Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.16.2 (PCP)
3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glial cells are closely associated with synapses and are modulated by neurotransmitters released during synaptic transmission. At many synapses, ATP is released during synaptic transmission and is involved in cell-cell signaling. Since glial cells have purinoceptors, it is possible that ATP mediates synaptic neuron-glia signaling. This work aims at determining which types of purinoceptors are present on perisynaptic Schwann cells, the perisynaptic glial cells at the frog neuromuscular junction, and test their sensitivity to endogenous purines by monitoring the relative changes of intracellular Ca2+. Local application of ATP induced the release of Ca2+ from internal stores. Adenosine induced Ca2+ responses that were blocked by A1 receptor antagonists and mimicked by an A1 receptor agonist and were caused by the release of Ca2+ from internal stores via a pertussis toxin-sensitive G-protein. A2 receptor antagonists had no effect on Ca2+ responses induced by adenosine. Me-S-ATP, an ATP analog, triggered Ca2+ release from internal stores via a pertussis toxin-sensitive G-protein, consistent with the activation of P2Y receptors. L-AMP-PCP, another ATP analog, induced Ca2+ entry mainly through L-type Ca2+ channels by a pertussis toxin-insensitive mechanism, consistent with the activation of P2X receptors. Blockade of adenosine receptors did not affect glial Ca2+ responses induced by nerve evoked transmitter release. However, blockade of ATP receptors reduced the size and increased the delay of the responses. Hence, purinoceptors are present on the perisynaptic Schwann cells and are activated by endogenous ATP released during synaptic transmission.
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PMID:Purinergic receptors and their activation by endogenous purines at perisynaptic glial cells of the frog neuromuscular junction. 747 66

The present study was undertaken to observe the changes of Ryanodine receptor of cardiac junctional sarcoplasmic reticulum (SR) in relation to membrane lipid microenvironment alteration during septic shock. The results showed that the Bmax for 3H-ryanodine binding to cardiac junctional SR was decreased by 41.3% (3.9 +/- 0.1 vs. sham 6.6 +/- 0.7 pmol/mg, P < 0.01) while the Kd value was unaffected during late septic shock (CLP 18 h). Ca2+ activated 3H-ryanodine binding significantly and reached a saturation value when Ca2+ concentration was 5 x 10(-5) mol/L, while the S0.5 and the Hill coefficient values remained unchanged during septic shock. Caffeine, ATP, and AMP-PCP activated while Mg2+, ruthenium red inhibited 3H-ryanodine binding in both groups but the A0.5 (concentration requires for half maximum activation) and the IC50 (concentration requires for half-maximum inhibition) for the above mentioned activators and inhibitors, were respectively unaffected during septic shock. Digestion of cardiac SR isolated from control rats with phospholipase A2 inhibited 3H-ryanodine binding, which could be dramatically recovered by the incorporation of phosphatidylcholine (PC), or phosphatidylserine (PS), or phosphatidylethanolamine (PE) into the isolated cardiac SR. Incorporation of above phospolipids into SR isolated from septic rats reversed shock-induced inhibition of 3H-ryanodine binding. It is concluded that the mechanism responsible for the inhibition of 3H-ryanodine binding of junctional SR during septic shock may be related to modification of membrane lipid microenvironment in response to PLA2 overactivation during septic shock.
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PMID:[Altered ryanodine receptor of rat cardiac sarcoplasmic reticulum and its underlying mechanism during septic shock]. 748 76

