共查询到20条相似文献,搜索用时 15 毫秒
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Extracellular UDP-glucose can activate the purinergic P2Y14 receptor. The aim of the present study was to examine the physiological importance of P2Y14 receptors in the vasculature. The data presented herein show that UDP-glucose causes contraction in mouse coronary and basilar arteries. The EC50 values and immunohistochemistry illustrated the strongest P2Y14 receptor expression in the basilar artery. In the presence of pertussis toxin, UDP-glucose inhibited contraction in coronary arteries and in the basilar artery it surprisingly caused relaxation. After organ culture of the coronary artery, the EC50 value decreased and an increased staining for the P2Y14 receptor was observed, showing receptor plasticity. 相似文献
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Laurie Erb Chen Cao Deepa Ajit Gary A. Weisman 《Biology of the cell / under the auspices of the European Cell Biology Organization》2015,107(1):1-21
Alzheimer's disease (AD) is the most common cause of dementia, affecting more than 10% of people over the age of 65. Age is the greatest risk factor for AD, although a combination of genetic, lifestyle and environmental factors also contribute to disease development. Common features of AD are the formation of plaques composed of beta‐amyloid peptides (Aβ) and neuronal death in brain regions involved in learning and memory. Although Aβ is neurotoxic, the primary mechanisms by which Aβ affects AD development remain uncertain and controversial. Mouse models overexpressing amyloid precursor protein and Aβ have revealed that Aβ has potent effects on neuroinflammation and cerebral blood flow that contribute to AD progression. Therefore, it is important to consider how endogenous signalling in the brain responds to Aβ and contributes to AD pathology. In recent years, Aβ has been shown to affect ATP release from brain and blood cells and alter the expression of G protein‐coupled P2Y receptors that respond to ATP and other nucleotides. Accumulating evidence reveals a prominent role for P2Y receptors in AD pathology, including Aβ production and elimination, neuroinflammation, neuronal function and cerebral blood flow. 相似文献
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Narinobu Harada 《Purinergic signalling》2010,6(2):211-220
In the inner ear, there is considerable evidence that extracellular adenosine 5′-triphosphate (ATP) plays an important role
in auditory neurotransmission as a neurotransmitter or a neuromodulator, although the potential role of adenosine signalling
in the modulation of auditory neurotransmission has also been reported. The activation of ligand-gated ionotropic P2X receptors
and G protein-coupled metabotropic P2Y receptors has been reported to induce an increase of intracellular Ca2+ concentration ([Ca2+]i) in inner hair cells (IHCs), outer hair cells (OHCs), spiral ganglion neurons (SGNs), and supporting cells in the cochlea.
ATP may participate in auditory neurotransmission by modulating [Ca2+]i in the cochlear cells. Recent studies showed that extracellular ATP induced nitric oxide (NO) production in IHCs, OHCs, and
SGNs, which affects the ATP-induced Ca2+ response via the NO-cGMP-PKG pathway in those cells by a feedback mechanism. A cross-talk between NO and ATP may therefore
exist in the auditory signal transduction. In the present article, I review the role of NO on the ATP-induced Ca2+ signalling in IHCs and OHCs. I also consider the possible role of NO in the ATP-induced Ca2+ signalling in SGNs and supporting cells. 相似文献
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Weisman GA Ajit D Garrad R Peterson TS Woods LT Thebeau C Camden JM Erb L 《Purinergic signalling》2012,8(3):559-578
