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)

Homologous desensitization of muscarinic acetylcholine receptors (mAChR) was studied using primary cultures of corticostriatal neurons from neonatal rats. Prolonged incubation with carbachol attenuated phospholipase C responsiveness to muscarinic agonists and decreased the number of cell surface mAChR, as measured by binding of N-[3H] methylscopolamine to neuronal monolayers. When neurons were exposed to carbachol for 15 min, 40% of the mAChR lost from the membrane domain was recovered in the cytosol; a decrease of the total neuronal receptors was detected following an incubation with the agonist lasting longer than 15 min. Both 8-Br-cyclic AMP and forskolin neither affected N-[3H]methylscopolamine binding to cell monolayers or did they prevent the agonist-mediated mAChR desensitization. 8-Br-cyclic GMP also failed to decrease mAChR number. Pertussis toxin failed to prevent the homologous desensitization of mAChR under conditions that blocked the agonist-mediated inhibition of forskolin-stimulated cyclic AMP formation. The phorbol ester 12-O-tetradecanoyl-phorbol-12, 13-acetate induced a concentration-dependent decrease of N-[3H]methylscopolamine binding to neuronal monolayers. However, the protein kinase C inhibitors sphingosine and the ganglioside monosialosyl-gangliotetraglicosylceramide inhibited the 12-O-tetradecanoyl-phorbol-12,13-acetate-induced but not the agonist-induced desensitization of mAChRs. Furthermore, incubation with muscarinic agonists failed to translocate protein kinase C from cytosol to plasma membranes, as measured by binding of the phorbol ester [3H]-4-beta-phorbol-12,13-dibutyrate to neuronal monolayers. In corticostriatal neurons the agonist-induced desensitization and internalization of mAChR involves neither protein kinase C and protein kinase A activation nor changes in cyclic GMP and cyclic AMP content.
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PMID:Molecular mechanisms of homologous desensitization and internalization of muscarinic receptors in primary cultures of neonatal corticostriatal neurons. 215 46

The gene encoding the 49-kilodalton protein that undergoes light-induced phosphorylation in the Drosophila photoreceptor has been isolated and characterized. The encoded protein has 401 amino acid residues and a molecular mass of 44,972 daltons, and it shares approximately 42 percent amino acid sequence identity with arrestin (S-antigen), which has been proposed to quench the light-induced cascade of guanosine 3',5'-monophosphate hydrolysis in vertebrate photoreceptors. Unlike the 49-kilodalton protein, however, arrestin, which appears to bind to phosphorylated rhodopsin, has not itself been reported to undergo phosphorylation. In vitro, Ca2+ was the only agent found that would stimulate the phosphorylation of the 49-kilodalton protein. The phosphorylation of this arrestin-like protein in vivo may therefore be triggered by a Ca2+ signal that is likely to be regulated by light-activated phosphoinositide-specific phospholipase C.
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PMID:A 49-kilodalton phosphoprotein in the Drosophila photoreceptor is an arrestin homolog. 215 71

Cyclic nucleotide phosphodiesterase activity in rat heart microsomes is attributable to several isoenzymatic forms: a cyclic AMP-specific, a cyclic GMP-specific, and a cyclic GMP-stimulated enzyme. Incubation of microsomes with an exogenous phospholipase C (C. welchii) induced a marked stimulation (+126%) of cyclic AMP phosphodiesterase and a moderate stimulation (+49%) of cyclic GMP-phosphodiesterase in the membrane-bound fraction. Besides, a notable fraction of activity was solubilized by the treatment. A parallel decrease in the activating effect of cyclic GMP on the hydrolysis of cyclic AMP was observed in the membranes (down to 18% of the control effect). It resulted from a marked stimulation of the basal activity, while the activated level was unaffected. The treatment by an exogenous phospholipase D induced more moderate modifications. The addition to microsomes of oleyl,acetyl-glycerol, but not of long chain-diacylglycerols, partly reproduced the phospholipase C effect. Phosphatidate also induced variations in phosphodiesterase activity, and could thus participate in the phospholipase effects. These results suggest that endogenous phospholipases, the activity of which is modulated by hormonal stimuli, might influence phosphodiesterase activity in cardiac membranes by producing phospholipid metabolites, with potential consequences on heart contractility.
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PMID:Phospholipid metabolism modulates cyclic nucleotide phosphodiesterase activity in rat heart microsomes. 216 7

