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)

In the dog iris sphincter, muscarinic acetylcholine receptors are coupled either to the stimulation of phospholipase C and muscle contraction or to the stimulation of adenylate cyclase and muscle relaxation, this was found to be dependent upon the concentration of the muscarinic agonist. In contrast to the dog, muscarinic receptors in iris sphincters from different mammalian species were found to be coupled to phospholipase C and contraction at all concentrations of carbachol investigated (1-100 microM). In the dog sphincter, lower concentrations (less than 5 microM) of carbachol stimulated myo-inositol 1,4,5-trisphosphate (IP3) production, inhibited cAMP formation and induced contraction, and higher concentrations (greater than 5 microM) enhanced cAMP formation, inhibited IP3 production and induced relaxation. The mechanisms for the stimulatory effects on cAMP formation through muscarinic receptors were investigated. Carbachol (25 microM) increased both basal and isoproterenol- and forskolin-stimulated cAMP levels. Atropine inhibited the carbachol-stimulated increase in cAMP levels in a dose-dependent manner with an IC50 of 9 nM. Intracellular Ca2+, derived from IP3-induced Ca2+ release and/or from muscarinic receptor-operated Ca2+ influx, and protein kinase C may mediate the muscarinic receptor-linked rise in intracellular cAMP. This conclusion is supported by the following findings. (1) At short time intervals (less than 1 min) carbachol (25 microM) increased IP3 production and contraction and this was followed (between 1 and 20 min) by cAMP formation and muscle relaxation. (2) Carbachol-stimulated IP3 production was detected at a concentration of the agonist 26-fold lower than that required for cAMP formation, and it was completely blocked by the phorbol ester, phorbol 12,13-dibutyrate (50 nM). (3) A Ca(2+)-calmodulin stimulated adenylate cyclase was demonstrated in membranes from dog iris sphincter but not in that from rabbit and bovine. (4) Trifluoperazine (0.1 microM), a calmodulin antagonist, inhibited the carbachol-stimulated cAMP accumulation. (5) The Ca2+ ionophore A23187 and the phorbol ester increased cAMP production in a dose-dependent manner. A23187 potentiated cAMP production induced by either carbachol or by the phorbol ester. (6) Muscarinic stimulation of cAMP production persisted even after the tissue was pretreated with the phorbol ester or staurosporine. (7) Nifedipine (0.01-0.5 microM), a Ca2+ channel antagonist, inhibited carbachol stimulation of cAMP production, suggesting the presence of a muscarinic receptor-operated Ca2+ influx pathway in this tissue.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Carbachol stimulates adenylate cyclase and phospholipase C and muscle contraction-relaxation in a reciprocal manner in dog iris sphincter smooth muscle. 132 47

Seizures induced by three convulsant treatments produced differential effects on the concentration of acetylcholine in rat brain. Status epilepticus induced by (i) coadministration of lithium and pilocarpine caused massive increases in the concentration of acetylcholine in the cerebral cortex and hippocampus, (ii) a high dose of pilocarpine did not cause an increase of acetylcholine, and (iii) kainate increased acetylcholine, but the magnitude was lower than with the lithium/pilocarpine model. The finding that the acetylcholine concentration increases in two models of status epilepticus in the cortex and hippocampus is in direct contrast with many in vitro reports in which excessive stimulation causes depletion of acetylcholine. The concentration of choline increased during seizures with all three models. This is likely to be due to calcium- and agonist-induced activation of phospholipase C and/or D activity causing cleavage of choline-containing lipids. The excessive acetylcholine present during status epilepticus induced by lithium and pilocarpine was responsive to pharmacological manipulation. Atropine tended to decrease acetylcholine, similar to its effects in controls. The N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, reduced the excessive concentration of acetylcholine, especially in the cortex. Inhibition of choline uptake by hemicholinium-3 (HC-3) administered icv reduced the acetylcholine concentration in controls and when given to rats during status epilepticus. These results demonstrate that the rat brain concentrations of acetylcholine and choline can increase during status epilepticus. The accumulated acetylcholine was not in a static, inactive compartment, but was actively turning-over and was responsive to drug treatments. Excessive concentrations of acetylcholine and/or choline may play a role in seizure maintenance and in the neuronal damage and lethality associated with status epilepticus.
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PMID:Seizures increase acetylcholine and choline concentrations in rat brain regions. 181 38

