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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fluoride ions (1-30 mM) stimulate phosphoinositide hydrolysis in guinea-pig ileum longitudinal smooth muscle slices, and this is not inhibited in the presence of indomethacin or nifedipine. This action is associated with a slow contractile response which peaks after approximately five minutes and then declines towards baseline; at this time the contractile response to a maximally effective concentration of carbachol is also inhibited. Fluoride-induced contractions are inhibited completely in the presence of nifedipine. Similarly, contractions induced by caffeine, which releases Ca2+ from intracellular stores, are also inhibited by nifedipine. These data are consistent with a model in which the activation of a G-protein by F- ions leads to the following sequential events: activation of phospholipase C, release of intracellular Ca2+, opening of voltage operated (i.e. dihydropyridine sensitive) Ca2+ channels and contraction. The transient nature of the fluoride contraction and the inhibition of the carbachol contraction may be due to a slow elevation of cAMP levels induced by F-.
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PMID:Does the hydrolysis of inositol phospholipids lead to the opening of voltage operated Ca2+ channels in guinea-pig ileum? Studies with fluoride ions and caffeine. 283 95

Serotonin (5-HT), histamine (HA), angiotensin II (ATII), prostaglandin F2 alpha (PGF2 alpha) and thromboxane A2 (TxA2) are known as vasoactive substances, each producing a characteristic contraction of cerebral arteries. These contractions are considered to be mediated by their specific receptors. Recent studies suggest that the activations of these receptors primarily stimulate the phospholipase C and/or phospholipase A2 localized within the same membrane. Stimulation of these enzymes consequently induces production of the second or third messengers such as inositol triphosphate (IP3), diacylglyceride (DAG), arachidonic acid (AA), and ultimately various prostaglandins. The present study is to examine how oxyhemoglobin (Oxy-Hb), another vasoactive substance, can modify these receptor-mediated contractions, and to compare the effects on high K+-, caffeine-and 1-oleoyl-2-acetyl-rac-glycerol (OAG)-induced contractions which are not mediated by the receptors on the cytoplasmic membrane. Helical strips of the bovine middle cerebral arteries (M2) were mainly used in this experiment, and the changes in muscular tensions during isometric contractions were recorded on the polygraph. 5-HT, HA, ATII, PGF2 alpha and cTxA2 (carbocyclic thromboxane A2) were used for each receptor activation. Indomethacin (IDM), a cyclooxygenase inhibitor and 2-nitro-4-carboxyphenyl-n, n-diphenyl-carbamate (NCDC), a phospholipase C inhibitor were used to analyze a possible acting site of Oxy-Hb in modifying these reseptor-mediated enzyme reactions. The results obtained are summarized as follows. (1) All contractions induced by either 5-HT, PGF2 alpha, cTxA2, HA or ATII (concentrations less than 10(-6) M) were markedly augmented as much as 4-8 times the normal, when they were examined in the presence of 10(-5)M Oxy-Hb.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Selective augmenting effect of oxy-Hb on the contractions of cerebral arteries elicited by various vasoactive substances]. 290 26

We designed the present study to determine whether Ca2+ release from intracellular stores contributes to flow-induced contraction. We carried out experiments on segments of rabbit facial vein under isometric conditions. Intraluminal flow by perfusion of physiological salt solution (10 to 80 microL/min) caused contraction in this vessel, which was significantly inhibited by (1) 30-minute pretreatment with 10 mumol/L ryanodine, the sarcoplasmic reticulum Ca2+ channel opener, and (2) 30-minute pretreatment with concomitant application of 20 mmol/L caffeine and 1 mumol/L cyclopiazonic acid in Ca(2+)-free medium to deplete the sarcoplasmic reticulum. In comparison, contraction initiated by 300 nmol/L histamine was significantly attenuated by the same interventions. K+ (25 mmol/L)-induced contraction was unaffected by ryanodine but was reduced after depletion of the sarcoplasmic reticulum. The phospholipase C inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (10 mumol/L) inhibited contractions induced by flow and histamine but not by K+. These findings indicate that Ca2+ release from intracellular stores, presumably via the phosphatidylinositol pathway, contributes to flow- and histamine- but not raised K(+)-induced contractions in this vessel.
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PMID:Intracellular Ca2+ release in flow-induced contraction of venous smooth muscle. 749 66

