for preventing hemorrhagic and septic shock.

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7

Burgard, Edward C., Wende Niforatos, Tim van Biesen, Kevin J. Lynch, Edward Touma, Randy E. Metzger, Elizabeth A. Kowaluk, and Michael F. Jarvis. "P2X Receptor–Mediated Ionic Currents in Dorsal Root Ganglion Neurons." Journal of Neurophysiology 82, no. 3 (September 1, 1999): 1590–98. http://dx.doi.org/10.1152/jn.1999.82.3.1590.

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Nociceptive neurons in the dorsal root ganglia (DRG) are activated by extracellular ATP, implicating P2X receptors as potential mediators of painful stimuli. However, the P2X receptor subtype(s) underlying this activity remain in question. Using electrophysiological techniques, the effects of P2X receptor agonists and antagonists were examined on acutely dissociated adult rat lumbar DRG neurons. Putative P2X-expressing nociceptors were identified by labeling neurons with the lectin IB4. These neurons could be grouped into three categories based on response kinetics to extracellularly applied ATP. Some DRG responses (slow DRG) were relatively slowly activating, nondesensitizing, and activated by the ATP analogue α,β-meATP. These responses resembled those recorded from 1321N1 cells expressing recombinant heteromultimeric rat P2X2/3 receptors. Other responses (fast DRG) were rapidly activating and desensitized almost completely during agonist application. These responses had properties similar to those recorded from 1321N1 cells expressing recombinant rat P2X3 receptors. A third group (mixed DRG) activated and desensitized rapidly (P2X3-like), but also had a slow, nondesensitizing component that functionally prolonged the current. Like the fast component, the slow component was activated by both ATP and α,β-meATP and was blocked by the P2X antagonist TNP-ATP. But unlike the fast component, the slow component could follow high-frequency activation by agonist, and its amplitude was potentiated under acidic conditions. These characteristics most closely resemble those of rat P2X2/3 receptors. These data suggest that there are at least two populations of P2X receptors present on adult DRG nociceptive neurons, P2X3 and P2X2/3. These receptors are expressed either separately or together on individual neurons and may play a role in the processing of nociceptive information from the periphery to the spinal cord.

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8

Kiyatkin, Michael E., Bin Feng, Erica S. Schwartz, and G. F. Gebhart. "Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization." American Journal of Physiology-Gastrointestinal and Liver Physiology 305, no. 9 (November 1, 2013): G638—G648. http://dx.doi.org/10.1152/ajpgi.00180.2013.

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The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity.

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Niane, Lalah M., David F. Donnelly, Vincent Joseph, and Aida Bairam. "Ventilatory and carotid body chemoreceptor responses to purinergic P2X receptor antagonists in newborn rats." Journal of Applied Physiology 110, no. 1 (January 2011): 83–94. http://dx.doi.org/10.1152/japplphysiol.00871.2010.

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Adenosine triphosphate, acting through purinergic P2X receptors, has been shown to stimulate ventilation and increase carotid body chemoreceptor activity in adult rats. However, its role during postnatal development of the ventilatory response to hypoxia is yet unknown. Using whole body plethysmography, we measured ventilation in normoxia and in moderate hypoxia (12% fraction of inspired O2, 20 min) before and after intraperitoneal injection of suramin (P2X2 and P2X3 receptor antagonist, 40 mg/kg) in 4-, 7-, 12-, and 21-day-old rats. Suramin reduced baseline breathing (∼20%) and the response to hypoxia (∼30%) in all rats, with a relatively constant effect across ages. We then tested the effect of the specific P2X3 antagonist, A-317491 (150 mg/kg), in rats aged 4, 7, and 21 days. As with suramin, A-317491 reduced baseline ventilation (∼55%) and the hypoxic response (∼40%) at all ages studied. Single-unit carotid body chemoreceptor activity was recorded in vitro in 4-, 7-, and 21-day-old rats. Suramin (100 μM) and A-317491 (10 μM) significantly depressed the sinus nerve chemosensory discharge rate (∼80%) in normoxia (Po2 ∼150 Torr) and hypoxia (Po2 ∼60 Torr), and this decrease was constant across ages. We conclude that, in newborn rats, P2X purinergic receptors are involved in the regulation of breathing under basal and hypoxic condition, and P2X3-containing receptors play a major role in carotid body function. However, these effects are not age dependent within the age range studied.

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LIGHT, ALAN R., YING WU, RONALD W. HUGHEN, and PETER B. GUTHRIE. "Purinergic receptors activating rapid intracellular Ca2+ increases in microglia." Neuron Glia Biology 2, no. 2 (December 1, 2005): 125–38. http://dx.doi.org/10.1017/s1740925x05000323.

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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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11

Liu, Cuiling, Simon Mather, Yu Huang, Christopher J. Garland, and Xiaoqiang Yao. "Extracellular ATP facilitates flow-induced vasodilatation in rat small mesenteric arteries." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 5 (May 2004): H1688—H1695. http://dx.doi.org/10.1152/ajpheart.00576.2003.

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ATP can be released from endothelial cells, and this release is increased by intraluminal flow in blood vessels. In the present study, the effect of extracellular ATP (1 μM) on flow-induced vasodilatation was investigated in isolated and pressurized rat small mesenteric arteries. In the absence of extracellular ATP, only 46% of arteries developed dilatation in response to flow, and this response was both transient and unstable. In marked contrast, with ATP present, all vessels developed a prolonged and stable dilatation in response to flow. Even in the vessels that failed to respond to flow in the absence of ATP, dilatation could be stimulated once ATP was present. The ability of ATP to facilitate flow-induced vasodilatation was mimicked by UTP (1 μM), a P2Y agonist, or 3′- O-(4-benzoyl)benzoyl ATP (BzATP; 10 μM), an agonist for P2X1, P2X7, and P2Y11 purinoceptors. The involvement of P2X7 purinoceptors was further supported by the inhibitory effect of KN-62 (1 μM), a P2X7 antagonist, on the action of BzATP. P2X1 and P2X3 purinoceptors were not involved because their receptor agonist α,β-methylene ATP had no effect. The facilitating effect of ATP on flow dilatation was also attenuated by the combined application of reactive blue 2 (100 μM), a P2Y antagonist, and suramin (100 μM), a nonselective P2X and P2Y antagonist. Furthermore, flow-induced dilatation obtained in the presence of ATP was reproducible. In contrast, in the additional presence of the ectonucleotidase inhibitor ARL-67156 (10 μM), although the first dilatation was normal, the responses to the second and later exposures to flow were greatly attenuated. The nonhydrolyzable ATP analogs adenosine-5′-(3-thiotriphosphate)trilithium salt (1 μM) and adenosine 5′-(β,γ-imido) triphosphate tetralithium salt hydrate (10 μM) had similar effects to those of ARL-67156. These data suggest that ATP acts through both P2X and P2Y purinoceptors to facilitate flow-induced vasodilatation and that ectonucleotidases prevent this effect by degrading ATP on the endothelial cell surface.

