Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although ATP is reported to modulate synaptic plasticity, the mechanism of action of ATP on synaptic transmission is not fully understood. Here we show that ATP enhances long-term potentiation (LTP), and P2X receptor antagonists inhibit this ATP effect, but do not affect paired pulse facilitation (PPF) in rat hippocampal slices. ATP rapidly increases intracellular calcium, and P2X receptor antagonists inhibit this increase in cultured dissociated neurons. These results indicate that ATP enhances LTP via activation of postsynaptic P2X receptors. A pertussis toxin-sensitive G-protein inhibitor significantly attenuates PPF, although it does not affect LTP, indicating that presynaptic P2Y receptors also play an important role in neuronal plasticity. We conclude that ATP modulates synaptic plasticity via dual effects on pre- and post-synaptic mechanisms.
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PMID:Dual effects of ATP on rat hippocampal synaptic plasticity. 1509 66

Guanosine has many trophic effects in the CNS, including the stimulation of neurotrophic factor synthesis and release by astrocytes, which protect neurons against excitotoxic death. Therefore, we questioned whether guanosine protected astrocytes against apoptosis induced by staurosporine. We evaluated apoptosis in cultured rat brain astrocytes, following exposure (3 h) to 100 nM staurosporine by acridine orange staining or by oligonucleosome, or caspase-3 ELISA assays. Staurosporine promoted apoptosis rapidly, reaching its maximal effect (approximately 10-fold over basal apoptotic values) in 18-24 h after its administration to astrocytes. Guanosine, added to the culture medium for 4 h, starting from 1 h prior to staurosporine, reduced the proportion of apoptotic cells in a concentration-dependent manner. The IC50 value for the inhibitory effect of guanosine is 7.5 x 10(-5) M. The protective effect of guanosine was not affected by inhibiting the nucleoside transporters by propentophylline, or by the selective antagonists of the adenosine A1 or A2 receptors (DPCPX or DMPX), or by an antagonist of the P2X and P2Y purine receptors (suramin). In contrast, pretreatment of astrocytes with pertussis toxin, which uncouples Gi-proteins from their receptors, abolished the antiapoptotic effect of guanosine. The protective effect of guanosine was also reduced by pretreatment of astrocytes with inhibitors of the phosphoinositide 3-kinase (PI3K; LY294002, 30 microM) or the MAPK pathway (PD98059, 10 microM). Addition of guanosine caused a rapid phosphorylation of Akt/PKB, and glycogen synthase kinase-3beta (GSK-3beta) and induced an upregulation of Bcl-2 mRNA and protein expression. These data demonstrate that guanosine protects astrocytes against staurosporine-induced apoptosis by activating multiple pathways, and these are mediated by a Gi-protein-coupled putative guanosine receptor.
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PMID:The antiapoptotic effect of guanosine is mediated by the activation of the PI 3-kinase/AKT/PKB pathway in cultured rat astrocytes. 1509 66

Uridine nucleotides are endogenous nucleotides which are released into the extracellular space from mechanical stressed endothelial and epithelial cells as well as lipopolysaccharide (lps)-stimulated monocytes. Here, we studied the biological activity of the selective purinoreceptor P2Y6 (P2YR6) agonist Uridine 5'diphosphate (UDP) as well as the P2YR2- and P2YR4-activating uridine 5'triphosphate (UTP) on human dendritic cells (DC). These cells in their immature state have the ability to migrate from blood to peripheral target sites where they sense dangerous signals and capture potential antigens. Moreover, mature DC induce innate immune responses and migrate from peripheral tissues to secondary lymphoid organs in order to activate naive T cells and initiate adaptive immunity. Here, we were able to show that uridine nucleotides stimulated Ca(2+) transients, actin polymerization, and chemotaxis in immature DC. Experiments with pertussis toxin, the stable pyrimidine agonist uridine 5'-O-(2-thiodiphosphate) (UDPgammaS) and receptor antagonists, as well as desensitization studies suggested that these uridine nucleotides activities were mediated by different G(i) protein-coupled receptors. During lps-induced maturation, DC lost their ability to respond towards uridine nucleotides with these activities. Instead, UDP, but not UTP, stimulated the release of the CXC-chemokine 8 (CXCL8) from mature DC in a reactive blue sensitive manner. Moreover, our study indicates that UDP stimulates different signaling pathways in immature and mature DC in order to favor the accumulation of immature DC and to augment the capacity to secrete CXCL8 in mature DC.
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PMID:Characterization of the biological activities of uridine diphosphate in human dendritic cells: Influence on chemotaxis and CXCL8 release. 1533 63