1. The effects of the benzopyran K-channel opener, BRL55834, on mechanical activity in bovine trachealis and rat portal vein were studied together with membrane currents in freshly-isolated single cells derived from these tissues. 2. BRL55834 (3 nM-1 microM) produced a concentration-dependent relaxation of bovine trachealis precontracted with 100 microM histamine and reduced the spontaneous mechanical activity of rat portal veins, effects which were antagonized by glibenclamide (1-10 microM) but were not reversible on washing. In contrast, charybdotoxin (250 nM) did not modify the spasmolytic effect of BRL55834 in bovine trachealis. 3. BRL55834 (10 nM-10 microM) did not relax segments of bovine trachealis precontracted with 80 mM KCl. 4. In some freshly-isolated single cells from bovine trachealis held at -10 mV, BRL55834 (3 microM) induced a time-independent outward K-current which was partially resistant to inhibition by glibenclamide (10 microM). In other cells, a very noisy, outwardly-rectifying and charybdotoxin-sensitive current developed in the presence of BRL55834 (3 microM) and in time-matched control cells. 5. In freshly-isolated single cells from rat portal vein held at -10 mV, BRL55834 (3 microM) induced a time- and calcium-independent outward K-current which was partially resistant (approximately 25% inhibition at +40 mV) to subsequent inhibition by glibenclamide (10 microM). In contrast, levcromakalim induced a time-independent outward K-current which was completely inhibited by glibenclamide 10 microM. 6. With the non-hydrolysable ATP analogue, AMP-PCP (5 mM), in the pipette, the ability of BRL55834 to induce a time-independent K-current in portal vein cells was markedly reduced (approximately 80% inhibition at +40 mV) whereas the effects of 10 microM levcromakalim were totally inhibited. 7. The glibenclamide-resistant current component induced by BRL55834 was totally inhibited by phentolamine (100 microM), a concentration that had no effect on the peak current (IBK(Ca)) induced by NS1619 (33 microM). 8. Stationary fluctuation analysis of the noise associated with the glibenclamide-insensitive K-current induced by BRL55834 in rat portal vein cells indicated that the unitary current flowing through the underlying channels was 0.26 pA at -10 mV, a value inconsistent with the involvement of BKCa. 9. It is concluded that the relaxations of both bovine trachea and rat portal vein produced by BRL55834 are associated with the opening of K-channels. These are probably identical to the ATP-sensitive K-channel opened by levcromakalim, although the involvement of an additional K-channel cannot be excluded. The reduced sensitivity of the BRL55834-induced changes to glibenclamide and toAMP-PCP may result from avid binding of BRL55834 to its site of action.
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PMID:Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide-resistant, ATP-sensitive potassium current. 758 99

Phencyclidine (PCP) and ketamine are known to block NMDA receptor mediated excitotoxicity by non-competitively blocking the NMDA receptor calcium channel. PCP and ketamine have the paradoxical effect of also inducing the heat shock gene, hsp70, in the cingulate and retrosplenial cortex of the rat. The present study shows that DNQX, a specific AMPA receptor antagonist, given as either a 5 mg/kg or 10 mg/kg intraperitoneal dose or into the lateral cerebral ventricle (5 microliters of 0.5 mg/ml) significantly diminished PCP (40 mg/kg) and ketamine (80, 100, 120 mg/kg) hsp70 induction in the posterior cingulate and retrosplenial cortex. The most dramatic decrease of hsp70 induction was seen with the intraventricular dose of DNQX. Present findings show that the AMPA receptor has a role in PCP/ketamine induction of hsp70 in the cortex. DNQX inhibition of PCP/ketamine hsp70 induction was likely related to AMPA receptor antagonism which prevented excess calcium influx via voltage-gated calcium channels.
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PMID:DNQX inhibits phencyclidine (PCP) and ketamine induction of the hsp70 heat shock gene in the rat cingulate and retrosplenial cortex. 758 95

Excess ATP is known to enhance Ca(2+)-ATPase activity and, among other effects, to accelerate the Ca2+ binding reaction. In previous work, we studied the pH dependence of this reaction and proposed a 3H+/2Ca2+ exchange at the transport sites, in agreement with the H+/Ca2+ counter transport. Here we studied the effect of ADP and nonhydrolyzable ATP analogues on the Ca2+ binding reaction at various pH values. At pH 6, where Ca2+ binding is monophasic and slow, ADP, adenosine 5'-(beta,gamma-methylene)triphosphate (AMP-PCP), or adenyl-5'-yl imidodiphosphate (AMPPNP) increased the Ca2+ binding rate constant 20-fold. At pH 7 and 8, where Ca2+ binding is biphasic, the nucleotides induce fast and monophasic Ca2+ binding. At pH 7, AMP-PCP accelerated Ca2+ binding with an apparent dissociation constant of 10 microM. At acidic pH, ADP, AMPPCP, or AMPPNP increased the equilibrium affinity of Ca2+ for ATPase, whereas at alkaline pH, these nucleotides had no effect. At pH 5.5, AMPPCP increased equilibrium Ca2+ binding with an apparent dissociation constant of 1 microM.
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PMID:The modulation of Ca2+ binding to sarcoplasmic reticulum ATPase by ATP analogues is pH-dependent. 759 71

