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1.
Previous studies indicated that a ganglioside 9acGD3 (9-O-acetyl GD3) antibody [the J-Ab (Jones antibody)] reduces GCP (granule cell progenitor) migration in vitro and in vivo. We here investigated, using cerebellar explants of post-natal day (P) 6 mice, the mechanism by which 9acGD3 reduces GCP migration. We found that immunoblockade of the ganglioside with the J-Ab or the lack of GD3 synthase reduced GCP in vitro migration and the frequency of Ca 2+ oscillations. Immunocytochemistry and pharmacological assays indicated that GCPs expressed P2Y 1Rs (P2Y 1 receptors) and that deletion or blockade of these receptors decreased the migration rate of GCPs and the frequency of Ca 2+ oscillations. The reduction in P2Y 1-mediated calcium signals seen in Jones-treated and GD3 synthase-null GCPs were paralleled by P2Y 1R internalization. We conclude that 9acGD3 controls GCP migration by influencing P2Y 1R cellular distribution and function. 相似文献
2.
Extracellular nucleotides have been identified as important signaling molecules. These nucleotides act on the P2 family of receptors that respond by either forming an ion-channel or by activation of a signal transduction cascade, both of which enable a cellular response. Although a role for P2 receptors in inflammation has been implied, the local expression pattern and kinetics of these receptors at sites of inflammation are not known. Therefore, we have studied the expression of the P2 receptors expressed by inflammatory cells or by cells in the vasculature, with special attention to P2X 1R, P2X 7R, P2Y 1R, and P2Y 2R. As a suitable model for studying inflammatory reactions, we have employed the foreign body reaction (FBR), a sterile inflammatory reaction induced by implanting degradable cross-linked dermal sheep collagen disks subcutaneously in the rat. We show that, in the vasculature, the expression of P2X 7R, P2Y 1R, and P2Y 2R increase until day 2. The expression of P2X 7R and P2Y 1R on macrophages and giant cells increased during the course of the inflammatory reaction which was studied for 21 days. The expression of the P2Y 2R on macrophages and giant cells inside the foreign body increases with time, whereas the expression on macrophages in the surrounding tissue is maximal at day 5. The expression of P2X 1R remains at a constant low level. The upregulation of P2X 7R, P2Y 1R, and P2Y 2R over time suggests a regulatory function for these receptors in inflammation. 相似文献
3.
We previously demonstrated that P2X7 receptors (P2X7Rs) expressed by cultured mouse astrocytes were activated without any exogenous stimuli, but its roles in non-stimulated resting astrocytes remained unknown. It has been reported that astrocytes exhibit engulfing activity, and that the basal activity of P2X7Rs regulates the phagocytic activity of macrophages. In this study, therefore, we investigated whether P2X7Rs regulate the engulfing activity of mouse astrocytes. Uptake of non-opsonized beads by resting astrocytes derived from ddY-mouse cortex time-dependently increased, and the uptaken beads were detected in the intracellular space. The bead uptake was inhibited by cytochalasin D (CytD), an F-actin polymerization inhibitor, and agonists and antagonists of P2X7Rs apparently decreased the uptake. Spontaneous YO-PRO-1 uptake by ddY-mouse astrocytes was reduced by the agonists and antagonists of P2X7Rs, but not by CytD. Down-regulation of P2X7Rs using siRNA decreased the bead uptake by ddY-mouse astrocytes. In addition, compared to in the case of ddY-mouse astrocytes, SJL-mouse astrocytes exhibited higher YO-PRO-1 uptake activity, and their bead uptake was significantly greater. These findings suggest that resting astrocytes exhibit engulfing activity and that the activity is regulated, at least in part, by their P2X7Rs. 相似文献
4.
Rapid phosphoester hydrolysis of endogenous purine and pyrimidine nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical nucleotide P2Y1 receptor (P2Y1R) agonists and antagonists. These included the riboside nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained (N)-methanocarba rings, which were previously reported to form nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A3 and A1ARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2Y1R activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to nucleotide agonists is due to AR activation by active nucleoside metabolites. 相似文献
5.