Purinergic signaling plays a unique role in the brain by integrating neuronal and glial cellular circuits. The metabotropic P1 adenosine receptors and P2Y nucleotide receptors and ionotropic P2X receptors control numerous physiological functions of neuronal and glial cells and have been implicated in a wide variety of neuropathologies. Emerging research suggests that purinergic receptor interactions between cells of the central nervous system (CNS) have relevance in the prevention and attenuation of neurodegenerative diseases resulting from chronic inflammation. CNS responses to chronic inflammation are largely dependent on interactions between different cell types (i.e., neurons and glia) and activation of signaling molecules including P2X and P2Y receptors. Whereas numerous P2 receptors contribute to functions of the CNS, the P2Y(2) receptor is believed to play an important role in neuroprotection under inflammatory conditions. While acute inflammation is necessary for tissue repair due to injury, chronic inflammation contributes to neurodegeneration in Alzheimer's disease and occurs when glial cells undergo prolonged activation resulting in extended release of proinflammatory cytokines and nucleotides. This review describes cell-specific and tissue-integrated functions of P2 receptors in the CNS with an emphasis on P2Y(2) receptor signaling pathways in neurons, glia, and endothelium and their role in neuroprotection. 相似文献
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Mary G. O’Keeffe Peter R. Thorne Gary D. Housley Simon C. Robson Srdjan M. Vlajkovic 《Histochemistry and cell biology》2010,133(4):425-436
Ectonucleoside triphosphate diphosphohydrolases (E-NTPDases) regulate complex extracellular P2 receptor signalling pathways
in mammalian tissues by hydrolysing extracellular nucleotides to the respective nucleosides. All enzymes from this family
(NTPDase1-8) are expressed in the adult rat cochlea. This study reports the changes in expression of NTPDase5 and NTPDase6
in the developing rat cochlea. These two intracellular members of the E-NTPDase family can be released in a soluble form and
show preference for nucleoside 5′-diphosphates, such as UDP and GDP. Here, we demonstrate differential spatial and temporal
patterns for NTPDase5 and NTPDase6 expression during cochlear development, which are indicative of both cytosolic and extracellular
action via pyrimidines. NTPDase5 is noted during the early postnatal period in developing sensory hair cells and supporting
Deiters’ cells of the organ of Corti, and primary auditory neurons located in the spiral ganglion. In contrast, NTPDase6 is
confined to the embryonic and early postnatal hair cell bundles. NTPDase6 immunolocalisation in the developing cochlea underpins
its putative role in hair cell bundle development, probably via cytosolic action, whilst NTPDase5 may have a broader extracellular
role in the development of sensory and neural tissues in the rat cochlea. Both NTPDase5 and NTPDase6 colocalize with UDP-preferring
P2Y4, P2Y6 and P2Y14 receptors during cochlear development, but this strong association was lost in the adult cochlea. Spatiotemporal topographic
expression of NTPDase5 and NTPDase6 and P2Y receptors in adult and developing cochlear tissues provide strong support for
the role of pyrimidinergic signalling in cochlear development. 相似文献
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In this study, the distribution patterns of P2Y1, P2Y2 P2Y4, P2Y6, P2Y12, and P2Y13 receptors in the anterior pituitary cells of rat were studied with double-labeling immunofluorescence and Western blot. The
results showed that P2Y receptors were widely expressed in the anterior pituitary. P2Y1 and P2Y4 receptors were found to be expressed in the majority of gonadotrophs and thyrotrophs, P2Y2 receptors were expressed in a small subpopulation of lactotrophs and almost all the folliculo-stellate cells, that were also
stained with S100 protein immunoreactivity. P2Y6 receptors were expressed in macrophages. P2Y13 receptors were expressed in a small subpopulation of cells in the rat anterior pituitary, the identity of which needs to
be clarified. P2Y1 and P2Y4 receptors are co-expressed in some gonadotrophs and thyrotrophs. Corticotrophs and somatotrophs were found not to express
P2Y receptors in this study. FSH and TSH were shown to coexist in the same endocrine cells in rat anterior pituitary. The
present data suggests that purines and/or pyrimidines could be involved in regulating the functions of gonadotrophs and thyrotrophs
via P2Y1 and P2Y4 receptors, some lactotrophs via P2Y2 receptors, and folliculo-stellate cells via P2Y2 receptors in the rat anterior pituitary. 相似文献