Whether phosphatidylinositol hydrolysis and a subsequent Ca2+ mobilization are responsible for muscarine-induced transient outward currents (IO) and non-selective cation currents (INS) in the guinea-pig chromaffin cell was investigated using the perforated patch method. IO, but not INS, failed to be reproduced in Ca(2+)-free solution and was markedly reduced by prior exposure to caffeine under Ca(2+)-free conditions or by addition to normal solution of cyclopiazonic acid (CPA), a Ca2+ ATPase inhibitor. Application of CPA in Ca(2+)-free solution, however, suppressed INS by about 50% in 73% of the cells tested. Bath application of 1.5 mM neomycin, a phospholipase C inhibitor, induced the time-dependent decline of IO with near abolition at 20 min or less, whereas it produced a time-independent decrease of INS and an inwardly rectifying K+ current. INS in the presence or absence of neomycin was well fitted to rectangular hyperbolas with the same ED50 of 2.17 microM, but with a 33% smaller maximum amplitude in the former, indicating a non-competitive inhibition by neomycin. We conclude that, while phosphatidylinositol hydrolysis mediates the production of IO, it does not mediate that of INS by muscarine.
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PMID:Phosphatidylinositol hydrolysis is involved in production of Ca(2+)-dependent currents, but not non-selective cation currents, by muscarine in chromaffin cells. 754 Jan 39

Mechanical stimulation of a single cell in an airway epithelial culture initiates an increase in intracellular Ca2+ concentration ([Ca2+]i) that propagates from cell to cell as an intercellular Ca2+ wave. These Ca2+ waves appear to require an increase in intracellular inositol 1,4,5-trisphosphate (IP3) concentration ([IP3]i) in the stimulated cell and are propagated between cells by the diffusion of IP3 through gap junctions. To test the hypothesis that the activation of phospholipase C (PLC) contributes to the elevation of [IP3]i and initiation of an intercellular Ca2+ wave, changes in [Ca2+]i induced by mechanical stimulation were measured by digital fluorescence microscopy in the presence of the PLC inhibitor, aminosteroid U73122. Following exposure to U73122 mechanical stimulation elevated [Ca2+]i of the stimulated cell, but did not initiate the propagation of an intercellular Ca2+ wave. By contrast, in the presence of U73343, a similar aminosteroid that does not inactivate PLC, mechanical stimulation increased the [Ca2+]i of the stimulated cell and initiated an intercellular Ca2+ wave. U73122 also blocked the elevation of [Ca2+]i of airway epithelial cells in response to ATP, a P2-receptor agonist that activates PLC to elevate [IP3]i and [Ca2+]i. In addition, the propagation of intercellular Ca2+ waves was not affected by the ryanodine-receptor agonists, caffeine or ryanodine. The hypotheses that: (1) an elevation of [IP3]i is required to initiate intercellular Ca2+ waves; (2) mechanical stimulation activates PLC; and (3) Ca2+ wave propagation in airway epithelial cells involves Ca2+ release from intracellular stores primarily via IP3 receptors are supported by these results.
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PMID:A role for phospholipase C activity but not ryanodine receptors in the initiation and propagation of intercellular calcium waves. 759 99