Extracellular ATP, N6-(L-2-phenylisopropyl)adenosine (PIA) and other purinergic agonists inhibited atrial natriuretic peptide (ANP)-induced cGMP accumulation in FRTL-5 thyroid cells. These agonists were functionally classified into three groups. Group 1 agonists represented by ATP inhibited the ANP action in association with phospholipase C activation in a partially islet-activating protein (IAP, pertussis toxin)-sensitive manner. Group 2 including GTP and 8-bromoadenosine 5'-triphosphate acted similarly to Group 1 except for total insensitivity of the former to IAP. The IAP-insensitive portion of Group 1 actions and the actions of Group 2 as well as of A23187, a Ca2+ ionophore which mimicked the Group 2 agonist actions, were almost completely inhibited by phosphodiesterase inhibitors such as M & B 22948 (2-O-propoxyphenyl-8-azapurin-6-one) and 3-isobutyl-1-methylxanthine. Group 3 including PIA and AMP did not affect phospholipase C, but inhibited the ANP performance in an IAP-sensitive fashion. This action of Group 3 and the IAP-sensitive portion of Group 1 actions were insensitive to the phosphodiesterase inhibitors. We conclude that ATP and other Group 1 agonists attenuated the ANP-induced cGMP accumulation by at least two mechanisms: 1) stimulation of cGMP hydrolysis via a phospholipase C-Ca2(+)-phosphodiesterase system and 2) inhibition of cGMP generation, probably by an IAP-sensitive G-protein-mediated inactivation of the ANP-receptor-coupled guanylate cyclase. Group 2 agonists stimulate only the first mechanisms, whereas Group 3 agonists prefer the second one.
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PMID:Inhibition of atrial natriuretic peptide-induced cGMP accumulation by purinergic agonists in FRTL-5 thyroid cells. Involvement of both pertussis toxin-sensitive and insensitive mechanisms. 217 85

A previous study revealed that elevation of platelet cyclic GMP induced by a pharmacological activator of soluble guanylate cyclase, 3-morpholinosydnonimine (SIN-1), induced a major inhibition of Ca2+ influx caused by thrombin, as detected by monitoring the fluorescence of the Ca2+ indicator quin-2. In contrast, activation of phospholipase C as well as Ca2+ mobilization presumably promoted by inositol-1,4,5-trisphosphate was less affected by SIN-1 treatment. In the present study, the effects of SIN-1 on Ca2+ influx have been investigated in more detail using platelets loaded with millimolar concentrations of quin-2. Under these conditions, Ca2+ entry from the medium into the platelet cytoplasm could be followed either by detecting fluorescence quenching by Mn2+ or by determination of 45Ca2+ uptake. Both events were inhibited by SIN-1 in a dose-dependent manner. Furthermore, the inhibition of 45Ca2+ uptake and of fluorescence increase observed in the presence of extracellular Ca2+ displayed remarkably parallel dose-response curves, suggesting that elevation of cyclic GMP brought about by SIN-1 inhibits the opening of "receptor-operated channels" whose precise nature remains to be determined.
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PMID:Inhibition of calcium influx in thrombin-stimulated platelets by SIN-1, an activator of soluble guanylate cyclase. 248 86

The mechanism of vasodilator-induced inhibition of platelet aggregation was investigated in human platelets. Cyclic nucleotide-elevating vasodilators stimulated cAMP- or cGMP-dependent protein phosphorylation, inhibited the activation of both protein kinase C and myosin light chain kinase, and inhibited the thrombin-induced hydrolysis of phosphatidylinositol-4,5-bisphosphate without affecting its resynthesis. The results suggest that cAMP- and cGMP-elevating vasodilators both inhibit platelet aggregation at an early step of the activation cascade, presumably at the level of phospholipase C.
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PMID:Cyclic nucleotide elevating vasodilators inhibit platelet aggregation at an early step of the activation cascade. 253 41

