China
Africa
Explore chapters and articles related to this topic
Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
The P2X4 receptor (encoded by the P2RX4 gene) belongs to the family of purinoceptors that opens in response to ATP binding at the extracellular side (Khakh and North, 2012). It is a trimeric 2-TM channel permeable to both Na+ and Ca2+ when activated by ATP (Figure 18.5). P2X4 is highly expressed in the PM of various tissues and involved in many cellular processes. Recent studies suggest that P2X4 receptors are stored in the lysosomal membrane and brought to the cell surface or to phagosomes in response to a variety of stimuli (Qureshi et al., 2007). Lysosomal P2X4 is activated by luminal ATP in a pH-dependent manner, i.e. it is minimally activated at acidic luminal pH, whereas lysosome alkalization dramatically increases its activity. Physiologically, P2X4 functions as a lysosomal Ca2+ channel which activation facilitates homotypic lysosome fusion using a CaM-dependent mechanism (Cao et al., 2015a). P2X4 is also expressed in lysosome-related vesicles such as Lamellar Bodies, large secretory lysosomes that store lung surfactant in alveolar type II epithelial cells and is inserted into the PM following lysosomal exocytosis. New evidence suggests that the activation of vesicular P2X4 receptors facilitates the secretion of pulmonary surfactant in pulmonary alveoli (Fois et al., 2018; Miklavc et al., 2011; Thompson et al., 2013).
The Opioid Epidemic
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Morphine-induced hyperalgesia appears to have a distinct pathway from tolerance. Hyperalgesia requires microglia. Specifically, morphine-induced hyperalgesia requires the expression of P2X4 receptor in the microglia. Chronic exposure to morphine causes an increase in P2X4 receptor expression by a µ-receptor-dependent mechanism. P2X4 receptor stimulation results in the release of brain-derived neurotrophic factor (BDNF). BDNF through TrkB downregulates a K+-Cl− cotransporter (KCC2) expression in lamina I neurons causing an impairment in Cl− extrusion through a µ-receptor-independent mechanism. So, a µ-receptor-dependent mechanism is required to activate the microglia, but a µ-receptor-independent mechanism is responsible for the microglia-neuron signaling. Toll-like receptor 4 (TLR4) was not involved in the µ-receptor independent mechanism.28
The mitotic phase of spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Recently, emerging players in the autocrine/paracrine regulation of spermatogonia have been identified. Sahin et al. have established a spermatogenesis regeneration model by first depleting spermatogenic cells except Aundiff using irradiation followed by the induction of spermatogonial differentiation by administration of gonadotrophin-releasing hormone agonist. Using this model, they observed that the Desert Hedgehog ligand Dhh, the Hedgehog receptor Ptc 2, and the receptor downstream signaling molecules Gli1 and Gli2 are expressed in Aundiff, suggesting the involvement of Hedgehog signaling in the autocrine regulation of spermatogonia.67 Apart from the involvement of cytokines and growth factors, a recent study has suggested the involvement of purinergic signaling in the autocrine/paracrine regulation of spermatogonia.68 Purinergic signaling is mediated by the binding of extracellular nucleotide or nucleoside such as ATP to the P2 receptor. Two subclasses of P2 receptors are metabotropic P2Y receptors (P2YRs) and ionotropic P2X receptors (P2XRs) that activate G-protein–coupled signaling and nucleotide-gated ion channels, respectively.69 By employing electrophysiological techniques, Flect et al. have shown that spermatogonia are sensitive to a board concentration range of extracellular ATP. They have further demonstrated two modes of ATP response: high-affinity (10-µM extracellular ATP) and low affinity (>300-µM extracellular ATP), which are mediated by P2X4 and P2X7 receptors, respectively.69 Further study is required to demonstrate the physiological role of purinergic signaling in the autocrine/paracrine regulation in spermatogonia.