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12

North, R. Alan. "Molecular Physiology of P2X Receptors." Physiological Reviews 82, no. 4 (January 10, 2002): 1013–67. http://dx.doi.org/10.1152/physrev.00015.2002.

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P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40–50% identical in amino acid sequence. Each subunit has two transmembrane domains, separated by an extracellular domain (∼280 amino acids). Channels form as multimers of several subunits. Homomeric P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7channels and heteromeric P2X2/3and P2X1/5channels have been most fully characterized following heterologous expression. Some agonists (e.g., αβ-methylene ATP) and antagonists [e.g., 2′,3′- O-(2,4,6-trinitrophenyl)-ATP] are strongly selective for receptors containing P2X1and P2X3subunits. All P2X receptors are permeable to small monovalent cations; some have significant calcium or anion permeability. In many cells, activation of homomeric P2X7receptors induces a permeability increase to larger organic cations including some fluorescent dyes and also signals to the cytoskeleton; these changes probably involve additional interacting proteins. P2X receptors are abundantly distributed, and functional responses are seen in neurons, glia, epithelia, endothelia, bone, muscle, and hemopoietic tissues. The molecular composition of native receptors is becoming understood, and some cells express more than one type of P2X receptor. On smooth muscles, P2X receptors respond to ATP released from sympathetic motor nerves (e.g., in ejaculation). On sensory nerves, they are involved in the initiation of afferent signals in several viscera (e.g., bladder, intestine) and play a key role in sensing tissue-damaging and inflammatory stimuli. Paracrine roles for ATP signaling through P2X receptors are likely in neurohypophysis, ducted glands, airway epithelia, kidney, bone, and hemopoietic tissues. In the last case, P2X7receptor activation stimulates cytokine release by engaging intracellular signaling pathways.

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Chiang, C. Y., S. Zhang, Y. F. Xie, J. W. Hu, J. O. Dostrovsky, M. W. Salter, and B. J. Sessle. "Endogenous ATP Involvement in Mustard-Oil-Induced Central Sensitization in Trigeminal Subnucleus Caudalis (Medullary Dorsal Horn)." Journal of Neurophysiology 94, no. 3 (September 2005): 1751–60. http://dx.doi.org/10.1152/jn.00223.2005.

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Central sensitization represents a sustained hypersensitive state of dorsal horn nociceptive neurons that can be evoked by peripheral inflammation or injury to nerves and tissues. It reflects neuroplastic changes such as increases in neuronal spontaneous activity, receptive field size, and responses to suprathreshold stimuli and a decrease in activation threshold. We recently demonstrated that purinergic receptor mechanisms in trigeminal subnucleus caudalis (Vc; medullary dorsal horn) are also involved in the initiation and maintenance of central sensitization in brain stem nociceptive neurons of trigeminal subnucleus oralis. The aim of the present study was to investigate whether endogenous ATP is involved in the development of central sensitization in Vc itself. The experiments were carried out on urethan/α-chloralose anesthetized and immobilized rats. Single neurons were recorded and identified as nociceptive-specific (NS) in the deep laminae of Vc. During continuous saline superfusion (0.6 ml/h it) over the caudal medulla, Vc neuronal central sensitization was readily induced by mustard oil application to the tooth pulp. However, this mustard-oil-induced central sensitization could be completely blocked by continuous intrathecal superfusion of the wide-spectrum P2X receptor antagonist pyridoxal-phosphate-6-azophenyl-2, 4-disulphonic acid tetra-sodium (33–100 μM) and by apyrase (an ectonucleotidase enzyme, 30 units/ml). Superfusion of the selective P2X1, P2X3 and P2X2/3 receptor antagonist 2′,3′- O-(2,4,6-trinitrophenyl) adenosine 5′-triphosphate (6–638 μM) partially blocked the Vc central sensitization. The two P2X receptor antagonists did not significantly affect the baseline nociceptive properties of the Vc neurons. These findings implicate endogenous ATP as an important mediator contributing to the development of central sensitization in nociceptive neurons of the deep laminae of the dorsal horn.

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Tsuzuki, Kenzo, Ariel Ase, Philippe Séguéla, Terumasa Nakatsuka, Cong-Yi Wang, Jin-Xiong She, and Jianguo G. Gu. "TNP-ATP-Resistant P2X Ionic Current on the Central Terminals and Somata of Rat Primary Sensory Neurons." Journal of Neurophysiology 89, no. 6 (June 2003): 3235–42. http://dx.doi.org/10.1152/jn.01171.2002.

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P2X receptors have been suggested to be expressed on the central terminals of Aδ-afferent fibers innervating dorsal horn lamina V and play a role in modulating sensory synaptic transmission. These P2X receptors have been widely thought to be P2X2+3 receptors. However, we have recently found that P2X receptor-mediated modulation of sensory transmission in lamina V is not inhibited by trinitrophenyl-adenosine triphosphate (TNP-ATP), a potent antagonist of P2X1, P2X3 homomers, and P2X2+3 heteromers. To provide direct evidence for the presence of TNP-ATP-resistant P2X receptors on primary afferent fibers, we examined α,β-methylene-ATP (αβmeATP)-evoked currents and their sensitivity to TNP-ATP in rat dorsal root ganglion (DRG) neurons. αβmeATP evoked fast currents, slow currents, and mixed currents that contained both fast and slow current-components. Fast currents and fast current components in the mixed currents were both completely inhibited by 0.1 μM TNP-ATP ( n = 14). Both slow currents and slow-current components in the mixed currents showed broad spectrum of sensitivity to 1 μM TNP-ATP, ranging from complete block (TNP-ATP-sensitive) to little block (TNP-ATP-resistant). TNP-ATP-resistant currents evoked by 10 μM αβmeATP could be largely inhibited by 10 μM iso-pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid. Cells with P2X currents that were highly resistant to TNP-ATP were found to be insensitive to capsaicin. These results suggest that TNP-ATP-resistant P2X receptor subtypes are expressed on capsaicin-insensitive Aδ-afferent fibers and play a role in modulating sensory transmission to lamina V neurons.