Skeletal muscle differentiation follows an organized sequence of events including commitment, cell cycle withdrawal, and cell fusion to form multinucleated myotubes. The role of adenosine 5'-triphosphate (ATP)-mediated signaling in differentiation of skeletal muscle myoblasts was evaluated in C(2)C(12) cells, a myoblast cell line. Cell differentiation was inhibited by P2X receptor blockers or by degradation of endogenous ATP with apyrase. However, pertussis toxin, known to block only a group of P2Y receptors, did not alter the differentiation process. Cells were heterogeneous in their expression of functional P2X receptors, evaluated by the uptake of fluorescent permeability tracers (Lucifer yellow and ethidium bromide), and by immunofluorescence of P2X(7) receptors. Moreover, xestospongin C, a selective and membrane-permeable inhibitor of IP(3) receptors, inhibited both myotube formation and myogenin expression. Based on these results, we suggest that the known increase in intracellular Ca(2+) concentration required for differentiation is due at least in part to Ca(2+) influx through P2X receptors and Ca(2+) release from intracellular stores. The possible involvement of P2X receptors and other pathways that might set the intracellular Ca(2+) at the level required for myoblast differentiation as well as the possible involvement of gap junction channels in the intercellular transfer of second messengers involved in coordinating myogenesis is proposed.
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PMID:The formation of skeletal muscle myotubes requires functional membrane receptors activated by extracellular ATP. 1557 71

Fast excitatory postsynaptic potentials (fEPSPs) occur in bursts in the myenteric plexus during evoked motor reflexes in the guinea-pig ileum in vitro. This study used electrophysiological methods to study fEPSPs during stimulus trains to mimic bursts of synaptic activity in vitro. The amplitude of fEPSPs or fast excitatory postsynaptic currents (EPSCs) declined (rundown) during stimulus trains at frequencies of 0.5, 5, 10 and 20 Hz. At 0.5 Hz, fEPSP or fEPSC amplitude declined by 50% after the first stimulus but remained constant for the remainder of the train. At 5, 10 and 20 Hz, synaptic responses ran down completely with time constants of 0.35, 0.21 and 0.11 s, respectively. Recovery from rundown occurred with a time constant of 7 s. Mecamylamine, a nicotinic cholinergic receptor antagonist, or PPADS, a P2X receptor antagonist, reduced fEPSP amplitude, but they had no effect on rundown. Responses caused by trains of ionophoretically applied ATP or ACh (to mimic fEPSPs) did not rundown. Blockade of presynaptic inhibitory muscarinic, adenosine A1, opioid, alpha2-adrenergic and 5-HT1A receptors or pertussis toxin (PTX) treatment did not alter rundown. Antidromic action potentials followed a 10-Hz stimulus train. Iberiotoxin (100 nM), a blocker of large conductance calcium activated K+ (BK) channels, did not alter rundown. These data suggest that synaptic rundown is not due to: (a) action potential failure; (b) nicotinic or P2X receptor desensitization; (c) presynaptic inhibition mediated by pertussis-toxin sensitive G-proteins, or (d) BK channel activation. Synaptic rundown is likely due to depletion of a readily releasable pool (RRP) of neurotransmitter.
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PMID:Dynamics of fast synaptic excitation during trains of stimulation in myenteric neurons of guinea-pig ileum. 1566 59