In dog thyroid slices prelabeled with myo-[2-3H]inositol, carbachol (10(-7)-10(-4) M) and NaF (10-20 mM) stimulated IP1, IP2 and IP3 generation. These effects did not require the presence of extracellular calcium. Atropine and PDBu inhibited the action of the cholinergic agonist. No effect of TSH (1-100 mU/ml) could be detected on PIP2 hydrolysis and IP production. These results suggest that IP3 could play a role in the metabolic actions of carbachol in the thyroid; a G-protein coupling the hormone-receptor binding to phospholipase C activation exists in the thyroid membrane; the well known TSH-induced increased PI turnover does not result in IP3 accumulation.
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PMID:Carbachol and sodium fluoride, but not TSH, stimulate the generation of inositol phosphates in the dog thyroid. 302 27

1. Rat isolated tracheal smooth muscle preparations respond to phospholipase A2 (PLA2) and phospholipase C (PLC) with contractile responses of highly variable magnitudes. Rat tracheae exposed to PLA2 or PLC for a period of 10-30 min, exhibit airway hyperreactivity (AH) to cooling (10 degrees C), i.e., respond with strong contractile responses. Phospholipase D neither contracted rat tracheae nor induced AH to cooling. 2. PLA2-induced AH to cooling was dependent on the presence of extracellular Ca2+ in the physiological solution. 3. Verapamil, azelastine, diltiazem and TMB-8 (each 10 microM) significantly attenuated PLA2-induced AH. This effect was not shared by nifedipine (10 microM). 4. Bepridil (10 microM), a Ca2+ and calmodulin antagonist, also significantly attenuated AH induced by PLA2. 5. Indomethacin (a cyclo-oxygenase inhibitor), AA-861 (a selective 5-lipoxygenase inhibitor), FPL 55712 (a leukotriene receptor antagonist), methysergide (a 5-hydroxytryptamine D-receptor antagonist) and pyrilamine (a histamine H1-receptor antagonist) exerted little or no effect on PLA2-induced AH to cooling. 6. Atropine significantly attenuated PLA2-induced AH suggesting the participation of acetylcholine. 7. Nordihydroguaiaretic acid (an antioxidant; 5-lipoxygenase inhibitor) and BW 755C (an antioxidant; a dual inhibitor of cyclo-oxygenase and 5-lipoxygenase) significantly attenuated PLA2-induced AH to cooling. 8. In conclusion, these data show that PLA2 (an enzyme involved in the synthesis of Paf-acether, prostaglandins, thromboxanes, leukotrienes, diacylglycerol, superoxide free radicals and lipid peroxides, etc.) induces AH to cooling and acetylcholine in rat trachea. The induction of AH to cooling is dependent on the presence of extracellular Ca2+ and is significantly attenuated by verapamil, diltiazem, bepridil, atropine and azelastine (an antiallergic/antiasthmatic drug).
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PMID:Phospholipase A2 induced airway hyperreactivity to cooling and acetylcholine in rat trachea: pharmacological modulation. 320 72

Synaptosomes, purified from rat cerebral cortex, were prelabeled with [3H]inositol to study phosphatidylinositol turnover in nerve terminals. Labeled synaptosomes were either depolarized with 40 mM K+ or exposed to carbamoylcholine (carbachol). K+ depolarization increased the level of inositol phosphates in a time-dependent manner. The inositol trisphosphate concentration increased rapidly and transiently, reaching maximum (250% of control) in less than 3 sec and returning to near basal levels by 30 sec. The inositol bisphosphate level also increased rapidly, but its elevated level (220% of control) was sustained during continued depolarization. The elevated level of inositol bisphosphate was reversed upon repolarization of the synaptosomes. The level of inositol monophosphate increased slowly to 120-130% of control. These effects of K+ depolarization depended on the presence of Ca2+ in the incubation medium. Carbachol stimulated the turnover of phosphatidylinositol in a dose- and time-dependent manner. The level of inositol trisphosphate increased only slightly (120-130% of control) during carbachol stimulation. The level of inositol bisphosphate increased to 210% of control, and this maximal response was seen from 15 to 60 min. Accumulation of inositol monophosphate (250% of control) was larger than that of inositol bisphosphate, but its time course was slower. Atropine and pirenzepine inhibited the carbachol effect with high affinities of 0.8 nM and 16 nM, respectively, indicating that the effect of carbachol was mediated by activation of a M1 muscarinic receptor. Incubation of synaptosomes in Ca2+-free buffer reduced the response to carbachol by 30%, and addition of EGTA abolished it. These data show that both Ca2+ influx and M1 muscarinic receptor activation stimulate phospholipase C activity in synaptosomes, suggesting that phosphatidylinositol turnover may be involved in regulating neurotransmitter release from nerve terminals.
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PMID:Membrane depolarization and carbamoylcholine stimulate phosphatidylinositol turnover in intact nerve terminals. 335 96