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Estrada, Juan A., Guillaume P. Ducrocq, Joyce S. Kim, and Marc P. Kaufman. "Intrathecal injection of brilliant blue G, a P2X7 antagonist, attenuates the exercise pressor reflex in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 319, no. 2 (August 1, 2020): R223—R232. http://dx.doi.org/10.1152/ajpregu.00093.2020.

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

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Nakatsuka, Terumasa, Kenzo Tsuzuki, Jennifer X. Ling, Hideki Sonobe, and Jianguo G. Gu. "Distinct Roles of P2X Receptors in Modulating Glutamate Release at Different Primary Sensory Synapses in Rat Spinal Cord." Journal of Neurophysiology 89, no. 6 (June 2003): 3243–52. http://dx.doi.org/10.1152/jn.01172.2002.

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Using spinal cord slice preparations and patch-clamp recordings in lamina II and lamina V regions, we tested a hypothesis that P2X receptor subtypes differentially modulate glutamate release from primary afferent terminals innervating different sensory regions. We found that activation of P2X receptors by α,β-methylene-ATP increased glutamate release onto >80% of DH neurons in both lamina regions. However, two distinct types of modulation, a transient and a long-lasting enhancement of glutamate release were observed. In lamina II recordings, >70% of the modulation was transient. In contrast, P2X receptor-mediated modulation was always long-lasting in lamina V. Pharmacologically, both transient and long-lasting types of modulation were blocked by 10 μM pyridxal-phospahte-6-azophenyl-2′,4′-disulphonic acid tetrasodium, a broad-spectrum P2X receptor antagonist. Transient modulation was not observed in the presence of 1 μM trinitrophenyl-ATP (TNP-ATP), a subtype-selective P2X receptor antagonist, suggesting that homomeric P2X3 receptors may be involved in the transient modulation in lamina II. The long-lasting modulation remained in the presence of 1 μM TNP-ATP. Selective removal of P2X3-expressing afferent terminals by the targeting toxin saporin-conjugated isolectin B4 or surgical removal of superficial DH did not affect P2X receptor-mediated long-lasting modulation in lamina V. Taken together, these results suggest that P2X receptor subtypes play distinct roles in sensory processing in functionally different sensory regions.

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Turner, Richard D., Raj K. Rajakulasingam, Angshu Bhowmik, and Graham H. Bothamley. "P2X3 receptor antagonist in chronic cough." Lancet 386, no. 9990 (July 2015): 244. http://dx.doi.org/10.1016/s0140-6736(15)61274-0.

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18

Kwong, Kevin, Marian Kollarik, Christina Nassenstein, Fei Ru, and Bradley J. Undem. "P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 5 (November 2008): L858—L865. http://dx.doi.org/10.1152/ajplung.90360.2008.

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The lungs and esophagus are innervated by sensory neurons with somata in the nodose, jugular, and dorsal root ganglion. These sensory ganglia are derived from embryonic placode (nodose) and neural crest tissues (jugular and dorsal root ganglia; DRG). We addressed the hypothesis that the neuron's embryonic origin (e.g., placode vs. neural crest) plays a greater role in determining particular aspects of its phenotype than the environment in which it innervates (e.g., lungs vs. esophagus). This hypothesis was tested using a combination of extracellular and patch-clamp electrophysiology and single-cell RT-PCR from guinea pig neurons. Nodose, but not jugular C-fibers innervating the lungs and esophagus, responded to α,β-methylene ATP with action potential discharge that was sensitive to the P2X3 (P2X2/3) selective receptor antagonist A-317491. The somata of lung- and esophagus-specific sensory fibers were identified using retrograde tracing with a fluorescent dye. Esophageal- and lung-traced neurons from placodal tissue (nodose neurons) responded similarly to α,β-methylene ATP (30 μM) with a large sustained inward current, whereas in neurons derived from neural crest tissue (jugular and DRG neurons), the same dose of α,β-methylene ATP resulted in only a transient rapidly inactivating current or no detectable current. It has been shown previously that only activation of P2X2/3 heteromeric receptors produce sustained currents, whereas homomeric P2X3 receptor activation produces a rapidly inactivating current. Consistent with this, single-cell RT-PCR analysis revealed that the nodose ganglion neurons innervating the lungs and esophagus expressed mRNA for P2X2 and P2X3 subunits, whereas the vast majority of jugular and dorsal root ganglia innervating these tissues expressed only P2X3 mRNA with little to no P2X2 mRNA expression. We conclude that the responsiveness of C-fibers innervating the lungs and esophagus to ATP and other purinergic agonists is determined more by their embryonic origin than by the environment of the tissue they ultimately innervate.

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McGaraughty, S., and M. F. Jarvis. "Antinociceptive properties of a selective non-nucleoside P2X3/P2X2/3 receptor antagonist." Drug News & Perspectives 18, no. 8 (2005): 501. http://dx.doi.org/10.1358/dnp.2005.18.8.942082.

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Marques, Rita D., Pauline I. A. de Bruijn, Mads V. Sorensen, Markus Bleich, Helle A. Praetorius, and Jens Leipziger. "Basolateral P2X receptors mediate inhibition of NaCl transport in mouse medullary thick ascending limb (mTAL)." American Journal of Physiology-Renal Physiology 302, no. 4 (February 15, 2012): F487—F494. http://dx.doi.org/10.1152/ajprenal.00570.2011.