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The role of nucleotides in intracellular energy provision and nucleic acid synthesis has been known for a long time. In the past decade, evidence has been presented that, in addition to these functions, nucleotides are also autocrine and paracrine messenger molecules that initiate and regulate a large number of biological processes. The actions of extracellular nucleotides are mediated by ionotropic P2X and metabotropic P2Y receptors, while hydrolysis by ecto-enzymes modulates the initial signal. An increasing number of studies have been performed to obtain information on the signal transduction pathways activated by nucleotide receptors. The development of specific and stable purinergic receptor agonists and antagonists with therapeutical potential largely contributed to the identification of receptors responsible for nucleotide-activated pathways. This article reviews the signal transduction pathways activated by P2Y receptors, the involved second messenger systems, GTPases and protein kinases, as well as recent findings concerning P2Y receptor signalling in C6 glioma cells. Besides vertical signal transduction, lateral cross-talks with pathways activated by other G protein-coupled receptors and growth factor receptors are discussed. 相似文献
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The current work presents results of experiments on the calcium response evoked by the stimulation by extracellular nucleotides
occurring in control, nonstarved glioma C6 cells and in cells after long-term (96 h) serum starvation. Three nucleotide receptors
were studied: P2Y1, P2Y2 and P2Y12. Two of them, P2Y1 and P2Y2, directly stimulate calcium response. The protein level of the P2Y2 receptor did not change during the serum starvation, while P2Y1 protein level fell dramatically. Observed changes in the calcium response generated by P2Y1 are directly correlated with the receptor protein level as well as with the amount of calcium present in the intracellular
calcium stores, partially depleted during starvation process. The third receptor, P2Y12, did not directly evoke calcium response, however it is activated by the same ligand as P2Y1. The experiments with AR-C69941MX, the P2Y12-specific antagonist, indicated that in control and serum-starved cells, calcium response evoked by P2Y1 receptor is potentiated by the activity of P2Y12-dependent signaling pathways. This potentiation may be mediated by P2Y12 inhibitory effect on the plasma membrane calcium pump. The calcium influx enhanced by the cooperation of P2Y1 and P2Y12 receptor activity directly depends on the capacitative calcium entrance mechanism. 相似文献
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Increased 5-HT3-mediated signalling in pelvic afferent neurons from mice deficient in P2X2 and/or P2X3 receptor subunits 总被引:1,自引:0,他引:1
Extracellular ATP and 5-hydroxytryptamine (5-HT) are both involved in visceral sensory pathways by interacting with P2X and 5-HT3 receptors, respectively. We have investigated the changes in P2X and 5-HT3-mediated signalling in pelvic afferent neurons in mice deficient in P2X2 and/or P2X3 subunits by whole-cell recording of L6–S2 dorsal root ganglion (DRG) neurons and by multi-unit recording of pelvic afferents of the colorectum. In wildtype DRG neurons, ATP evoked transient, sustained or mixed (biphasic) inward currents. Transient currents were absent in P2X3
−/− neurons, whereas sustained currents were absent in P2X2
−/− DRG neurons. Neither transient nor sustained currents were observed following application of ATP or α,β-methylene ATP (α,β-meATP) in P2X2/P2X3
Dbl−/− DRG neurons. 5-HT was found to induce a fast inward current in 63% of DRG neurons from wildtype mice, which was blocked by tropisetron, a 5-HT3 receptor antagonist. The percentage of DRG neurons responding to 5-HT was significantly increased in P2X 2
−/−, P2X3
−/− and P2X2/P2X3
Dbl−/− mice, and the amplitude of 5-HT response was significantly increased in P2X2/P2X3
Dbl−/− mice. The pelvic afferent response to colorectal distension was attenuated in P2X2/P2X3
Dbl−/− mice, but the response to serosal application of 5-HT was enhanced. Furthermore, tropisetron resulted in a greater reduction in pelvic afferent responses to colorectal distension in the P2X2/P2X3
Dbl−/− preparations. These data suggest that P2X receptors containing the P2X2 and/or P2X3 subunits mediate purinergic activation of colorectal afferents and that 5-HT signalling in pelvic afferent neurons is up-regulated in mice lacking P2X2 or P2X3 receptor genes. This effect is more pronounced when both subunits are absent. 相似文献