The effect of ischemia on phosphatidylinositol (PI) degrading enzymes in brain homogenate, cytosol and synaptosomes was investigated to evaluate the involvement of cholinergic receptor in PI hydrolysis during ischemia. The activity of phospholipase C in cytosol was not changed by ischemic insult. PI degradation in synaptosomes was significantly (60%) enhanced by ischemia. Atropine and gamma-butyrolactone abolished the ischemic effect on PI degradation, suggesting that the cholinergic receptor system mediates breakdown of PI during ischemia.
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PMID:Phosphatidylinositol degradation in ischemic brain specifically activated by synaptosomal enzymes. 358 67

Previous studies showed that lithium, beginning at therapeutic plasma concentrations in the treatment of manic depression, increased the accumulation of second-messenger inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in cerebral cortex slices of guinea pig and rhesus monkey [Lee, Dixon, Reichman, Moummi, Los and Hokin (1992) Biochem. J. 282, 377-385; Dixon, Lee, Los and Hokin (1992) J. Neurochem. 59, 2332-2335; Dixon, Los and Hokin (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 8358-8362]. These studies have now been extended to a peripheral tissue, mouse pancreatic minilobules. In the presence of carbachol, concentrations of lithium from 1 to 20 mM sharply and progressively increased the accumulation of Ins(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate, followed by a decrease. Assay of these inositol polyphosphates by either the prelabelling technique or mass assay gave similar results. Atropine quenching of cholinergically stimulated pancreatic minilobules led to a rapid disappearance of Ins(1,4,5)P3. This disappearance was impeded by lithium. This suggested that the lithium-induced elevation in Ins(1,4,5)P3 was due to inhibition of the 5-phosphatase and, on the basis of the markedly elevated concentrations of inositol 1,3,4-trisphosphate [Ins(1,3,4)P3] and inositol 1,4-bisphosphate in the presence of lithium, probably by feedback inhibition by these latter two compounds. An additional mechanism, i.e. a stimulatory effect of lithium on phospholipase C, cannot, however, be ruled out. The other reaction product of phospholipase C, inositol cyclic 1:2,4,5-trisphosphate, also increased in the presence of lithium. This may also be due to inhibition of the 5-phosphatase, which is the exclusive mechanism for removal of this compound. The effects of lithium on the accumulation of other inositol phosphates paralleled that of Ins(1,4,5)P3, with the exception of inositol 3,4-bisphosphate, which decreased. This was presumably due to the inhibition of Ins(1,3,4)P3 1-phosphatase by lithium. Unlike mouse cerebral cortex slices [Lee, Dixon, Reichman, Moummi, Los and Hokin (1992) Biochem. J. 282, 377-385], inositol supplementation was not required to demonstrate lithium-stimulated Ins(1,4,5)P3 accumulation in mouse pancreatic minilobules. This indicates that inositol depletion sufficient to impair lithium-stimulated Ins(1,4,5)P3 accumulation does not occur in mouse pancreatic minilobules, even though an elevation of cytidine diphosphodiacylglycerol occurred, indicating some inositol depletion due to lithium. Elevation of Ins(1,4,5)P3 by lithium may be a general phenomenon in the central nervous system and peripheral tissues under non-rate-limiting concentrations of inositol.
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PMID:Lithium stimulates accumulation of second-messenger inositol 1,4,5-trisphosphate and other inositol phosphates in mouse pancreatic minilobules without inositol supplementation. 799 41

To understand the effects of acetylcholine (ACh) on fluid-absorbing epithelia, we carried out experiments on Necturus gallbladder epithelium. Binding studies with 1-quinuclidinyl[phenyl-4(N)-3H]benzilate (QNB) demonstrated that Necturus gallbladder epithelial cells express high-affinity muscarinic receptors. The effects of ACh and carbachol were exerted from the basolateral surface and consisted of a transient hyperpolarization of both cell membranes and a concomitant decrease in the apparent fractional resistance of the apical membrane. Atropine blocked both effects. ACh also elicited transient elevations of inositol 1,4,5-trisphosphate and intracellular free calcium ([Ca2+]i) levels, the latter by both release from intracellular stores and basolateral influx. The phospholipase C antagonist U-73122 inhibited the effects of ACh, whereas inhibition of prostaglandin and guanosine 3',5'-cyclic monophosphate synthesis with indomethacin or methylene blue, respectively, had no effect. In conclusion, Necturus gallbladder epithelium expresses muscarinic receptors in the basolateral membrane. Receptor activation stimulates phospholipase C and elevates cellular levels of inositol 1,4,5-trisphosphate and [Ca2+]i. The elevation in [Ca2+]i activates K+ channels but apparently not Cl- channels.
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PMID:Muscarinic stimulation of gallbladder epithelium. I. Electrophysiology and signaling mechanisms. 827 20