Adherent-Invasive E. coli enhances colonic hypersensitivity and P2X receptors expression during post-infectious period
Published in Gut Microbes, 2018
Amandine Lashermes, Ludivine Boudieu, Julie Barbier, Benoit Sion, Agathe Gelot, Nicolas Barnich, Denis Ardid, Frédéric Antonio Carvalho
Few animal models reproducing PI-IBS symptoms and etiology are available. The 2 most common are a model of bacterial infection with Campylobacter jejuni, mainly used in rats, and a model of parasitic infection with Trichinella spiralis.5 Mice infection by this intestinal parasite leads to enteric inflammation caused by innate inflammatory response and post-infectious afferent nerve hypersensitivity. Keating et al. have shown that the mechanisms involved in infection with Trichinella spiralis are dependent on P2X7 receptors.6 P2X receptors (P2XRs), in particular P2X3, P2X4, and P2X7, are ATP-gated ion channels involved in the transmission of visceral nociceptive information from the gut to the central nervous system.7 In humans, increased numbers of mucosa-associated E. coli have been observed in CD patients.8 These patients also have an abnormal ileal expression of carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 5 and 6. CEACAM6 acts as a receptor for AIEC LF82.9 Moreover, Dogan et al. reported that E. coli with an IBD-associated AIEC pathotype are common in IBS patients.10
The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration
Published in Platelets, 2022
Martine Baumann, Benoît Lack, Isabelle Guillaumat, Mark J. Murphy, Markus A. Riederer
In a separate set of experiments, potential antagonistic activity was evaluated in assay systems with recombinant P2X1, P2X2, P2X3, P2X4 and P2X7 receptors, respectively. For assay verification, the unselective P2 purinergic antagonist pyridoxalphosphate-6-azophenyl-2ʹ,4ʹ-disulfonic acid (PPADS) antagonized the effect of 1 μM ATP on P2X1, P2X2, P2X3, P2X4 receptors, respectively [39]. In addition, the 1-Benzyl-5-phenyltetrazole P2X7 antagonist compound 17a reported by Nelson et al. [40] antagonized the P2X7 YoPro assay. In contrast, selatogrel tested at 25 μM did not antagonize any of the P2X purinergic receptors tested.
Pharmacological modulation of P2X4 in inflammatory bowel diseases: the way towards novel therapeutics?
Published in Journal of Drug Targeting, 2023
Vanessa D’Antongiovanni, Carolina Pellegrini, Matteo Fornai, Zoltan H. Nemeth, György Haskó, Luca Antonioli
The role played by extracellular ATP in modulating immune responses, via P2Rs, under physiological and pathological conditions has been demonstrated in the last years. In this context, current body of knowledge indicate the receptor subtype P2X4 a pivotal player in the pathophysiological mechanisms of many disorders characterised by immune dysfunctions, including GI diseases. Indeed, P2X4Rs are widely expressed on cells of both the innate and adaptive arms of the immune system as well as in the intestinal tract, thus highlighting their significant involvement in the physiological modulation of secretory and motor gut activity, as well as in the pathophysiology of intestinal inflammation, gut dysfunctions and abdominal pain associated with IBDs. For these reasons, P2X4R is emerging as potential therapeutic targets for treatment of such pathological conditions. In this regard, the use of selective P2X4 antagonists showed beneficial effects in counteracting the inflammatory burst in murine models of colitis, acting on both the innate and acquired component of the immune system as well as on inflammasome complex. In parallel, the pharmacological modulation of P2X4 appear to be an interesting method for the management of visceral pain and gut dysfunctions associated with IBDs. However, several aspects pertaining to the regulation of digestive functions by P2X4Rs remain unclear and deserve extensive investigation. In particular, due to the scanty of data, some important issues remain to be addressed: (1) What is the pathophysiological meaning of P2X4R subtype in the onset and development of IBDs? (2) What is the role of P2X4Rs in the pathophysiological events underlying gut dysmotility and visceral pain associated with IBDs? (3) The pharmacological modulation of P2X4R could represent a useful strategy for the therapeutic management of gut dysmotility associated with colitis? (4) What are the molecular mechanisms underlying the interplay between P2X4Rs and enteric neuro-immune system in the onset and development of CD and UC?