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Extracellular nucleotides regulate epithelial transport via luminal and basolateral P2 receptors. Renal epithelia express multiple P2 receptors, which mediate significant inhibition of solute absorption. Recently, we identified several P2 receptors in the medullary thick ascending limb (mTAL) including luminal and basolateral P2Y2 receptors (Jensen ME, Odgaard E, Christensen MH, Praetorius HA, Leipziger J. J Am Soc Nephrol 18: 2062–2070, 2007). In addition, we found evidence for a basolateral P2X receptor. Here, we investigate the effect of basolateral ATP on NaCl absorption in isolated, perfused mouse mTALs using the electrical measurement of equivalent short-circuit current ( I′sc). Nonstimulated mTALs transported at a rate of 1,197 ± 104 μA/cm2 ( n = 10), which was completely blockable with luminal furosemide (100 μM). Basolateral ATP (100 μM) acutely (1 min) and reversibly reduced the absorptive I′sc. After 2 min, the reduction amounted to 24.4 ± 4.0% ( n = 10). The nonselective P2 receptor antagonist suramin blocked the effect. P2Y receptors were found not to be involved in this effect. The P2X receptor agonist 2-methylthio ATP mimicked the ATP effect, and the P2X receptor antagonist periodate-oxidized ATP blocked it. In P2X7−/− mice, the ATP effect remained unaltered. In contrast, in P2X4−/− mice the ATP-induced inhibition of transport was reduced. A comprehensive molecular search identified P2X4, P2X5, and P2X1 receptor subunit mRNA in isolated mouse mTALs. These data define that basolateral ATP exerts a significant inhibition of Na+ absorption in mouse mTAL. Pharmacological, molecular, and knockout mouse data identify a role for the P2X4 receptor. We suggest that other P2X subunits like P2X5 are part of the P2X receptor complex. These data provide the novel perspective that an ionotropic receptor and thus a nonselective cation channel causes transport inhibition in an intact renal epithelium.

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Lu, Yi, Qian Jiang, Lihua Yu, Zhan-ying Lu, Shuang-ping Meng, Dingfeng Su, Geoffrey Burnstock та Bei Ma. "17β-Estradiol Rapidly Attenuates P2X3 Receptor-Mediated Peripheral Pain Signal Transduction via ERα and GPR30". Endocrinology 154, № 7 (22 квітня 2013): 2421–33. http://dx.doi.org/10.1210/en.2012-2119.

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Abstract Estrogen has been reported to affect pain perception, although the underlying mechanisms remain unclear. In this investigation, pain behavior testing, patch clamp recording, and immunohistochemistry were used on rats and transgenic mice to determine which estrogen receptors (ERs) and the related signaling pathway are involved in the rapid modulation of estrogen on P2X3 receptor-mediated events. The results showed that 17β-estradiol (E2) rapidly inhibited pain induced by α,β-methylene ATP (α,β-me-ATP), a P2X1 and P2X3 receptor agonist in ovariectomized rats and normal rats in diestrus. The ERα agonist 4,49,499-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) and G protein-coupled receptor 30 (GPR30) agonist G-1 mimicked the estrogen effect, whereas the ERβ agonist diarylpropionitrile (DPN) had no effect. In cultured rat dorsal root ganglion (DRG) neurons, PPT and G-1 but not DPN significantly attenuated α,β-me-ATP–mediated currents, with the dose-response curve of these currents shifted to the right. The inhibitory effect of E2 on P2X3 currents was blocked by G-15, a selective antagonist to the GPR30 estrogen receptor. E2 lacked this effect in DRG neurons from ERα-knockout mice but partly remained in those from ERβ-knockout mice. The P2X3 and GPR30 receptors were coexpressed in the rat DRG neurons. Furthermore, the ERK1/2 inhibitor U0126 reversed the inhibitory effect of E2 on α,β-me-ATP–induced pain and of PPT or G-1 on P2X3 receptor-mediated currents. The cAMP-protein kinase A (PKA) agonist forskolin, but not the PKC agonist phorbol-12-myristate-13-acetate (PMA), mimicked the estrogen-inhibitory effect on P2X3 receptor currents, which was blocked by another ERK1/2 inhibitor, PD98059. These results suggest that estrogen regulates P2X3-mediated peripheral pain by acting on ERα and GPR30 receptors expressed in primary afferent neurons, which probably involves the intracellular cAMP-PKA-ERK1/2 pathway.

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Wang, Shusheng, Hong-Yan Zhu, Yi Jin, Youlang Zhou, Shufen Hu, Tong Liu, Xinghong Jiang, and Guang-Yin Xu. "Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 8 (April 15, 2015): G710—G719. http://dx.doi.org/10.1152/ajpgi.00395.2014.

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The mechanism of pain in chronic pancreatitis (CP) is poorly understood. The aim of this study was designed to investigate roles of norepinephrine (NE) and P2X receptor (P2XR) signaling pathway in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Mechanical hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. P2XR-mediated responses of pancreatic dorsal root ganglion (DRG) neurons were measured utilizing calcium imaging and whole cell patch-clamp-recording techniques. Western blot analysis and immunofluorescence were performed to examine protein expression. TNBS injection produced a significant upregulation of P2X3R expression and an increase in ATP-evoked responses of pancreatic DRG neurons. The sensitization of P2X3Rs was reversed by administration of β-adrenergic receptor antagonist propranolol. Incubation of DRG neurons with NE significantly enhanced ATP-induced intracellular calcium signals, which were abolished by propranolol, and partially blocked by protein kinase A inhibitor H-89. Interestingly, TNBS injection led to a significant elevation of NE concentration in DRGs and the pancreas, an upregulation of β2-adrenergic receptor expression in DRGs, and amplification of the NE-induced potentiation of ATP responses. Importantly, pancreatic hyperalgesia was markedly attenuated by administration of purinergic receptor antagonist suramin or A317491 or β2-adrenergic receptor antagonist butoxamine. Sensitization of P2X3Rs, which was likely mediated by adrenergic signaling in primary sensory neurons, contributes to pancreatic pain, thus identifying a potential target for treating pancreatic pain caused by inflammation.

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Gever, Joel R., Rothschild Soto, Robert A. Henningsen, Renee S. Martin, David H. Hackos, Sandip Panicker, Werner Rubas, et al. "AF-353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist." British Journal of Pharmacology 160, no. 6 (April 19, 2010): 1387–98. http://dx.doi.org/10.1111/j.1476-5381.2010.00796.x.