P2X4 receptors (P2X4Rs), a subtype of the purinergic P2X family, play important roles in regulating neuronal and glial functions in the nervous system. We have previously shown that the expression of P2X4Rs is upregulated in activated microglia after peripheral nerve injury and that activation of the receptors by extracellular ATP is crucial for maintaining nerve injury-induced pain hypersensitivity. However, the regulation of P2X4R expression on the cell surface of microglia is poorly understood. Here, we identify the CC chemokine receptor CCR2 as a regulator of P2X4R trafficking to the cell surface of microglia. In a quantitative cell surface biotinylation assay, we found that applying CCL2 or CCL12, endogenous ligands for CCR2, to primary cultured microglial cells, increased the levels of P2X4R protein on the cell surface without changing total cellular expression. This effect of CCL2 was prevented by an antagonist of CCR2. Time-lapse imaging of green fluorescent protein (GFP)-tagged P2X4R in living microglial cells showed that CCL2 stimulation increased the movement of P2X4R-GFP particles. The subcellular localization of P2X4R immunofluorescence was restricted to lysosomes around the perinuclear region. Notably, CCL2 changed the distribution of lysosomes with P2X4R immunofluorescence within microglial cells and induced release of the lysosomal enzyme β-hexosaminidase, indicating lysosomal exocytosis. Moreover, CCL2-stimulated microglia enhanced Akt phosphorylation by ATP applied extracellularly, a P2X4R-mediated response. These results indicate that CCL2 promotes expression of P2X4R protein on the cell surface of microglia through exocytosis of P2X4R-containing lysosomes, which may be a possible mechanism for pain hypersensitivity after nerve injury. 相似文献
6.
The distribution of P2Y 2 receptor-immunoreactive (ir) neurons and fibers and coexistence of P2Y 2 with P2X 2 and P2X 3 receptors, neuropeptide Y (NPY), calretinin (CR), calbindin (CB) and nitric oxide synthase (NOS) was investigated with immunostaining
methods. The results showed that P2Y 2-ir neurons and fibers were distributed widely in myenteric and submucous plexuses of the guinea pig stomach corpus, jejunum,
ileum and colon. The typical morphology of P2Y 2-ir neurons was a long process with strong positive staining on the same side of the cell body. The P2Y 2-ir neurons could be Dogiel type 1. About 40–60% P2X 3-ir neurons were immunoreactive for P2Y 2 in the myenteric plexus and all the P2X 3-ir neurons expressed the P2Y 2 receptor in the submucosal plexus; almost all the NPY-ir neurons and the majority of CR-ir neurons were also immunoreactive
for P2Y 2, especially in the myenteric plexus of the small intestine; no P2Y 2-ir neurons were immunoreactive for P2X 2 receptors, CB and NOS. It is shown for the first time that S type/Dogiel type 1 neurons with fast P2X and slow P2Y receptor-mediated
depolarizations could be those neurons expressing both P2Y 2-ir and P2X 3-ir and that they are widely distributed in myenteric and submucosal plexuses of guinea pig gut. 相似文献
7.
Contact of T lymphocytes with nicotinamide adenine dinucleotide (NAD) or ATP causes cell death that requires expression of purinergic receptor P2X(7) (P2X(7)R). T cell subsets differ in their responses to NAD and ATP, which awaits a mechanistic explanation. Here, we show that sensitivity to ATP correlates with P2X(7)R expression levels in CD4 cells, CD8 cells and CD4(+)CD25(+) cells from both C57BL/6 and BALB/c mice. But P2X(7)R ligands do not only induce cell death but also shedding of CD62L. It is shown here that in CD62L(high) T cells, CD62L shedding correlates with low expression of P2X(7)Rs and lower cell death, whereas in CD62L(low) cells P2X(7)R expression and death are higher. The possibility is therefore investigated that P2X(7)Rs induce T cell activation. Experiments show that spontaneous T cell proliferation is somewhat higher in cells expressing P2X(7)Rs, but this effect we suggest is caused by P2X(7)R expression on accessory cells. 相似文献
8.
