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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).
Pharmacology of the lower urinary tract
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
There is good evidence that the transmitter responsible for the NANC component is ATP, acting on P2X receptors found in the detrusor smooth muscle membranes of rats and humans.15,146,147 The receptor subtype predominating in both species seemed to be the P2X1 subtype. Moore et al.148 reported that detrusor from patients with idiopathic detrusor instability had a selective absence of P2X3 and P2X5 receptors, and suggested that this specific lack might impair control of detrusor contractility and contribute to the pathophysiology of urge incontinence. On the other hand, O’Reilly et al.142 found that in patients with idiopathic detrusor instability, P2X2 receptors were significantly elevated, whereas other P2X receptor subtypes were significantly decreased. They were unable to detect a purinergic component of nerve-mediated contractions in control (normal) bladder specimens, but there was a significant purinergic component of approximately 50% in unstable bladder specimens. They concluded that this abnormal purinergic transmission in the bladder might explain symptoms in these patients. The same group confirmed that the P2X1 receptor was the predominant purinoceptor subtype also in the human male bladder.142 They found that the amount of P2X1 receptor per smooth muscle cell was larger in obstructed than in control bladders. This suggests an increase in purinergic function in the OAB arising from bladder outlet obstruction.
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.
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
In the last years, several lines of evidence have outlined a critical role of extracellular adenosine triphosphate (ATP) in modulating immune responses [4,5]. In particular, during inflammation, ATP is released massively from immune and parenchymal cells, acting as a ‘danger’ signal, which, through the activation of purinergic P2 receptors plays a critical role in immune cell migration, chemotaxis, and cytokine release [6]. In this context, purinergic P2X4 receptor (P2X4R) subtype has captured the attention due to its role in the pathophysiological mechanisms of many disorders characterised by immune dysfunctions, including IBDs [7]. Indeed, once activated by ATP in nanomolar concentrations, P2X4R elicits a pro-inflammatory response with the release of pro-inflammatory cytokines, such as IL-1β and IL-18, with consequent exacerbation of the inflammatory response [8,9].
Down-expression of P2RX2, KCNQ5, ERBB3 and SOCS3 through DNA hypermethylation in elderly women with presbycusis
Published in Biomarkers, 2018
Amal Bouzid, Ibtihel Smeti, Leila Dhouib, Magali Roche, Imen Achour, Aida Khalfallah, Abdullah Ahmed Gibriel, Ilhem Charfeddine, Hammadi Ayadi, Joel Lachuer, Abdelmonem Ghorbel, Christine Petit, Saber Masmoudi
Both KCNQ5 and P2RX2 ion channels were previously described in inner ear. KCNQ5, potassium channel voltage gated KQT-like subfamily Q member 5, is highly expressed in the inner ear (Spitzmaul et al. 2013) of mouse models and adult zebrafish (Wu et al. 2014) as well as in guinea pig and rat cochlea (Liang et al. 2006). Voltage-gated potassium channels play key roles in hearing, as evidenced by deafness resulting from disruption of genes encoding, for example, KCNQ1 or KCNQ4 subunits. P2RX2, purinergic receptor P2X ligand gated ion channel 2, mediates variety of cellular responses including excitatory postsynaptic responses in sensory neurons. It acts as a key signaling molecule involved in normal cochlear homeostasis and hearing sensitivity (Thorne et al. 2002). Reduced P2RX2 receptor-mediated regulation of endocochlear potential in the ageing mouse cochlea resulted in hearing sensitivity impairment (Telang et al. 2010). Haplo-insufficiency in P2RX2 gene causes human autosomal dominant deafness (DFNA41) characterized by onset of progressive high-frequency sensorineural HI usually in the second decade (Yan et al. 2013). In this case, DNA methylation changes and down-expression of the P2RX2 gene may account for function disruption of the inner ear.
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