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Pathophysiology of astroglial purinergic signalling 总被引:1,自引:0,他引:1
Astrocytes are fundamental for central nervous system (CNS) physiology and are the fulcrum of neurological diseases. Astroglial cells control development of the nervous system, regulate synaptogenesis, maturation, maintenance and plasticity of synapses and are central for nervous system homeostasis. Astroglial reactions determine progression and outcome of many neuropathologies and are critical for regeneration and remodelling of neural circuits following trauma, stroke, ischaemia or neurodegenerative disorders. They secrete multiple neurotransmitters and neurohormones to communicate with neurones, microglia and the vascular walls of capillaries. Signalling through release of ATP is the most widespread mean of communication between astrocytes and other types of neural cells. ATP serves as a fast excitatory neurotransmitter and has pronounced long-term (trophic) roles in cell proliferation, growth, and development. During pathology, ATP is released from damaged cells and acts both as a cytotoxic factor and a proinflammatory mediator, being a universal "danger" signal. In this review, we summarise contemporary knowledge on the role of purinergic receptors (P2Rs) in a variety of diseases in relation to changes of astrocytic functions and nucleotide signalling. We have focussed on the role of the ionotropic P2X and metabotropic P2YRs working alone or in concert to modify the release of neurotransmitters, to activate signalling cascades and to change the expression levels of ion channels and protein kinases. All these effects are of great importance for the initiation, progression and maintenance of astrogliosis-the conserved and ubiquitous glial defensive reaction to CNS pathologies. We highlighted specific aspects of reactive astrogliosis, especially with respect to the involvement of the P2X(7) and P2Y(1)R subtypes. Reactive astrogliosis exerts both beneficial and detrimental effects in a context-specific manner determined by distinct molecular signalling cascades. Understanding the role of purinergic signalling in astrocytes is critical to identifying new therapeutic principles to treat acute and chronic neurological diseases. 相似文献
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Growing evidence reveals that microorganisms in the gut are linked to metabolic health and disease risk in human beings to a considerable extent. The focus of research at this stage must tend to focus on cause-and-effect studies. In addition to being a component of DNA and RNA, purine metabolites can be involved in purine signalling in the body as chemical messengers. Abnormalities in purinergic signalling may lead to neuropathy, rheumatic immune diseases, inflammation, tumors, and a wide range of other diseases. It has proved that gut microbes are involved in purinergic signalling. The relationship between these gut-derived purinergic signalling molecules and host metabolism may be one of the important clues to our understanding of the mechanisms by which the microbiota affects host metabolism. 相似文献
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Adenine and uridine nucleotides evoke Ca(2+) signals via four subtypes of P2Y receptor in cultured aortic smooth muscle cells, but the mechanisms underlying the different patterns of these Ca(2+) signals are unresolved. Cytosolic Ca(2+) signals were recorded from single cells and populations of cultured rat aortic smooth muscle cells, loaded with a fluorescent Ca(2+) indicator and stimulated with agonists that allow subtype-selective activation of P2Y1, P2Y2, P2Y4, or P2Y6 receptors. Activation of P2Y1, P2Y2, and P2Y6 receptors caused homologous desensitisation, while activation of P2Y2 receptors also caused heterologous desensitisation of the other subtypes. The Ca(2+) signals evoked by each P2Y receptor subtype required activation of phospholipase C and release of Ca(2+) from intracellular stores via inositol 1,4,5-trisphosphate (IP(3)) receptors, but they were unaffected by inhibition of ryanodine or nicotinic acid adenine dinucleotide phosphate (NAADP) receptors. Sustained Ca(2+) signals were independent of the Na(+)/Ca(2+) exchanger and were probably mediated by store-operated Ca(2+) entry. Analyses of single cells established that most cells express P2Y2 receptors and at least two other P2Y receptor subtypes. We conclude that four P2Y receptor subtypes evoke Ca(2+) signals in cultured aortic smooth muscle cells using the same intracellular (IP(3) receptors) and Ca(2+) entry pathways (store-operated Ca(2+) entry). Different rates of homologous desensitisation and different levels of receptor expression account for the different patterns of Ca(2+) signal evoked by each P2Y receptor subtype. 相似文献