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24

Feng, Qi-fan, An-dong Zhang, Man Xing, Xi Wang, Shu-ren Ming, and Yue-lai Chen. "Electroacupuncture Alleviates Bladder Overactivity via Inhabiting Bladder P2X3 Receptor." Evidence-Based Complementary and Alternative Medicine 2020 (March 17, 2020): 1–12. http://dx.doi.org/10.1155/2020/4080891.

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Electroacupuncture (EA) has been widely applied for overactive bladder, but the mechanism of its action remains to be clarified. This study was aimed to investigate EA regulating the effect of purinergic signaling in the OAB of rats. Electroacupuncture (continuous wave, 30 Hz, 1 mA) was applied to stimulate the Ciliao point (BL32) and the Huiyang point (BL35) of rats. Results showed that when the P2X3 receptor in bladder peripheral level and the spinal cord central level was involved in the bladder micturition reflex of the afferent signaling, intravenous administration P2X3 antagonist AF-353 can significantly inhibit urination in naive rats and OAB of rats and increase bladder volume and micturition pressure. EA stimulation alleviated bladder overactivity significantly and after the P2X3 receptor was blocked, the EA effect was weakened. EA stimulation can effectively reduce the P2X3 mRNA and protein expression in OAB of rats, spinal cord (L6-S1), and DRG (L6-S1) and can significantly reduce the number of positive P2X3 cells in OAB of rats, spinal cord (L6-S1), and DRG (L6-S1). These findings suggest that EA stimulation could alleviate bladder overactivity, and the function is closely related to the inhabited P2X3 receptor in the bladder.

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25

Smith, Jaclyn A., Rayid Abdulqawi, Rachel Dockry, Kimberley Holt, Gary Layton, Bruce G. McCarthy, and Anthony P. Ford. "P2X3 receptor antagonist in chronic cough – Authors' reply." Lancet 386, no. 9990 (July 2015): 244–45. http://dx.doi.org/10.1016/s0140-6736(15)61275-2.

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26

Red. "P2X3-Rezeptor-Antagonist — eine Option gegen chronischen Husten?" MMW - Fortschritte der Medizin 162, no. 10 (May 2020): 63. http://dx.doi.org/10.1007/s15006-020-0531-7.

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27

Obrecht, Astrid S., Nicole Urban, Michael Schaefer, Anni Röse, Achim Kless, Jannis E. Meents, Angelika Lampert, et al. "Identification of aurintricarboxylic acid as a potent allosteric antagonist of P2X1 and P2X3 receptors." Neuropharmacology 158 (November 2019): 107749. http://dx.doi.org/10.1016/j.neuropharm.2019.107749.

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Helms, Nick, Maria Kowalski, Peter Illes, and Thomas Riedel. "Agonist Antagonist Interactions at the Rapidly Desensitizing P2X3 Receptor." PLoS ONE 8, no. 11 (November 1, 2013): e79213. http://dx.doi.org/10.1371/journal.pone.0079213.

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Kee, Sydney Ann, Tamara Haque, Jordan Dailey, and John J. Ryan. "P2X3 is a Female-Dominant Activator of Mast Cells." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 49.14. http://dx.doi.org/10.4049/jimmunol.208.supp.49.14.

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Abstract Asthma is characterized by increased mucus production, airway hyperresponsiveness and airway inflammation, all promoted by mast cell activation. There is a clear bias for greater incidence and acuity of asthma among females, but the reasons for this are not clear. Women are 60% more likely to be diagnosed with asthma and three times more likely to be hospitalized for it. In a search for possible new and upcoming drugs that might be repurposed to suppress mast cell function, we discovered that the ATP receptor P2X3, most often studied in neuropathic pain, has a role in mast cell activation. The P2X3 antagonist BLU-5937 suppressed IL-33 mediated-mast cell cytokine secretion in vitro and reduced neutrophilic peritonitis in vivo in female mice. In contrast, male mice and mast cells cultured from them showed no suppression when treated with BLU-5937. In addition, female mast cell responses were much stronger than males when activated with IL-33 in vitro. We also found that IL-33 elicits rapid ATP secretion by mast cells, possibly forming an autocrine loop via P2X3. These data coincided with little detectable P2X3 expression on male mast cells. We hypothesize that IL-33-mediated mast cell activation is more potent in females due to P2X3 receptor signaling. Our data support the theory that P2X3 is a female-dominant mast cell activator that can be targeted to reduce allergic inflammation. This research is novel because it could explain the sexual dimorphism in allergic disease and elucidate the role of P2X3 in the immune system. Supported by 1RO1 AI164710

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Shabir, Saqib, William Cross, Lisa A. Kirkwood, Joanna F. Pearson, Peter A. Appleby, Dawn Walker, Ian Eardley, and Jennifer Southgate. "Functional expression of purinergic P2 receptors and transient receptor potential channels by the human urothelium." American Journal of Physiology-Renal Physiology 305, no. 3 (August 1, 2013): F396—F406. http://dx.doi.org/10.1152/ajprenal.00127.2013.

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In addition to its role as a physical barrier, the urothelium is considered to play an active role in mechanosensation. A key mechanism is the release of transient mediators that activate purinergic P2 receptors and transient receptor potential (TRP) channels to effect changes in intracellular Ca2+. Despite the implied importance of these receptors and channels in urothelial tissue homeostasis and dysfunctional bladder disease, little is known about their functional expression by the human urothelium. To evaluate the expression and function of P2X and P2Y receptors and TRP channels, the human ureter and bladder were used to separate urothelial and stromal tissues for RNA isolation and cell culture. RT-PCR using stringently designed primer sets was used to establish which P2 and TRP species were expressed at the transcript level, and selective agonists/antagonists were used to confirm functional expression by monitoring changes in intracellular Ca2+ and in a scratch repair assay. The results confirmed the functional expression of P2Y4 receptors and excluded nonexpressed receptors/channels (P2X1, P2X3, P2X6, P2Y6, P2Y11, TRPV5, and TRPM8), while a dearth of specific agonists confounded the functional validation of expressed P2X2, P2X4, P2Y1, P2Y2, TRPV2, TRPV3, TRPV6 and TRPM7 receptors/channels. Although a conventional response was elicited in control stromal-derived cells, the urothelial cell response to well-characterized TRPV1 and TRPV4 agonists/antagonists revealed unexpected anomalies. In addition, agonists that invoked an increase in intracellular Ca2+ promoted urothelial scratch repair, presumably through the release of ATP. The study raises important questions about the ligand selectivity of receptor/channel targets expressed by the urothelium. These pathways are important in urothelial tissue homeostasis, and this opens the possibility of selective drug targeting.