1. The object of the present study was to clarify the neurotransmitters controlling membrane responses to electrical field stimulation (EFS) in the longitudinal smooth muscle cells of the chicken anterior mesenteric artery. 2. EFS (5 pulses at 20 Hz) evoked a depolarization of amplitude 19.7+/-2.1 mV, total duration 29.6+/-3.1 s and latency 413.0+/-67.8 ms. This depolarization was tetrodotoxin (TTX)-sensitive and its amplitude was partially decreased by atropine (0.5 microM); however, its duration was shortened by further addition of prazosin (10 microM). 3. Atropine/prazosin-resistant component was blocked by the nonspecific purinergic antagonist, suramin, in a dose-dependent manner, indicating that this component is mediated by the neurotransmitter adenosine 5'-triphosphate (ATP). 4. Neither desensitization nor blocking of P2X receptor with its putative receptor agonist alpha,beta-methylene ATP (alpha,beta-MeATP, 1 microM) and its antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic (PPADS, up to 50 microM), had significant effect on the purinergic depolarization. In contrast, either desensitization or blocking of P2Y receptor with its putative agonist 2-methylthioATP (2-MeSATP, 1 microM) and its antagonist Cibacron blue F3GA (CBF3GA, 10 microM) abolished the purinergic depolarization, indicating that this response is mediated through P2Y but not P2X receptor. 5. The purinergic depolarization was inhibited by pertussis toxin (PTX, 600 ng ml(-1)). Furthermore, it was significantly inhibited by a phospholipase C (PLC) inhibitor, U-73122 (10 microM), indicating that the receptors involved in mediating the purinergic depolarization are linked to a PTX-sensitive G-protein, which is involved in a PLC-mediated signaling pathway. 6. Data of the present study suggest that the EFS-induced excitatory membrane response occurring in the longitudinal smooth muscle of the chicken anterior mesenteric artery is mainly purinergic in nature and is mediated via P2Y purinoceptors.
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PMID:An electrophysiological study of excitatory purinergic neuromuscular transmission in longitudinal smooth muscle of chicken anterior mesenteric artery. 1568 11

We have found that opioid and P2X receptors are functionally coupled in the sensory nerve fibres and neurons of rat. When examined in the skin-nerve preparation, the ATP-evoked discharges of nerve fibres belonging to n. saphenous were inhibited by various opiates in a naloxone-dependent manner. The functional coupling between opioid and purinergic receptors was studied in the neuronal cell bodies isolated from dorsal root and nodose ganglia. Both fast (mediated by P2X(3) receptors) and slow (P2X(2/3) heteromeric receptors) responses of sensory neurons to ATP were inhibited by opioids. The inhibition of slow responses developed in a characteristic biphasic manner: an initial short phase of potentiation (lasting for 300-400 s) was followed by long-lasting inhibition of the response (for about 50% when saturated). Both phases of the response were initiated by the application of the highly selective ligand for mu-receptors, endomorphin 1 (30 nM). Intracellular GTPgammaS caused a partial inhibition of the ATP responses and opioids were not effective against the residual response. Intracellular GDP eliminated the effects of opioids, while pertussis toxin (PTX) abolished only the inhibition phase. Thus, P2X receptors in the sensory neurons are affected by opioids via multiple G protein-dependent pathways.
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PMID:Opioids inhibit purinergic nociceptors in the sensory neurons and fibres of rat via a G protein-dependent mechanism. 1581 99

We provide both molecular and pharmacological evidence that the metabotropic, purinergic, P2Y(6), P2Y(12) and P2Y(13) receptors and the ionotropic P2X(4) receptor contribute strongly to the rapid calcium response caused by ATP and its analogues in mouse microglia. Real-time PCR demonstrates that the most prevalent P2 receptor in microglia is P2Y(6) followed, in order, by P2X(4), P2Y(12), and P2X(7) = P2Y(13). Only very small quantities of mRNA for P2Y(1), P2Y(2), P2Y(4), P2Y(14), P2X(3) and P2X(5) were found. Dose-response curves of the rapid calcium response gave a potency order of: 2MeSADP>ADP=UDP=IDP=UTP>ATP>BzATP, whereas A2P4 had little effect. Pertussis toxin partially blocked responses to 2MeSADP, ADP and UDP. The P2X(4) antagonist suramin, but not PPADS, significantly blocked responses to ATP. These data indicate that P2Y(6), P2Y(12), P2Y(13) and P2X receptors mediate much of the rapid calcium responses and shape changes in microglia to low concentrations of ATP, presumably at least partly because ATP is rapidly hydrolyzed to ADP. Expression of P2Y(6), P2Y(12) and P2Y(13) receptors appears to be largely glial in the brain, so that peripheral immune cells and CNS microglia share these receptors. Thus, purinergic, metabotropic, P2Y(6), P2Y(12), P2Y(13) and P2X(4) receptors might share a role in the activation and recruitment of microglia in the brain and spinal cord by widely varying stimuli that cause the release of ATP, including infection, injury and degeneration in the CNS, and peripheral tissue injury and inflammation which is signaled via nerve signaling to the spinal cord.
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PMID:Purinergic receptors activating rapid intracellular Ca increases in microglia. 1665 67