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Natalia Buzzi Paola Scodelaro BilbaoRicardo Boland Ana Russo de Boland 《Biochimica et Biophysica Acta (BBA)/General Subjects》2009,1790(12):1651-1659
Background
ATP exerts diverse effects on various cell types via specific purinergic P2Y receptors. Intracellular signaling cascades are the main routes of communication between P2Y receptors and regulatory targets in the cell.Methods and results
We examined the role of ATP in the modulation of ERK1/2, JNK1/2, and p38 MAP kinases (MAPKs) in human colon cancer Caco-2 cells. Immunoblot analysis showed that ATP induces the phosphorylation of MAPKs in a time- and dose-dependent manner, peaking at 5 min at 10 µM ATP. Moreover, ATPγS, UTP, and UDP but not ADP or ADPβS increased phosphorylation of MAPKs, indicating the involvement of, at least, P2Y2/P2Y4 and P2Y6 receptor subtypes. RT–PCR studies and PCR product sequencing supported the expression of P2Y2 and P2Y4 receptors in this cell line. Spectrofluorimetric measurements showed that cell stimulation with ATP induced transient elevations in intracellular calcium concentration. In addition, ATP-induced phosphorylation of MAPKs in Caco-2 cells was dependent on Src family tyrosine kinases, calcium influx, and intracellular Ca2+ release and was partially dependent on the cAMP/PKA and PKC pathways and the EGFR.General significance
These findings provide new molecular basis for further understanding the mechanisms involved in ATP functions, as a signal transducer and activator of MAP kinase cascades, in colon adenocarcinoma Caco-2 cells. 相似文献17.
Induction of COX-2 and reactive gliosis by P2Y receptors in rat cortical astrocytes is dependent on ERK1/2 but independent of calcium signalling 总被引:6,自引:0,他引:6
Brambilla R Neary JT Cattabeni F Cottini L D'Ippolito G Schiller PC Abbracchio MP 《Journal of neurochemistry》2002,83(6):1285-1296
The present study has been aimed at characterizing the ATP/P2 receptor (and transductional pathways) responsible for the morphological changes induced in vitro by alphabetamethyleneATP on rat astrocytes obtained from cerebral cortex, a brain area highly involved in neurodegenerative diseases. Exposure of cells to this purine analogue resulted in elongation of cellular processes, an event reproducing in vitro a major hallmark of in vivo reactive gliosis. alphabetamethyleneATP-induced gliosis was prevented by the P2X/P2Y blocker pyridoxalphosphate-6-azophenyl-2'-4'-disulfonic acid, but not by the selective P2X antagonist 2',3'-O-(2,4,6-trinitrophenyl)-ATP, ruling out a role for ligand-gated P2X receptors. Conversely, the Gi/Go protein inactivator pertussis toxin completely prevented alphabetamethyleneATP-induced effects. No effects were induced by alphabetamethyleneATP on intracellular calcium concentrations. RT-PCR and western blot analysis showed that alphabetamethyleneATP-induced gliosis involves up-regulation of cyclooxygenase-2 (but not lipooxygenase). Also this effect was fully prevented by pyridoxalphosphate-6-azophenyl-2'-4'-disulfonic acid. Experiments with inhibitors of mitogen-activated protein kinases (MAPK) suggest that extracellular signal regulated protein kinases (ERK)1/2 mediate both cyclooxygenase-2 induction and the associated in vitro gliosis. These findings suggest that purine-induced gliosis involves the activation of a calcium-independent G-protein-coupled P2Y receptor linked to ERK1/2 and cyclooxygenase-2. Based on the involvement of cyclooxygenase-2 and inflammation in neurodegenerative diseases, these findings open up new avenues in the identification of novel biological targets for the pharmacological manipulation of neurodegeneration. 相似文献
18.