Phorbol ester, which activates protein kinase C (PKC), modulates vasoconstrictor-induced tension in vascular smooth muscle. Recently, Staphylococcal aureus alpha-toxin, which produces too small pores in the plasma membrane to allow passage of proteins, such as PKC, is used to investigate the signal transduction system in vascular smooth muscle cells. In order to elucidate the role of PKC on vascular smooth muscle contraction, we examined whether PKC activation influences the relationship between intracellular Ca2+ ([Ca2+]i) and tension in Wistar rat superior mesenteric artery (SMA) using vascular smooth muscle permeabilized with Staphylococcal alpha-toxin. [Ca2+]i was clamped at specified values (10(-8.5)-10(-4) mol/L) using EGTA-Ca2+ buffer. In alpha-toxin non-treated rings of SMA, isometric tension was evoked by 10 mmol/L caffeine and 10-30 mmol/L external potassium (high K+) in the absence or presence of phorbol 12, 13-dibutyrate (PDBu), a PKC activator, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), and staurosporine (PKC inhibitors). PDBu significantly augmented caffeine- and high K(+)-evoked contractions. H-7 and staurosporine significantly attenuated caffeine- and high K(+)-evoked contractions augmented by PDBu. Moreover, H-7 significantly suppressed high K(+)-induced contraction in the absence of PDBu. In alpha-toxin permeabilized artery, PDBu shifted the [Ca2+]i-force relationship curve to the left. These results suggest that PKC activates vascular smooth muscle contraction by increasing the sensitivity of the contractile apparatus to Ca2+.
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PMID:Role of protein kinase C in relationship between Ca2+ and contractile elements in rat alpha-toxin-permeabilized mesenteric artery. 759 22

Calcium flux is required for the mammalian sperm acrosome reaction, an exocytotic event triggered by egg binding, which results in a dramatic rise in sperm intracellular calcium. Calcium-dependent membrane fusion results in the release of enzymes that facilitate sperm penetration through the zona pellucida during fertilization. We have characterized inositol 1,4,5-trisphosphate (IP3)-gated calcium channels and upstream components of the phosphoinositide signaling system in mammalian sperm. Peptide antibodies colocalized G alpha q/11 and the beta 1 isoform of phospholipase C (PLC beta 1) to the anterior acrosomal region of mouse sperm. Western blotting using a polyclonal antibody directed against purified brain IP3 receptor (IP3R) identified a specific 260 kD band in 1% Triton X-100 extracts of rat, hamster, mouse and dog sperm. In each species, IP3R immunostaining localized to the acrosome cap. Scatchard analysis of [3H]IP3 binding to rat sperm sonicates revealed a curvilinear plot with high affinity (Kd = 26 nM, Bmax = 30 pmol/mg) and low affinity (Kd = 1.6 microM, Bmax = 550 pmol/mg) binding sites, reflecting among the highest receptor densities in mammalian tissue. Immunoelectron microscopy confirmed the acrosomal localization in rat sperm. The IP3R fractionated with acrosomes by discontinuous sucrose gradient centrifugation and was enriched in the medium of acrosome-reacted sperm. ATP-dependent 45Ca2+ loading of digitonin permeabilized rat sperm was decreased by 45% in the presence of 10 microM IP3. The IP3-mediated release of calcium was blocked by heparin. Thapsigargin, a sequiterpene lactone inhibitor of the microsomal Ca(2+)-ATPase, stimulated the acrosome reaction of mouse sperm to the same extent as the Ca2+ ionophore, A23187. The failure of caffeine and ryanodine to affect calcium accumulation suggested that thapsigargin acted through an IP3-sensitive store. The presence of G alpha q/11, PLC beta 1 and a functional IP3R in the anterior acrosomal region of mammalian sperm, as well as thapsigargin's induction of the acrosome reaction, implicate IP3-gated calcium release in the mammalian acrosome reaction.
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PMID:Inositol 1,4,5-trisphosphate receptors selectively localized to the acrosomes of mammalian sperm. 764 3