1. [3H]Noradrenaline (NA) AND [14C]acetylcholine (ACh) released by electrical field stimulation were measured simultaneously in strips from the body of rat urinary bladder. 2. [3H]NA and [14C]ACh release was greater during continuous stimulation (CS; 10 Hz, 100 shocks) or in the presence of eserine than during intermittent train stimulation (IS; 10 Hz, 10 shocks every 5 s, 10 times). Atropine (1 microM) or pirenzepine (0.05-0.1 microM) blocked the CS- or eserine-facilitated release. 3. The protein kinase C (PKC) activator phorbol dibutyrate (PDB; 0.05 and 0.5 microM) increased the release of both [3H]NA and [14C]ACh in a concentration-dependent manner. Atropine blocked the PDB-induced facilitation of ACh release but not the facilitation of NA release. 4. The protein kinase A (PKA) activator 8-Br-cAMP did not affect ACh release but enhanced NA release. 5. The PKC inhibitor H-7 (50-100 microM) inhibited the CS- or eserine-facilitated release of both ACh and NA, but did not affect the non-facilitated release evoked by IS. H-7 also inhibited 0.5 microM PDB-induced facilitation of ACh release but not NA release. 6. Down-regulating PKC by pretreatment for 30 min with 5 microM PDB decreased the facilitated release of ACh and the eserine-induced facilitation of NA release. 7. Electrically evoked contractions of the bladder strips exhibited a biphasic response to PDB (2.5 microM), which consisted of an initial enhancement of the peak amplitude and area followed after 20 min by an inhibition of contractions. H-7 inhibited the electrically evoked contractions in a dose-dependent fashion. 8. It is concluded that a phospholipase C-PKC signal transduction pathway is essential for muscarinic receptor-induced facilitation of ACh and NA release but is not involved in the non-facilitated release of transmitters in the rat urinary bladder.
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PMID:M1 muscarinic receptor-induced facilitation of ACh and noradrenaline release in the rat bladder is mediated by protein kinase C. 891 Feb 12

1. Cytosolic Ca2+ concentration ([Ca2+]i) during exposure to acetylcholine or caffeine was measured in mouse duodenal myocytes loaded with fura-2. Acetylcholine evoked a transient increase in [Ca2+]i followed by a sustained rise which was rapidly terminated after drug removal. Although L-type Ca2+ currents participated in the global Ca2+ response induced by acetylcholine, the initial peak in [Ca2+]i was mainly due to release of Ca2+ from intracellular stores. 2. Atropine, 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, a muscarinic M3 antagonist), pirenzepine (a muscarinic M1 antagonist), methoctramine and gallamine (muscarinic M2 antagonists) inhibited the acetylcholine-induced Ca2+ release, with a high affinity for 4-DAMP and atropine and a low affinity for the other antagonists. Selective protection of muscarinic M2 receptors with methoctramine during 4-DAMP mustard alkylation of muscarinic M3 receptors provided no evidence for muscarinic M2 receptor-activated [Ca2+]i increase. 3. Acetylcholine-induced Ca2+ release was blocked by intracellular dialysis with a patch pipette containing either heparin or an anti-phosphatidylinositol antibody and by external application of U73122 (a phospholipase C inhibitor). 4. Acetylcholine-induced Ca2+ release was insensitive to external pretreatment with pertussis toxin, but concentration-dependently inhibited by intracellular dialysis with a patch pipette solution containing an anti-alpha q/alpha 11 antibody. An antisense oligonucleotide approach revealed that only the Gq protein was involved in acetylcholine-induced Ca2+ release. 5. Intracellular applications of either an anti-beta com antibody or a peptide corresponding to the G beta gamma binding domain of the beta-adrenoceptor kinase 1 had no effect on acetylcholine-induced Ca2+ release. 6. Our results show that, in mouse duodenal myocytes, acetylcholine-induced release of Ca2+ from intracellular stores is mediated through activation of muscarinic M3 receptors which couple with a Gq protein to activate a phosphatidylinositol-specific phospholipase C.
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PMID:Specific Gq protein involvement in muscarinic M3 receptor-induced phosphatidylinositol hydrolysis and Ca2+ release in mouse duodenal myocytes. 917 86


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