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McCord, Jennifer L., Hirotsugu Tsuchimochi, and Marc P. Kaufman. "P2X2/3 and P2X3 receptors contribute to the metaboreceptor component of the exercise pressor reflex." Journal of Applied Physiology 109, no. 5 (November 2010): 1416–23. http://dx.doi.org/10.1152/japplphysiol.00774.2010.

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The exercise pressor reflex is due to activation of thin fiber afferents within contracting muscle. These afferents are in part stimulated by ATP activation of purinergic 2X (P2X) receptors during contraction. Which of the P2X receptors contribute to the reflex is unknown; however, P2X2/3 and P2X3 receptor subtypes are good candidates because they are located on thin fiber afferents and are involved in sensory neurotransmission. To determine if P2X2/3 and P2X3 receptors evoke the metabolic component of the exercise pressor reflex, we examined the effect of two P2X2/3 and P2X3 antagonists, A-317491 (10 mg/kg) and RO-3 (10 mg/kg), on the pressor response to injections of α,β-methylene ATP (α,β-MeATP; 50 μg/kg), freely perfused static contraction, contraction of the triceps surae muscles while the circulation was occluded, and postcontraction circulatory occlusion in decerebrate cats. We found that the antagonists reduced the pressor response to α,β-MeATP injection (before Δ 20 ± 3 mmHg; drug Δ 11 ± 3 mmHg; P < 0.05), suggesting the antagonists were effective in blocking P2X2/3 and P2X3 receptors. P2X2/3 and P2X3 receptor blockade reduced the pressor response to freely perfused contraction (before Δ 33 ± 5 mmHg; drug Δ 15 ± 5 mmHg; P < 0.05), contraction with the circulation occluded (before Δ 52 ± 7 mmHg; drug Δ 20 ± 4 mmHg; P < 0.05), and during postcontraction circulatory occlusion (before Δ 15 ± 1 mmHg; drug Δ 5 ± 1 mmHg; P < 0.05). Our findings suggest that P2X2/3 and P2X3 receptors contribute to the metabolic component of the exercise pressor reflex in decerebrate cats.

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Hanna, Ramy L., and Marc P. Kaufman. "Activation of thin-fiber muscle afferents by a P2X agonist in cats." Journal of Applied Physiology 96, no. 3 (March 2004): 1166–69. http://dx.doi.org/10.1152/japplphysiol.01020.2003.

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The responses of group III and IV triceps surae muscle afferents to intra-arterial injection of α,β-methylene ATP (50 μg/kg) was examined in decerebrate cats. We found that this P2X3 agonist stimulated only three of 18 group III afferents but 7 of 9 group IV afferents ( P < 0.004). The three group III afferents stimulated by α,β-methylene ATP conducted impulses below 4 m/s. Pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid, a P2-receptor antagonist, prevented the stimulation of these afferents by α,β-methylene ATP. We conclude that P2X3 agonists stimulate only the slowest conducting group III muscle afferents as well as group IV afferents.

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Thériault, Olivier, Hugo Poulin, George R. Thomas, Albert D. Friesen, Waleed A. Al-Shaqha, and Mohamed Chahine. "Pyridoxal-5′-phosphate (MC-1), a vitamin B6 derivative, inhibits expressed P2X receptors." Canadian Journal of Physiology and Pharmacology 92, no. 3 (March 2014): 189–96. http://dx.doi.org/10.1139/cjpp-2013-0404.

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P2X receptors are cation-permeable ligand-gated ion channels that open in response to the binding of ATP. These receptors are present in many excitable cells, including neurons, striated muscle cells, epithelial cells, and leukocytes. They mediate fast excitatory neurotransmission in the central and peripheral nervous systems and are thought to be involved in neuropathic pain, inflammation, and cell damage following ischemia–reperfusion injuries. P2X receptors are thus a target for the development of new therapeutics to treat chronic pain and inflammation. In this study, we characterized the inhibition caused by pyridoxal-5′-phosphate, a natural metabolite of vitamin B6 (MC-1), of P2X2, P2X4, P2X7, and P2X2/3 receptors stably expressed in HEK293 cells using the patch-clamp technique in the whole-cell configuration. We also tested a new approach using VC6.1, a modified cameleon calcium-sensitive fluorescent protein, to characterize the inhibition of P2X2 and P2X2/3. MC-1 blocked these two P2X receptors, with an IC50 of 7 and 13 μmol/L, respectively. P2X2 exhibited the highest affinity for VC6.1, and the chimeric receptor P2X2/3, the lowest. The patch-clamp and imaging approaches gave similar results and indicated that VC6.1 may be useful for high throughput drug screening. Pyridoxal-5′-phosphate is an efficient P2X blocker and can be classified as a P2X antagonist.

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Dunn, P. M., M. Liu, Y. Zhong, B. F. King, and G. Burnstock. "Diinosine pentaphosphate: an antagonist which discriminates between recombinant P2X3 and P2X2/3 receptors and between two P2X receptors in rat sensory neurones." British Journal of Pharmacology 130, no. 6 (July 2000): 1378–84. http://dx.doi.org/10.1038/sj.bjp.0703404.

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Ma, Xiaqing, Tao Xu, Hao Xu, and Wei Jiang. "Blockade and reversal of spinal morphine tolerance by P2X3 receptor antagonist." Behavioural Pharmacology 26, no. 3 (April 2015): 260–67. http://dx.doi.org/10.1097/fbp.0000000000000105.

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Ito, Katsuaki, Akihito Iwami, Hiromi Katsura, and Masahiro Ikeda. "Therapeutic effects of the putative P2X3/P2X2/3 antagonist A-317491 on cyclophosphamide-induced cystitis in rats." Naunyn-Schmiedeberg's Archives of Pharmacology 377, no. 4-6 (October 5, 2007): 483–90. http://dx.doi.org/10.1007/s00210-007-0197-z.

