Tissue distribution of P2X 4 receptors studied with an ectodomain antibody

Bo, Xuenong; Kim, Miran; Nori, Stefania Lucia; Schoepfer, Ralf; Burnstock, Geoffrey; North, Richard

doi:10.1007/s00441-003-0758-5

Cited by 74 publications

(58 citation statements)

References 35 publications

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“…Likewise, our immunohistochemical findings revealed expressions within endothelial cells in some organs, within alveolar macrophages and bronchial epithelial cells in the lung, within the epithelial cells of proximal tubules, and within hepatocytes, neurons, and Purkinje cells, but only a very weak expression within cardiomyocytes. These results are consistent with the Western blotting and immunohistochemical results obtained in normal rats by Bo et al 24 In addition, we observed P2X1R and P2Y2R mRNA in several organs, including the brain and liver, in normal rats (using semiquantitative RT-PCR), and we demonstrated that in the normal condition, P2X1R was abundant in the lung, whereas P2Y2R was abundant in the liver. In contrast, Rice et al 25 reported P2Y2R mRNA expression in heart, kidney, lung, spleen and testis, but no expression in rat brain or liver.…”

Section: Discussionsupporting

confidence: 93%

Expression of P2X4R mRNA and Protein in Rats With Hypobaric Hypoxia-Induced Pulmonary Hypertension

Ohata

Ogata

Nakanishi

et al. 2011

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp he pulmonary hypertension that develops in hypobaric hypoxia is characterized by structural remodeling of the heart (eg, right ventricular hypertrophy). 1-7 Over the past 20 years or so, various factors and influences, including the adrenergic-receptor system, have been shown to be involved in such cardiovascular remodeling processes. [8][9][10][11][12] It is well known that hypoxia stimulates endothelial cells to release adenosine triphosphate (ATP). Purinergic P2 nucleotide receptors on endothelial cells bind this ATP, triggering secretion of nitric oxide and consequent vasodilation. The P2 class of nucleotide receptors includes the P2X receptor, which is a ligand-gated receptor channel, and the G protein-coupled P2Y receptor. 13,14 Recently, the P2X4 receptor (P2X4R) has been reported to control vascular tone and vessel remodeling in at least some blood vessels. 15-19 Interestingly, P2X4R is an important subunit of the native cardiac myocyte P2X receptor, 17 and cardiac-restricted overexpression of P2X4R can induce an enhanced contractile state of the intact heart. 20 More recently, it was found that cardiac overexpression of P2X4R increased cardiac contractility and survival in a model of myocardial infarction-induced cardiac failure. 21 It has therefore emerged as a key factor in the enhancement of cardiac performance. However, no reports have been published of alterations in P2X4R expression in certain organs, especially the heart, upon exposure to hypobaric hypoxia, and little is known about any changes in P2X4R expression in hypoxia-induced pulmonary hypertension (in which only RV is exposed to pressure overload).Even if changes in P2X4R expression occur during exposure to hypobaric hypoxia and show an apparent relation to the pulmonary pressure overload, it needs to be firmly established: (1) whether the changes in P2X4R (at both the protein and mRNA levels) occurring in certain organs, especially the heart, are coupled to the elevation in pulmonary arterial pressure seen after exposure to hypobaric hypoxia; (2) whether the changes in P2X4R protein occurring in certain organs as an adaptation to hypobaric hypoxic exposure are mirrored by similar changes at the mRNA level; and (3) whether the dis- Expression of P2X4R mRNA and Protein in RatsWith Hypobaric Hypoxia-Induced Pulmonary HypertensionYuichiro Ohata, MD; Sho Ogata, MD; Kuniaki Nakanishi, MD; Fumiko Kanazawa; Maki Uenoyama; Sadayuki Hiroi, PhD; Susumu Tominaga; Toshiaki Kawai, MD Background: The experimental pulmonary hypertension that develops in hypobaric hypoxia is characterized by structural remodeling of the heart. The P2X4 receptor (P2X4R) controls vascular tone and vessel remodeling in several blood vessels, and it has emerged as a key factor in the enhancement of cardiovascular performance.

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Section: Discussionsupporting

confidence: 93%

Expression of P2X4R mRNA and Protein in Rats With Hypobaric Hypoxia-Induced Pulmonary Hypertension

Ohata

Ogata

Nakanishi

et al. 2011

Circ J

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“…Finally, in the context of chlamydial infection, it is worthwhile noting the tissue distribution of P2X 4 : vaginal epithelia had the greatest abundance of P2X 4 among rat tissues (8), and P2X 4 was the most abundantly expressed purinergic receptor in a cancer cell line of human cervical epithelial cells (63).…”

Section: Discussionmentioning

confidence: 99%

Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X ₄ Receptors

et al. 2012

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Bacterial 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 P2X 7 receptors. We show here that the proinflammatory mediator, ATP, is released from Chlamydia 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 P2X 4 receptors. A specific role for P2X 4 was confirmed using cells overexpressing P2X 4 . 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. Danger signals comprise a varied group of extracellular molecules which indicate a potentially harmful physiological state and for which specific sensory mechanisms exist (38,40,51,55,56). Well-known danger signals include extracellular ATP, adenosine, uric acid crystals, the chromatin component HMGB1, and heat shock proteins. However, the level of danger posed elicits different cellular responses. For example, ATP is released from resting cells (nanomolar range) (5, 37), stressed and dying cells (micromolar range) (23), and physically compromised cells (millimolar range), although actual concentrations depend heavily on cell type and environment. Cells in the adjacent tissue must then decide whether to modify their own behavior in response to the extracellular signal, and whether to amplify the response by secreting other signaling molecules such as cytokines.The cells sense extracellular ATP and other nucleotides and nucleosides via a family of membrane receptors called purinergic receptors. These receptors are subdivided by function and homology into three classes: P2X are ligand-gated ion channels sensitive to ATP, P2Y are G-protein-coupled receptors stimulated by adenine and uracil nucleotides, and P1 receptors are also G protein coupled but are sensitive to adenosine (11,45). The tissue distribution and sensitivity to the ligands vary significantly within each family (12), such that slightly different concentrations of ligand can have different effects at a single cell type, and the same concentration of ligand can have contrasting effects on different cell types.While purinergic receptors have been best characterized in the central nervous system, the...