The sympathetic nervous system has been shown to exert a trophic influence on vascular smooth muscle cells (VSMC). Therefore, we studied the growth-regulating effects of the sympathetic cotransmitters ATP, neuropeptide Y (NPY), and norepinephrine (NE). ATP in concentrations of 1-100 microM greatly increased the incorporation of [3H]thymidine in VSMC from rat aorta and vena cava. ATP also increased cell number and total protein content. The maximal effect on [3H]thymidine incorporation was greater than for epidermal growth factor (20 ng/ml) or insulin (1 microgram/ml) and approximately one-half that of 10% fetal calf serum. The potency series of other nucleotides and analogues of ATP was ATP > beta, gamma-methyleneATP (AMP-PCP) > ADP > adenosine > alpha, beta- methyleneATP (AMP-CPP) > 2-methylthioATP, indicating involvement of a P2 receptor, however, it does not meet proposed pharmacological criteria of either the P2x or P2y subclass. Several proposed P2 receptor antagonists were without effect. The effect of ATP could be mediated by a "nucleotide receptor," since UTP also stimulated [3H]thymidine incorporation. In our model, there was a strong correlation between the mitogenic effects of ATP, AMP-CPP, AMP-PCP, and UTP and their ability to stimulate influx of extracellular Ca2+ (Ca2+o). Moreover, the mitogenic effect of ATP was increased by high concentrations of Ca2+o. Taken together with data showing the lack of involvement of several other second-messenger systems, this indicates a critical role for Ca2+o in mediating the mitogenic effects of ATP. Amiloride, known to inhibit the action of several growth factors, also inhibited ATP-induced mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitogenic effects of ATP on vascular smooth muscle cells vs. other growth factors and sympathetic cotransmitters. 769 83

We have identified a 70-kDa cytosolic protein (GTBP70) in rat adipocytes that binds to glutathione S-transferase fusion proteins corresponding to the cytoplasmic domains of the facilitative glucose transporter isoforms Glut1, Glut2, and Glut4. GTBP70 did not bind to irrelevant fusion proteins, indicating that the binding is specific to the glucose transporter. GTBP70 binding to the glucose transporter showed little isoform specificity but was significantly subdomain-specific; it bound to the C-terminal domain and the central loop, but not to the N-terminal domain of Glut4. The GTBP70 binding to Glut4 was not affected by the presence of 2 mM EDTA, 2.4 mM Ca2+, or 150 mM K+. The binding was inhibited by ATP in a dose-dependent manner, with 50% inhibition at 10 mM ATP. This inhibition was specific to ATP, as ADP and AMP-PCP (adenosine 5'-(beta, gamma-methylenetriphosphate)) were without effect. GTBP70 did not react with antibodies against phosphotyrosine, phosphothreonine, or phosphoserine, suggesting that it is not a phosphoprotein. The binding of GTBP70 to Glut4 was not affected by the pretreatment of adipocytes with insulin. When these experiments were repeated using rat hepatocyte cytosols, no ATP-sensitive 70-kDa protein binding to the glucose transporter fusion proteins was evident, suggesting that either GTBP70 expression or its function is cell-specific. These findings strongly suggest the possibility that GTBP70 may play a key role in glucose transporter regulation in insulin target cells such as adipocytes.
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PMID:ATP-sensitive binding of a 70-kDa cytosolic protein to the glucose transporter in rat adipocytes. 771 80