Dinucleoside polyphosphates or Ap(n)A are a family of dinucleotides formed by two adenosines joined by a variable number of phosphates. Ap(4)A, Ap(5)A, and Ap(6)A are stored together with other neurotransmitters into secretory vesicles and are co-released to the extracellular medium upon stimulation. These compounds can interact extracellularly with some ATP receptors, both metabotropic (P2Y) and ionotropic (P2X). However, specific receptors for these substances, other than ATP receptors, have been described in presynaptic terminals form rat midbrain. These specific dinucleotide receptors are of ionotropic nature and their activation induces calcium entry into the terminals and the subsequent neurotransmitter release. Calcium signals that cannot be attributable to the interaction of Ap(n)A with ATP receptors have also been described in cerebellar synaptosomes and granule cell neurons in culture, where Ap(5)A induces CaMKII activation. In addition, cerebellar astrocytes express a specific Ap(5)A receptor coupled to ERK activation. Ap(5)A engaged to MAPK cascade by a mechanism that was insensitive to pertussis toxin and required the involvement of src and ras proteins. Diadenosine polyphosphates, acting on their specific receptors and/or ATP receptors, can also interact with other neurotransmitter systems. This broad range of actions and interactions open a promising perspective for some relevant physiological roles for the dinucleotides. However, the physiological significance of these compounds in the CNS is still to be determined.
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PMID:Dinucleoside polyphosphates and their interaction with other nucleotide signaling pathways. 1668 66

At the neuromuscular junction, ATP is co-released with the neurotransmitter acetylcholine (ACh) and once in the synaptic space, it is degraded to the presynaptically active metabolite adenosine. Intracellular recordings were performed on diaphragm fibers of CF1 mice to determine the action of extracellular ATP (100 muM) and the slowly hydrolysable ATP analog 5'-adenylylimidodiphosphate lithium (betagamma-imido ATP) (30 muM) on miniature end-plate potential (MEPP) frequency. We found that application of ATP and betagamma-imido ATP decreased spontaneous secretion by 45.3% and 55.9% respectively. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A(1) adenosine receptor antagonist and alpha,beta-methylene ADP sodium salt (alphabeta-MeADP), which is an inhibitor of ecto-5'-nucleotidase, did not prevent the inhibitory effect of ATP, demonstrating that the nucleotide is able to modulate spontaneous ACh release through a mechanism independent of the action of adenosine. Blockade of Ca(2+) channels by both, Cd(2+) or the combined application of nitrendipine and omega-conotoxin GVIA (omega-CgTx) (L-type and N-type Ca(2+) channel antagonists, respectively) prevented the effect of betagamma-imido ATP, indicating that the nucleotide modulates Ca(2+) influx through the voltage-dependent Ca(2+) channels related to spontaneous secretion. betagamma-Imido ATP-induced modulation was antagonized by the non-specific P2 receptor antagonist suramin and the P2Y receptor antagonist 1-amino-4-[[4-[[4-chloro-6-[[3(or4)-sulfophenyl] amino]-1,3,5-triazin-2-yl]amino]-3-sulfophenyl] amino]-9,10-dihydro-9,10-dioxo-2-anthracenesulfonic acid (reactive blue-2), but not by pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt (PPADS), which has a preferential antagonist effect on P2X receptors. Pertussis toxin and N-ethylmaleimide (NEM), which are blockers of G(i/o) proteins, prevented the action of the nucleotide, suggesting that the effect is mediated by P2Y receptors coupled to G(i/o) proteins. The protein kinase C (PKC) antagonist chelerythrine and the calmodulin antagonist N-(6-aminohexil)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) occluded the effect of betagamma-imido ATP, while the protein kinase A (PKA) antagonist KT-5720 and the inhibitor of the calcium/calmodulin-dependent protein kinase II (CAMKII) KN-62 failed to do so. betagamma-Imido ATP did not affect 10, 15 and 20 mM K(+)-evoked release and application of reactive blue-2 before incubation in high K(+) induced a higher asynchronous secretion. Thus, our results show that at mammalian neuromuscular junctions, ATP induces presynaptic inhibition of spontaneous ACh release due to the modulation of Ca(2+) channels related to tonic secretion through the activation of P2Y receptors coupled to G(i/o) proteins. We also demonstrated that at increasing degrees of membrane depolarization evoked by K(+), endogenously released ATP induces presynaptic inhibition as a means of preventing excessive neurotransmitter secretion.
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PMID:Presynaptic inhibition of spontaneous acetylcholine release mediated by P2Y receptors at the mouse neuromuscular junction. 1684 2


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