Acute inflammation is important for tissue repair; however, chronic inflammation contributes to neurodegeneration in Alzheimer's disease (AD) and occurs when glial cells undergo prolonged activation. In the brain, stress or damage causes the release of nucleotides and activation of the G q protein-coupled P2Y 2 nucleotide receptor subtype (P2Y 2R) leading to pro-inflammatory responses that can protect neurons from injury, including the stimulation and recruitment of glial cells. P2Y 2R activation induces the phosphorylation of the epidermal growth factor receptor (EGFR), a response dependent upon the presence of a SH3 binding domain in the intracellular C terminus of the P2Y 2R that promotes Src binding and transactivation of EGFR, a pathway that regulates the proliferation of cortical astrocytes. Other studies indicate that P2Y 2R activation increases astrocyte migration. P2Y 2R activation by UTP increases the expression in astrocytes of α Vβ 3/5 integrins that bind directly to the P2Y 2R via an Arg-Gly-Asp (RGD) motif in the first extracellular loop of the P2Y 2R, an interaction required for G o and G 12 protein-dependent astrocyte migration. In rat primary cortical neurons (rPCNs) P2Y 2R expression is increased by stimulation with interleukin-1β (IL-1β), a pro-inflammatory cytokine whose levels are elevated in AD, in part due to nucleotide-stimulated release from glial cells. Other results indicate that oligomeric β-amyloid peptide (Aβ 1-42), a contributor to AD, increases nucleotide release from astrocytes, which would serve to activate upregulated P2Y 2Rs in neurons. Data with rPCNs suggest that P2Y 2R upregulation by IL-1β and subsequent activation by UTP are neuroprotective, since this increases the non-amyloidogenic cleavage of amyloid precursor protein. Furthermore, activation of IL-1β-upregulated P2Y 2Rs in rPCNs increases the phosphorylation of cofilin, a cytoskeletal protein that stabilizes neurite outgrowths. Thus, activation of pro-inflammatory P2Y 2Rs in glial cells can promote neuroprotective responses, suggesting that P2Y 2Rs represent a novel pharmacological target in neurodegenerative and other pro-inflammatory diseases. 相似文献
9.
The G protein-coupled receptor P2Y 2 nucleotide receptor (P2Y 2R) has been shown to be up-regulated in a variety of tissues in response to stress or injury. Recent studies have suggested that P2Y 2Rs may play a role in immune responses, wound healing, and tissue regeneration via their ability to activate multiple signaling pathways, including activation of growth factor receptors. Here, we demonstrate that in human salivary gland (HSG) cells, activation of the P2Y 2R by its agonist induces phosphorylation of ERK1/2 via two distinct mechanisms, a rapid, protein kinase C-dependent pathway and a slower and prolonged, epidermal growth factor receptor (EGFR)-dependent pathway. The EGFR-dependent stimulation of UTP-induced ERK1/2 phosphorylation in HSG cells is inhibited by the adamalysin inhibitor tumor necrosis factor-α protease inhibitor or by small interfering RNA that selectively silences ADAM10 and ADAM17 expression, suggesting that ADAM metalloproteases are required for P2Y 2R-mediated activation of the EGFR. G protein-coupled receptors have been shown to promote proteolytic release of EGFR ligands; however, neutralizing antibodies to known ligands of the EGFR did not inhibit UTP-induced EGFR phosphorylation. Immunoprecipitation experiments indicated that UTP causes association of the EGFR with another member of the EGF receptor family, ErbB3. Furthermore, stimulation of HSG cells with UTP induced phosphorylation of ErbB3, and silencing of ErbB3 expression inhibited UTP-induced phosphorylation of both ErbB3 and EGFR. UTP-induced phosphorylation of ErbB3 and EGFR was also inhibited by silencing the expression of the ErbB3 ligand neuregulin 1 (NRG1). These results suggest that P2Y 2R activation in salivary gland cells promotes the formation of EGFR/ErbB3 heterodimers and metalloprotease-dependent neuregulin 1 release, resulting in the activation of both EGFR and ErbB3. 相似文献
10.
The pro‐inflammatory cytokine interleukin‐1β (IL‐1β), whose levels are elevated in the brain in Alzheimer's and other neurodegenerative diseases, has been shown to have both detrimental and beneficial effects on disease progression. In this article, we demonstrate that incubation of mouse primary cortical neurons (mPCNs) with IL‐1β increases the expression of the P2Y 2 nucleotide receptor (P2Y 2R) and that activation of the up‐regulated receptor with UTP, a relatively selective agonist of the P2Y 2R, increases neurite outgrowth. Consistent with the accepted role of cofilin in the regulation of neurite extension, results indicate that incubation of IL‐1β‐treated mPCNs with UTP increases the phosphorylation of cofilin, a response absent in PCNs isolated from P2Y 2R ?/? mice. Other findings indicate that function‐blocking anti‐α vβ 3/5 integrin antibodies prevent UTP‐induced cofilin activation in IL‐1β‐treated mPCNs, suggesting that established P2Y 2R/α vβ 3/5 interactions that promote G 12‐dependent Rho activation lead to cofilin phosphorylation involved in neurite extension. Cofilin phosphorylation induced by UTP in IL‐1β‐treated mPCNs is also decreased by inhibitors of Ca 2+/calmodulin‐dependent protein kinase II (CaMKII), suggesting a role for P2Y 2R‐mediated and G q‐dependent calcium mobilization in neurite outgrowth. Taken together, these studies indicate that up‐regulation of P2Y 2Rs in mPCNs under pro‐inflammatory conditions can promote cofilin‐dependent neurite outgrowth, a neuroprotective response that may be a novel pharmacological target in the treatment of neurodegenerative diseases. 相似文献
11.
Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiology/pathophysiology. Pyrimidine nucleotides activate four G protein-coupled P2Y receptors (P2YRs): P2Y 2 and P2Y 4 (UTP-activated), P2Y 6, and P2Y 14. Previously, we showed that uridine 5′-triphosphate (UTP) activating P2Y 2R reduced infarct size and improved mouse heart function after myocardial infarct (MI). Here, we examined the cardioprotective role of P2Y 2R in vitro and in vivo following MI using uridine-5′-tetraphosphate δ-phenyl ester tetrasodium salt (MRS2768), a selective and more stable P2Y 2R agonist. Cultured rat cardiomyocytes pretreated with MRS2768 displayed protection from hypoxia [as revealed by lactate dehydrogenase (LDH) release and propidium iodide (PI) binding], which was reduced by P2Y 2R antagonist, AR-C118925 (5-((5-(2,8-dimethyl-5 H-dibenzo[ a, d][ 7]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2 H)-yl)methyl)- N-(1 H-tetrazol-5-yl)furan-2-carboxamide). In vivo, echocardiography and infarct size staining of triphenyltetrazolium chloride (TTC) in 3 groups of mice 24 h post-MI: sham, MI, and MI+MRS2768 indicated protection. Fractional shortening (FS) was higher in MRS2768-treated mice than in MI alone (40.0 ± 3.1 % vs. 33.4 ± 2.7 %, p < 0.001). Troponin T and tumor necrosis factor-α (TNF-α) measurements demonstrated that MRS2768 pretreatment reduced myocardial damage ( p < 0.05) and c-Jun phosphorylation increased. Thus, P2Y 2R activation protects cardiomyocytes from hypoxia in vitro and reduces post-ischemic myocardial damage in vivo. 相似文献
12.
Phylogenetic analysis of transmembrane regions of GPCRs using PHYLIP indicated that the orphan receptor P2Y 10 receptor was classified into the cluster consisting nucleotide and lipid receptors. Based on the results, we studied the abilities of nucleotides and lipids to activate the P2Y 10 receptors. As a result, sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) evoked intracellular Ca 2+ increases in the CHO cells stably expressing the P2Y 10 fused with a G 16α protein. These Ca 2+ responses were inhibited by S1P receptor and LPA receptor antagonists. The introduction of siRNA designed for P2Y 10 receptor into the P2Y 10-CHO cells effectively blocked both S1P- and LPA-induced Ca 2+ increases. RT-PCR analysis showed that the mouse P2Y 10 was expressed in reproductive organs, brain, lung and skeletal muscle, suggesting the receptor plays physiological roles throughout the whole body. In conclusion, the P2Y 10 receptor is the first receptor identified as a dual lysophospholipid receptor. 相似文献
13.
A 2A adenosine receptor (A 2AR), P2Y 1 receptor (P2Y 1R) and P2Y 12 receptor (P2Y 12R) are predominantly expressed on human platelets. The individual role of each of these receptors in platelet aggregation has been actively reported. Previously, hetero-oligomerization between these three receptors has been shown to occur. Here, we show that Ca 2+ signaling evoked by the P2Y 1R agonist, 2-methylthioladenosine 5’ diphosphate (2MeSADP) was significantly inhibited by the A 2AR antagonist (ZM241385 and SCH442416) and the P2Y 12R antagonist (ARC69931MX) using HEK293T cells expressing the three receptors. It was confirmed that inhibition of P2Y 1R signaling by A 2AR and P2Y 12R antagonists was indeed mediated through A 2AR and P2Y 12R using 1321N1 human astrocytoma cells which do not express P2Y receptors. We expect that intermolecular signal transduction and specific conformational changes occur among components of hetero-oligomers formed by these three receptors. 相似文献
14.