In pancreatic acini, administration of the phospholipase C inhibitor, U-73122, abolished Ca2+ oscillations and amylase secretion induced by CCK but had much less effect on the action of CCK analog JMV-180. In contrast, the phospholipase A2 inhibitor, ONO-RS-082, inhibited both Ca2+ spikes and amylase secretion induced by JMV-180, but it had little effect on the action of CCK-8. Both arachidonic acid (AA) and a cytochrome P-450 inhibitor, SKF-96365, generated Ca2+ spikes from the agonist-sensitive pool. AA was capable of releasing Ca2+ from the endoplasmic reticulum (ER), suggesting the direct Ca2+ releasing pathway. There is no evidence of Ca(2+)-induced Ca2+ release (CICR) since neither caffeine, a CICR potentiator, nor ryanodine, a CICR inhibitor, modulated agonist-induced Ca2+ oscillations and Ca2+ release from the ER. On the contrary, increasing concentrations of caffeine abolished agonist-induced Ca2+ spikes. Therefore we have demonstrated that depending on the agonists used, CCK receptor activation may result in the differential involvement of the phosphoinositol and arachidonic acid pathways to mediate calcium oscillation and amylase secretion.
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PMID:Differential involvement of phospholipase A2/arachidonic acid and phospholipase C/phosphoinositol pathways during cholecystokinin receptor activated Ca2+ oscillations in pancreatic acini. 768 62

Calcium signaling within astrocytes in the CNS may play a role comparable to that of electrical signaling within neurons. ATP is a molecule known to produce Ca2+ responses in astrocytes, and has been implicated as a mediator of intercellular Ca2+ signaling in other types of nonexcitable cells. We characterized the signal transduction pathway for ATP-evoked Ca2+ responses in cultured astrocytes from the dorsal spinal cord. Nearly 100% of these astrocytes respond to extracellularly applied ATP, which causes release of Ca2+ from an intracellular pool that is sensitive to thapsigargin and insensitive to caffeine. We found that intracellular administration of IP3 also caused release of Ca2+ from a thapsigargin-sensitive intracellular pool, and that IP3 abolished the response to ATP. The ATP-evoked Ca2+ response was blocked by the IP3 receptor antagonist heparin, applied intracellularly, but not by N-desulfated heparin, which is not an antagonist at these receptors. The Ca2+ response caused by ATP was also blocked by a phospholipase C inhibitor, U-73122, but not by its inactive analog, U-73343. Increases in [Ca2+]i were elicited by intracellular application of activators of heterotrimeric G-proteins, GTP gamma S and AIF4-. On the other hand, [Ca2+], was unaffected by a G-protein inhibitor, GDP beta S, but it did abolish the Ca2+ response to ATP. Pretreating the cultures with pertussis toxin did not affect responses to ATP. Our results indicate that in astrocytes ATP-evoked release of intracellular Ca2+ is mediated by IP3 produced as a result of activating phospholipase C coupled to ATP receptors via a G-protein that is insensitive to pertussis toxin. ATP is known to be released under physiological and pathological circumstances, and therefore signaling via the PLC-IP3 pathway in astrocytes is a potentially important mechanism by which ATP may play a role in CNS function.
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PMID:ATP causes release of intracellular Ca2+ via the phospholipase C beta/IP3 pathway in astrocytes from the dorsal spinal cord. 772 40

The effects of trimebutine on Ca2+ release and modulation of Ca2+ sensitivity of contractile elements induced by carbachol (CCh) were investigated using a tension measuring method in beta-escin-treated skinned smooth muscle of the longitudinal muscle layer of guinea pig ileum. Trimebutine (10-100 microM) concentration-dependently inhibited tension development brought about by Ca2+ release from intracellular stores induced by CCh (10 microM), but did not affect those induced by inositol 1,4,5-trisphosphate (IP3, 25 microM) or caffeine (5 mM). The inhibitory effect was reversible. Trimebutine (100 microM) neither altered the Ca2+ sensitivity of the contractile elements nor affected the effects of GTP gamma S (50 microM) and CCh (100 microM) in potentiating Ca2+ sensitivity of the contractile elements after the Ca2+ storage function had been eliminated by A23187. These results suggest that trimebutine inhibits CCh-induced Ca2+ release by acting at some point during the coupling of muscarinic receptors through a G-protein to phospholipase C and thus reducing the accumulation of IP3.
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PMID:Effect of trimebutine on contractile responses in skinned ileal smooth muscle. 779 25


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