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Mansoor, Steven E., Wei Lü, Wout Oosterheert, Mrinal Shekhar, Emad Tajkhorshid, and Eric Gouaux. "X-ray structures define human P2X3 receptor gating cycle and antagonist action." Nature 538, no. 7623 (September 14, 2016): 66–71. http://dx.doi.org/10.1038/nature19367.

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Wang, Jixin, Eric Moore, Stefanie Kane, Christopher Salvatore, and Sean Cook. "A Single Amino Acid Mutation Turns a P2X3 Antagonist into an Agonist." Biophysical Journal 96, no. 3 (February 2009): 485a. http://dx.doi.org/10.1016/j.bpj.2008.12.2505.

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Li, Xue, Jie Yuan, Xuan Yu, Qin Zhang та Bangyong Qin. "Effect of PKC/NF-κB on the Regulation of P2X3 Receptor in Dorsal Root Ganglion in Rats with Sciatic Nerve Injury". Pain Research and Management 2020 (18 вересня 2020): 1–8. http://dx.doi.org/10.1155/2020/7104392.

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Background. Protein kinase C (PKC), nuclear factor-kappa B p65 (NF-κB p65), and P2X3 receptor (P2X3R) play significant roles in the sensitization and transduction of nociceptive signals, which are considered as potential targets for the treatment of neuropathic pain. However, the mechanisms and relationships among them have not been clearly clarified. Methods. 80 rats were randomized and divided into 10 groups (n = 8). Sciatic chronic constriction injury (CCI) rats were intrathecally administered with bisindolylmaleimide I (GF109203X), a PKC-selective antagonist once a day, or pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor twice a day. Sham-operated rats were intrathecally administered with saline. Thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) were evaluated in all the groups before CCI operation (baseline) and on the 1st, 3rd, 7th, 10th, and 14th day after CCI operation. Protein levels of p-PKCα, p-NF-κB p65, and P2X3R were analyzed in the CCI ipsilateral L4–6 dorsal root ganglions (DRGs). Results. Intrathecal injection of GF109203X or PDTC alleviated the TWL and MWT in the following 2 weeks after CCI surgery. The protein levels of p-PKCα, p-NF-κB p65, and P2X3R in the ipsilateral DRGs significantly increased after CCI operation, which could be partly reversed by intrathecal administration of GF109203X or PDTC. Conclusion. The upregulation of p-PKCα, p-NF-κB p65, and P2X3R expression in the DRGs of CCI rats was involved in the occurrence and development of neuropathic pain. Phosphorylated PKCα and phosphorylated NF-κB p65 regulated with each other. Phosphorylated NF-κB p65 and PKCα have a mutual regulation relationship with P2X3R, respectively, while the specific regulatory mechanism needs further research.

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40

Jarvis, Michael F., Bruce Bianchi, John T. Uchic, Jayne Cartmell, Chih-Hung Lee, Michael Williams, and Connie Faltynek. "[3H]A-317491, a Novel High-Affinity Non-Nucleotide Antagonist That Specifically Labels Human P2X2/3 and P2X3 Receptors." Journal of Pharmacology and Experimental Therapeutics 310, no. 1 (March 15, 2004): 407–16. http://dx.doi.org/10.1124/jpet.103.064907.

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41

Zhang, Xiaoyang, Yasuhiko Igawa, Osamu Ishizuka, Osamu Nishizawa, and Andersson Kari-Erik. "Effects of TNP-ATP, a P2X3 receptor antagonist, on micturition in conscious rats." Japanese Journal of Urology 94, no. 2 (2003): 170. http://dx.doi.org/10.5980/jpnjurol.94.170_4.

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Wu, Gang, Garth T. Whiteside, Gary Lee, Scott Nolan, Mark Niosi, Michelle S. Pearson, and Victor I. Ilyin. "A-317491, a selective P2X3/P2X2/3 receptor antagonist, reverses inflammatory mechanical hyperalgesia through action at peripheral receptors in rats." European Journal of Pharmacology 504, no. 1-2 (November 2004): 45–53. http://dx.doi.org/10.1016/j.ejphar.2004.09.056.

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Hansen, Rikke Rie, Arafat Nasser, Sarah Falk, Signe B. Baldvinsson, Pernille H. Ohlsson, Justyna M. C. Bahl, Michael F. Jarvis, Ming Ding, and Anne-Marie Heegaard. "Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice." European Journal of Pharmacology 688, no. 1-3 (August 2012): 27–34. http://dx.doi.org/10.1016/j.ejphar.2012.05.008.

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44

Hu, Shufen, Qian Sun, Wan-Jie Du, Jian Song, Xin Li, Ping-An Zhang, Ji-Tian Xu, and Guang-Yin Xu. "Adult Stress Promotes Purinergic Signaling to Induce Visceral Pain in Rats with Neonatal Maternal Deprivation." Neuroscience Bulletin 36, no. 11 (September 9, 2020): 1271–80. http://dx.doi.org/10.1007/s12264-020-00575-7.

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AbstractChronic visceral pain is one of the primary symptoms of patients with irritable bowel syndrome (IBS), which affects up to 15% of the population world-wide. The detailed mechanisms of visceral pain remain largely unclear. Our previous studies have shown that neonatal maternal deprivation (NMD) followed by adult multiple stress (AMS) advances the occurrence of visceral pain, likely due to enhanced norepinephrine (NE)-β2 adrenergic signaling. This study was designed to explore the roles of P2X3 receptors (P2X3Rs) in the chronic visceral pain induced by combined stress. Here, we showed that P2X3Rs were co-expressed in β2 adrenergic receptor (β2-AR)-positive dorsal root ganglion neurons and that NE significantly enhanced ATP-induced Ca2+ signals. NMD and AMS not only significantly increased the protein expression of P2X3Rs, but also greatly enhanced the ATP-evoked current density, number of action potentials, and intracellular Ca2+ concentration of colon-related DRG neurons. Intrathecal injection of the P2X3R inhibitor A317491 greatly attenuated the visceral pain and the ATP-induced Ca2+ signals in NMD and AMS rats. Furthermore, the β2-AR antagonist butoxamine significantly reversed the expression of P2X3Rs, the ATP-induced current density, and the number of action potentials of DRG neurons. Overall, our data demonstrate that NMD followed by AMS leads to P2X3R activation, which is most likely mediated by upregulation of β2 adrenergic signaling in primary sensory neurons, thus contributing to visceral hypersensitivity.