The P2X7 receptor (P2X7R) is a member of the ATP-gated ion channel family that exhibits distinct electrophysiological and pharmacological properties. This includes low sensitivity to ATP, lack of desensitization, a sustained current growth during prolonged receptor stimulation accompanied with development of permeability to large organic cations, and the coupling of receptor activation to cell blebbing and death. The uniquely long C-terminus of P2X7R accounts for many of these receptor-specific functions. The aim of this study was to understand the role of conserved ectodomain cysteine residues in P2X7R function. Single- and double-point threonine mutants of C119-C168, C129-C152, C135-C162, C216-C226, and C260-C269 cysteine pairs were expressed in HEK293 cells and studied using whole-cell current recording. All mutants other than C119T-P2X7R responded to initial and subsequent application of 300-μM BzATP and ATP with small amplitude monophasic currents or were practically nonfunctional. The mutagenesis-induced loss of function was due to decreased cell-surface receptor expression, as revealed by assessing levels of biotinylated mutants. Coexpression of all double mutants with the wild-type receptor had a transient or, in the case of C119T/C168T double mutant, sustained inhibitory effect on receptor trafficking. The C119T-P2X7R mutant was expressed on the plasma membrane and was fully functional with a slight decrease in the sensitivity for BzATP, indicating that interaction of liberated Cys168 with another residue rescues the trafficking of receptor. Thus, in contrast to other P2XRs, all disulfide bonds of P2X7R are individually essential for the proper receptor trafficking. 相似文献
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Lin-Chien Huang Peter R. Thorne Srdjan M. Vlajkovic Gary D. Housley 《Purinergic signalling》2010,6(2):231-248
Purinergic signaling has broad physiological significance to the hearing organ, involving signal transduction via ionotropic
P2X receptors and metabotropic G-protein-coupled P2Y and P1 (adenosine), alongside conversion of nucleotides and nucleosides
by ecto-nucleotidases and ecto-nucleoside diphosphokinase. In addition, ATP release is modulated by acoustic overstimulation
or stress and involves feedback regulation. Many of these principal elements of the purinergic signaling complex have been
well characterized in the cochlea, while the characterization of P2Y receptor expression is emerging. The present study used
immunohistochemistry to evaluate the expression of five P2Y receptors, P2Y1, P2Y2, P2Y4, P2Y6, and P2Y12, during development of the rat cochlea. Commencing in the late embryonic period, the P2Y receptors studied were found in
the cells lining the cochlear partition, associated with establishment of the electrochemical environment which provides the
driving force for sound transduction. In addition, early postnatal P2Y2 and P2Y4 protein expression in the greater epithelial ridge, part of the developing hearing organ, supports the view that initiation
and regulation of spontaneous activity in the hair cells prior to hearing onset is mediated by purinergic signaling. Sub-cellular
compartmentalization of P2Y receptor expression in sensory hair cells, and diversity of receptor expression in the spiral
ganglion neurons and their satellite cells, indicates roles for P2Y receptor-mediated Ca2+-signaling in sound transduction and auditory neuron excitability. Overall, the dynamics of P2Y receptor expression during
development of the cochlea complement the other elements of the purinergic signaling complex and reinforce the significance
of extracellular nucleotide and nucleoside signaling to hearing. 相似文献
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ATP-mediated signaling has widespread actions in the nervous system from neurotransmission to regulation of proliferation.
In addition, ATP is released during injury and associated to immune and inflammatory responses. Still, the potential of therapeutic
intervention of purinergic signaling during pathological states is only now beginning to be explored because of the large
number of purinergic receptors subtypes involved, the complex and often overlapping pharmacology and because ATP has effects
on every major cell type present in the CNS. In this review, we will focus on a subclass of purinergic-ligand-gated ion channels,
the P2X7 receptor, its pattern of expression and its function in the spinal cord where it is abundantly expressed. We will
discuss the mechanisms for P2X7R actions and the potential that manipulating the P2X7R signaling pathway may have for therapeutic
intervention in pathological events, specifically in the spinal cord. 相似文献