Mast cell degranulation affects many conditions, e.g., asthma and urticaria. We explored the potential role of the P2Y 14 receptor (P2Y 14R) and other P2Y subtypes in degranulation of human LAD2 mast cells. All eight P2YRs were expressed at variable levels in LAD2 cells (quantitative real-time RT-PCR). Gene expression levels of ADP receptors, P2Y 1R, P2Y 12R, and P2Y 13R, were similar, and P2Y 11R and P2Y 4R were highly expressed at 5.8- and 3.8-fold of P2Y 1R, respectively. Least expressed P2Y 2R was 40-fold lower than P2Y 1R, and P2Y 6R and P2Y 14R were ≤50 % of P2Y 1R. None of the native P2YR agonists alone induced β-hexosaminidase (β-Hex) release, but some nucleotides significantly enhanced β-Hex release induced by C3a or antigen, with a rank efficacy order of ATP > UDPG ≥ ADP >> UDP, UTP. Although P2Y 11R and P2Y 4R are highly expressed, they did not seem to play a major role in degranulation as neither P2Y 4R agonist UTP nor P2Y 11R agonists ATPγS and NF546 had a substantial effect. P2Y 1R-selective agonist MRS2365 enhanced degranulation, but ~1,000-fold weaker compared to its P2Y 1R potency, and the effect of P2Y 6R agonist 3-phenacyl-UDP was negligible. The enhancement by ADP and ATP appears mediated via multiple receptors. Both UDPG and a synthetic agonist of the P2Y 14R, MRS2690, enhanced C3a-induced β-Hex release, which was inhibited by a P2Y 14R antagonist, specific P2Y 14R siRNA and pertussis toxin, suggesting a role of P2Y 14R activation in promoting human mast cell degranulation. 相似文献
15.
P2X7-type purinergic receptors are distributed throughout the nervous system where they contribute to physiological and pathological functions. In the retina, this receptor is found in both inner and outer cells including microglia modulating signaling and health of retinal cells. It is involved in retinal neurodegenerative disorders such as retinitis pigmentosa and age-related macular degeneration (AMD). Experimental studies demonstrated that saffron protects photoreceptors from light-induced damage preserving both retinal morphology and visual function and improves retinal flicker sensitivity in AMD patients. To evaluate a possible interaction between saffron and P2X7 receptors (P2X7Rs), different cellular models and experimental approaches were used. We found that saffron positively influences the viability of mouse primary retinal cells and photoreceptor-derived 661W cells exposed to ATP, and reduced the ATP-induced intracellular calcium increase in 661W cells. Similar results were obtained on HEK cells transfected with recombinant rat P2X7R but not on cells transfected with rat P2X2R. Finally, patch-clamp experiments showed that saffron inhibited cationic currents in HEK-P2X7R cells. These results point out a novel mechanism through which saffron may exert its protective role in neurodegeneration and support the idea that P2X7-mediated calcium signaling may be a crucial therapeutic target in the treatment of neurodegenerative diseases. 相似文献
16.
P2Y receptors are G protein-coupled receptors composed of eight known subunits (P2Y 1, 2, 4, 6, 11, 12, 13, 14), which are involved in different functions in neural tissue. The present study investigates the expression pattern of P2Y 4 receptors in the rat central nervous system (CNS) using immunohistochemistry and in situ hybridization. The specificity of
the immunostaining has been verified by preabsorption, Western blot, and combined use of immunohistochemistry and in situ
hybridization. Neurons expressing P2Y 4 receptors were distributed widely in the rat CNS. Heavy P2Y 4 receptor immunostaining was observed in the magnocellular neuroendocrine neurons of the hypothalamus, red nucleus, pontine
nuclei, mesencephalic trigeminal nucleus, motor trigeminal nucleus, ambiguous nucleus, inferior olive, hypoglossal nucleus,
and dorsal motor vagus nucleus. Both neurons and astrocytes express P2Y 4 receptors. P2Y 4 receptor immunostaining signals were mainly confined to cell bodies and dendrites of neurons, suggesting that P2Y 4 receptors are mainly involved in regulating postsynaptic events. In the hypothalamus, all the vasopressin (VP) and oxytocin
(OT) neurons and all the orexin A neurons were immunoreactive for P2Y 4 receptors. All the neurons expressing P2Y 4 receptors were found to express N-methyl- d-aspartate receptor 1 (NR1). These data suggest that purines and pyrimidines might be involved in regulation of the release
of the neuropeptides VP, OT, and orexin in the rat hypothalamus via P2Y 4 receptors. Further, the physiological and pathophysiological functions of the neurons may operate through coupling between
P2Y 4 receptors and NR1. 相似文献
17.