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“…It is noteworthy that P2X 4 is the most widely distributed P2X subunit in the central nervous system (Norenberg and Illes, 2000;Bo et al, 2003). However, native P2X receptor phenotypes in the brain do not resemble heterologously expressed homo/heteromeric P2X 4 channels (North, 2002).…”

Section: Discussionmentioning

confidence: 99%

Functional Properties of Internalization-Deficient P2X₄ Receptors Reveal a Novel Mechanism of Ligand-Gated Channel Facilitation by Ivermectin

Toulmé¹,

Soto²,

Garret³

et al. 2005

Mol Pharmacol

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Although P2X receptors within the central nervous system mediate excitatory ATP synaptic transmission, the identity of central ATP-gated channels has not yet been elucidated. P2X 4 , the most widely expressed subunit in the brain, was previously shown to undergo clathrin-dependent constitutive internalization by direct interaction between activator protein (AP)2 adaptors and a tyrosine-based sorting signal specifically present in the cytosolic C-terminal tail of mammalian P2X 4 sequences. In this study, we first used internalization-deficient P2X 4 receptor mutants to show that suppression of the endocytosis motif significantly increased the apparent sensitivity to ATP and the ionic permeability of P2X 4 channels. These unique properties, observed at low channel density, suggest that interactions with AP2 complexes may modulate the function of P2X 4 receptors. In addition, ivermectin, an allosteric modulator of several receptor channels, including mammalian P2X 4 , did not potentiate the maximal current of internalization-deficient rat or human P2X 4 receptors. We demonstrated that binding of ivermectin onto wild-type P2X 4 channels increased the fraction of plasma membrane P2X 4 receptors, whereas surface expression of internalization-deficient P2X 4 receptors remained unchanged. Disruption of the clathrin-mediated endocytosis with the dominant-negative mutants Eps15 or AP-50 abolished the ivermectin potentiation of wild-type P2X 4 channel currents. Likewise, ivermectin increased the membrane fraction of nicotinic ␣7 acetylcholine (n␣7ACh) receptors and the potentiation of acetylcholine current by ivermectin was suppressed when the same dominant-negative mutants were expressed. These data showed that potentiation by ivermectin of both P2X 4 and n␣7ACh receptors was primarily caused by an increase in the number of cell surface receptors resulting from a mechanism dependent on clathrin/AP2-mediated endocytosis.ATP mediates fast excitatory neurotransmission in the peripheral and central nervous system through direct activation of P2X receptors. ATP P2X receptors form a family of nonselective cation channels (North, 2002) composed of at least seven subunits (P2X 1-7 ). Among these subunits, the P2X 4 subtype is the most widely distributed in the brain, displaying some regional and cellular overlapping distribution with P2X 2 or P2X 6 subunits (Norenberg and Illes, 2000). The localization of P2X 4 subunits at postsynaptic specialization of hippocampal or cerebellar neurons (Rubio and Soto, 2001) as well as at axon terminals (Le et al., 1998) suggests a pivotal role for P2X 4 -containing receptors in fast ATP synaptic transmission or the modulation of neurotransmitter release. However, the functional properties of postsynaptic ATP-mediated responses found in the brain do not correlate with those of any recombinant P2X receptors formed by combination of these subunits. For instance, recombinant mammalian P2X 4 receptors are moderately desensitizing ␣␤-methylene-ATP-insensitive channels (for review, North, 2002...

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Tissue distribution of P2X 4 receptors studied with an ectodomain antibody

Cited by 74 publications

References 35 publications

Expression of P2X4R mRNA and Protein in Rats With Hypobaric Hypoxia-Induced Pulmonary Hypertension

Expression of P2X4R mRNA and Protein in Rats With Hypobaric Hypoxia-Induced Pulmonary Hypertension

Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X ₄ Receptors

Functional Properties of Internalization-Deficient P2X₄ Receptors Reveal a Novel Mechanism of Ligand-Gated Channel Facilitation by Ivermectin

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Tissue distribution of P2X 4 receptors studied with an ectodomain antibody

Cited by 74 publications

References 35 publications

Expression of P2X4R mRNA and Protein in Rats With Hypobaric Hypoxia-Induced Pulmonary Hypertension

Expression of P2X4R mRNA and Protein in Rats With Hypobaric Hypoxia-Induced Pulmonary Hypertension

Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X 4 Receptors

Functional Properties of Internalization-Deficient P2X4 Receptors Reveal a Novel Mechanism of Ligand-Gated Channel Facilitation by Ivermectin

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Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X ₄ Receptors

Functional Properties of Internalization-Deficient P2X₄ Receptors Reveal a Novel Mechanism of Ligand-Gated Channel Facilitation by Ivermectin