We investigate the mechanisms underlying the intracellular calcium pulse that occurs in response to extracellular adenosine triphosphate (ATP) in osteoclasts. We find that pre-loading of GDP-beta-S abolishes the response in Ca(2+)-free medium, demonstrating an internal release of Ca2+ via a pathway that involves a G protein. GDP-beta-S does not block in normal Ca(2+)-containing medium, suggesting that ATP also induces a Ca2+ influx across the cell membrane. We confirmed this using the Mn2+ quenching technique, which shows significant opening of Ca2+ channels. We find a smaller response to adenosine diphosphate (ADP) and 2-methylthio-ATP (2-MeSATP), but no response to beta, gamma-methylene-ATP (AMP-PCP), adenosine monophosphate (AMP) or uridine triphosphate (UTP). Prior application of AMP and UTP, but not AMP-PCP, blocks the response to ATP. Our results indicate that the receptor is a P2 subtype that is not characteristic of any previously reported P2 receptor or combination of P2 receptors.
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PMID:Mechanisms of ATP-induced Ca2+ signaling in osteoclasts. 771 10

The role of the putative sigma receptor in mediating neuroprotection against glutamate-induced neuronal injury was examined in mature cultured rat cortical neurons. With the exception of the selective sigma 1 ligand (+)-3-PPP, all of the sigma ligands tested were neuroprotective, preventing glutamate-induced morphological changes and increases in LDH release. Their rank order of neuroprotective potency (and EC50 values) was as follows: (+)-SKF 10,047 (0.81 microM) > (+)- cyclazocine (2.3 microM) > dextromethorphan (3.1 microM) = haloperidol (3.7 microM) > (+)-pentazocine (8.5 microM) > DTG (42.7 microM) = carbetapentane (46.3 microM). When corrected for relative sigma versus PCP binding affinity, it appears that a positive correlation exists between neuroprotective potency and sigma 1 site affinity. However, there does not appear to be a significant correlation between neuroprotective potency and the sigma 2 site. Critically, none of the sigma ligands were neurotoxic when tested alone at concentrations at least 5-30 times their respective neuroprotective EC50 values. Results from preliminary experiments with the selective sigma 1 ligand (+)-pentazocine indicated that sigma-mediated neuroprotection may involve the buffering of glutamate-induced calcium flux. Collectively, the results of these in vitro experiments demonstrate that sigma ligands are neuroprotective and therefore deserve further exploration as potential therapeutic agents in in vivo models of CNS injury and neurodegenerative disorders.
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PMID:Sigma receptor-mediated neuroprotection against glutamate toxicity in primary rat neuronal cultures. 772 32

The effect of phencyclidine (PCP) on the gamma-aminobutyric acid-ergic (GABAergic) transmission in the striatum of freely-moving rats was investigated using an in vivo microdialysis. The high potassium (100 mM) increased the extracellular GABA level to 4000% of the basal level. Although the basal GABA level in the striatal dialysate did not show either calcium dependency or tetrodotoxin (TTX) sensitivity, the high potassium evoked GABA level was reduced by 82% under calcium-free conditions (with 12.5 mM magnesium) and by 54% in the presence of 10 microM TTX. The systemic administration of PCP (7.5 mg/kg) or the local perfusion of PCP (100 microM and 1 mM) significantly inhibited the high potassium evoked GABA release in the rat striatum. The local perfusion of MK-801 (10 microM and 100 microM), a more potent and selective N-methyl-D-aspartate (NMDA) receptor antagonist, also inhibited the high potassium evoked striatal GABA release. These drugs did not show any significant effect on the basal extracellular GABA level. NMDA (1 mM) either partly or completely blocked the effect of PCP (1 mM) or MK-801 (100 microM) on the high potassium evoked striatal GABA release. On the other hand, nomifensine (100 microM), a dopamine uptake blocker, did not show any effect on the high potassium evoked GABA release. These results suggest that PCP inhibited the striatal GABAergic neuronal transmission through its antagonism of the NMDA receptor.
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PMID:The effect of phencyclidine on the basal and high potassium evoked extracellular GABA levels in the striatum of freely-moving rats: an in vivo microdialysis study. 772 33


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