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Allsopp, Rebecca C., Louise K. Farmer, Alistair G. Fryatt, and Richard J. Evans. "P2X Receptor Chimeras Highlight Roles of the Amino Terminus to Partial Agonist Efficacy, the Carboxyl Terminus to Recovery from Desensitization, and Independent Regulation of Channel Transitions." Journal of Biological Chemistry 288, no. 29 (June 5, 2013): 21412–21. http://dx.doi.org/10.1074/jbc.m113.464651.

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P2X receptor subtypes can be distinguished by their sensitivity to ATP analogues and selective antagonists. We have used chimeras between human P2X1 and P2X2 receptors to address the contribution of the extracellular ligand binding loop, transmembrane segments (TM1 and TM2), and intracellular amino and carboxyl termini to the action of partial agonists (higher potency and efficacy of BzATP and Ap5A at P2X1 receptors) and antagonists. Sensitivity to the antagonists NF449, suramin, and PPADS was conferred by the nature of the extracellular loop (e.g. nanomolar for NF449 at P2X1 and P2X2-1EXT and micromolar at P2X2 and P2X1-2EXT). In contrast, the effectiveness of partial agonists was similar to P2X1 levels for both of the loop transfers, suggesting that interactions with the rest of the receptor played an important role. Swapping TM2 had reciprocal effects on partial agonist efficacy. However, TM1 swaps increased partial agonist efficacy at both chimeras, and this was similar for swaps of both TM1 and 2. Changing the amino terminus had no effect on agonist potency but increased partial agonist efficacy at P2X2-1N and decreased it at P2X1-2N chimeras, demonstrating that potency and efficacy can be independently regulated. Chimeras and point mutations also identified residues in the carboxyl terminus that regulated recovery from channel desensitization. These results show that interactions among the intracellular, transmembrane, and extracellular portions of the receptor regulate channel properties and suggest that transitions to channel opening, the behavior of the open channel, and recovery from the desensitized state can be controlled independently.

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Bae, Jinsu, Yeo-Ok Kim, Xuehao Han, Myung-Ha Yoon, Woong-Mo Kim, and Yong-Chul Kim. "Synthesis and Structure–Activity Relationship Studies of Benzimidazole-4,7-dione-Based P2X3 Receptor Antagonists as Novel Anti-Nociceptive Agents." Molecules 27, no. 4 (February 16, 2022): 1337. http://dx.doi.org/10.3390/molecules27041337.

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P2X3 receptors (P2X3R) are ATP-gated ion channels predominantly expressed in C- and Aδ-fiber primary afferent neurons and have been introduced as a novel therapeutic target for neurological disorders, including neuropathic pain and chronic cough. Because of its localized distribution, antagonism of P2X3R has been thoroughly considered, and the avoidance of issues related to CNS side effects has been proven in clinical trials. In this article, benzimidazole-4,7-dione-based derivatives were introduced as a new chemical entity for the development of P2X3R antagonists. Starting from the discovery of a hit compound from the screening of 8364 random library compounds in the Korea Chemical Bank, which had an IC50 value of 1030 nM, studies of structure–activity and structure–property relationships enabled further optimization toward improving the antagonistic activities as well as the drug’s physicochemical properties, including metabolic stability. As for the results, the final optimized compound 14h was developed with an IC50 value of 375 nM at P2X3R with more than 23-fold selectivity versus P2X2/3R, along with properties of metabolic stability and improved solubility. In neuropathic pain animal models evoked by either nerve ligation or chemotherapeutics in male Sprague-Dawley rats, compound 14h showed anti-nociceptive effects through an increase in the mechanical withdrawal threshold as measured by von Frey filament following intravenous administration.

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Jung, Young-Hwan, Yeo Ok Kim, Jung Hyun Han, Yong-Chul Kim та Myung Ha Yoon. "Isobolographic Analysis of Drug Combinations With Intrathecal BRL52537 (κ-Opioid Agonist), Pregabalin (Calcium Channel Modulator), AF 353 (P2X3 Receptor Antagonist), and A804598 (P2X7 Receptor Antagonist) in Neuropathic Rats". Anesthesia & Analgesia 125, № 2 (серпень 2017): 670–77. http://dx.doi.org/10.1213/ane.0000000000001883.

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Inoue, Hiroyuki, Hidetaka Kuroda, Wataru Ofusa, Sadao Oyama, Maki Kimura, Tatsuya Ichinohe, and Yoshiyuki Shibukawa. "Functional Coupling between the P2X7 Receptor and Pannexin-1 Channel in Rat Trigeminal Ganglion Neurons." International Journal of Molecular Sciences 22, no. 11 (June 1, 2021): 5978. http://dx.doi.org/10.3390/ijms22115978.

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

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Roadcap, Brad, Azher Hussain, Dan Dreyer, Keynu Carter, Neal Dube, Yang Xu, Melanie Anderson, et al. "Clinical application of volumetric absorptive microsampling to the gefapixant development program." Bioanalysis 12, no. 13 (July 2020): 893–904. http://dx.doi.org/10.4155/bio-2020-0074.

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In this paper we show the application of the Tasso OnDemand™, a novel automated sample collection device, in conjunction with volumetric absorptive microsampling (VAMS) for the development of gefapixant, a P2X3 receptor antagonist currently under clinical development for the treatment of refractory and unexplained chronic cough and endometriosis-related pain. A LC–MS/MS bioanalytical method was developed and validated using VAMS to support this development program. This method was utilized in a drug–drug interaction study to establish a mathematical bridging relationship with data obtained from a validated plasma assay used to support the program. The VAMS bioanalytical method and the predictability of the mathematical relationship is reported and discussed here.

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50

Garceau, Denis, and Nathalie Chauret. "BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration." Pulmonary Pharmacology & Therapeutics 56 (June 2019): 56–62. http://dx.doi.org/10.1016/j.pupt.2019.03.007.

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