The distribution of P2Y 6 and P2Y 12 receptor-immunoreactive (ir) neurons and fibers and their coexistence with calbindin, calretinin and nitric oxide synthase
(NOS) has been investigated with single and double labeling immunostaining methods. The results showed that 30–36% of the
ganglion cells in the myenteric plexus are strongly P2Y 6 receptor-ir neurons; they are distributed widely in the myenteric plexus of stomach, jejunum, ileum and colon, but not in
the submucosal plexus, with a typical morphology of multipolar neurons with a long axon-like process. About 42–46% of ganglion
cells in both the myenteric and submucosal plexuses show P2Y 12 receptor-ir. About 28–35% of P2Y 6 receptor-ir neurons were found to coexist with NOS and 41–47% of them coexist with calretinin, but there was no coexistence
of P2Y 6 receptor-ir with calbindin. In contrast, all P2Y 12 receptor-ir neurons were immunopositive for calbindin, although occasionally P2Y 12 receptor-ir neurons without calbindin immunoreactivity were found, while none of the P2Y 12 receptor-ir neurons were found to coexist with calretinin or NOS in the gastrointestinal system of guinea pig. The P2Y 12 receptor-ir neurons coexpressing calbindin-ir in the small intestine are Dogiel type II/AH, intrinsic primary afferent neurons. 相似文献
18.
The P2Y 2 receptor is a G-protein-coupled receptor with adenosine 5′-triphosphate (and UTP) as natural ligands. It is thought to be involved in bone physiology in an anti-osteogenic manner. As several non-synonymous single nucleotide polymorphisms (SNPs) have been identified within the P2Y 2 receptor gene in humans, we examined associations between genetic variations in the P2Y 2 receptor gene and bone mineral density (BMD) (i.e., osteoporosis risk), in a cohort of fracture patients. Six hundred and ninety women and 231 men aged ≥50 years, visiting an osteoporosis outpatient clinic at Maastricht University Medical Centre for standard medical follow-up after a recent fracture, were genotyped for three non-synonymous P2Y 2 receptor gene SNPs. BMD was measured at three locations (total hip, lumbar spine, and femoral neck) using dual-energy X-ray absorptiometry. Differences in BMD between different genotypes were tested using analysis of covariance. In women, BMD values at all sites were significantly different between the genotypes for the Leu46Pro polymorphism, with women homozygous for the variant allele showing the highest BMD values (0.05 > p > 0.01). The Arg312Ser and Arg334Cys polymorphisms showed no differences in BMD values between the different genotypes. This is the first report that describes the association between the Leu46Pro polymorphism of the human P2Y 2 receptor and the risk of osteoporosis. 相似文献
19.
Many previous studies have demonstrated that P2X 7 receptors (P2X 7Rs) have a pleiotropic function in different pathological conditions and could represent a novel target for the treatment of a range of diseases. In particular, recent studies have explored the role of P2X 7R in fibrosis, the pathological outcome of most chronic inflammatory diseases. The aim of this review is to discuss the biological features of P2X 7R and summarize the current knowledge about the putative role of the P2X 7R in triggering fibrosis in a wide spectrum of organs such as the lung, kidney, liver, pancreas, and heart. 相似文献
20.
Here we elaborated an analytical approach for the simulation of dose-response curves mediated by cellular receptors coupled to PLC and Ca 2+ mobilization. Based on a mathematical model of purinergic Ca 2+ signaling in taste cells, the analysis of taste cells responsiveness to nucleotides was carried out. Consistently with the expression of P2Y 2 and P2Y 4 receptors in taste cells, saturating ATP and UTP equipotently mobilized intracellular Ca 2+. Cellular responses versus concentration of BzATP, a P2Y 2 agonist and a P2Y 4 antagonist, implicated high and low affinity BzATP receptors. Suramin modified the BzATP dose-response curve in a manner that suggested the low affinity receptor to be weakly sensitive to this P2Y antagonist. Given that solely P2Y 2 and P2Y 11 are BzATP receptors, their high sensitivity to suramin is poorly consistent with the suramin effects on BzATP responses. We simulated a variety of dose-response curves for different P2Y receptor sets and found that the appropriate fit of the overall pharmacological data was achievable only with dimeric receptors modeled as P2Y 2/P2Y 4 homo- and heterodimers. Our computations and analytical analysis of experimental dose-response curves raise the possibility that ATP responsiveness of mouse taste cells is mediated by P2Y 2 and P2Y 4 receptors operative mostly in the dimeric form. 相似文献
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