The inhibitory effect of cyclic GMP on collagen-induced platelet activation was studied using 8-bromo cyclic GMP (8brcGMP) in washed rabbit platelets. Addition of collagen (1 micrograms/ml) to platelet suspension caused shape change and aggregation associated with thromboxane (TX) A2 formation. 8brcGMP (10-1000 microM) inhibited collagen-induced platelet aggregation and TXA2 formation in a concentration-dependent manner. 8brcGMP did not affect platelet cyclooxygenase pathways, but markedly inhibited collagen-induced arachidonic acid (AA) liberation from membrane phospholipids in [3H]AA-prelabeled platelets, indicating that the inhibitory effect of 8brcGMP on collagen-induced aggregation is due to an inhibition of AA liberation. In [32P]orthophosphate-labeled platelets, collagen stimulated phosphorylation of a 20,000 dalton (20-kD) and 40-kD proteins. 8BrcGMP stimulated phosphorylation of a specific protein having molecular weight of 46-kD and inhibited collagen-induced both 20- and 40-kD protein phosphorylation. Collagen could stimulate the AA liberation without activation of phospholipase C or Na+-H+ exchange, but could not in the absence of extracellular Ca2+. These findings suggest that cyclic GMP inhibits collagen-induced AA liberation which is mediated by an extracellular Ca2+-dependent phospholipase A2. However, cyclic GMP seems to inhibit the Ca2+-activated phospholipase A2 indirectly, since 8brcGMP had no effect on Ca2+ ionophore A23187-induced platelet aggregation or AA liberation. It is therefore suggested that cyclic GMP may regulate collagen-induced increase in an availability of extracellular Ca2+ which is responsible for phospholipase A2 activation in rabbit platelets.
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PMID:Inhibitory effect of 8-bromo cyclic GMP on an extracellular Ca2+-dependent arachidonic acid liberation in collagen-stimulated rabbit platelets. 254 81

1. Single smooth muscle cells were obtained from the rabbit portal vein by enzymic digestion and membrane currents under voltage clamp measured by whole-cell patch clamp technique. 2. When held at depolarized potentials, spontaneous outward currents (STOCs) were discharged; it is likely that these represent the cyclical storage and release within the cell of calcium in relation to Ca-activated K-channels. 3. Application of lower concentrations of carbachol (10(-5)M) or caffeine (10(-3)M) accelerated STOC discharge. Higher concentrations of caffeine (10(-2)M) or carbachol (10(-4)M), or noradrenaline (10(-5)M), produced an outward current of 1-5 nA which disappeared within 5-15s and which was considered to result from the discharge of calcium stores; STOC discharge was abolished for a period. 4. Ryanodine (10(-5)-10(-4)M) or a non-hydrolysable GTP analogue, GTP gamma S (10(-5)-10(-3)M) introduced into the cell abolished STOC discharge within 2-5 min. STOCs were large in cells filled with GDP beta S (10(-3)M) and the action of GTP gamma S introduced at various concentrations was antagonized. 5. GTP gamma S (10(-4)-10(-3)M) in the cell reduced or abolished outward current to caffeine (10(-2)M) noradrenaline (10(-5)M) or carbachol (10(-4)M); the effect on caffeine outward current was antagonized by GDP beta S (10(-3)M) introduced into the cell. GDP beta S reduced noradrenaline outward current but not caffeine outward current implying the existence of a G-protein step in noradrenaline-evoked Ca-store release, possibly regulating phospholipase C enzyme activity and D-myo inositol 1,4,5 trisphosphate formation. 6. If cyclic AMP (10(-3)M) or cyclic GMP (10(-3)M) was introduced into the cell, or 8-bromo cyclic AMP (0.5 x 10(-3)M) or 8-bromo cyclic GMP (0.5 x 10(-3)M) applied to the cell in the bathing solution, STOC discharge was only slightly affected. However, the outward current to caffeine applied after noradrenaline was much enhanced. 7. The results could be explained if cyclic GMP and cyclic AMP enhance calcium storage whereas GTP gamma S depletes calcium stores, an action antagonized by GDP beta S.
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PMID:Actions of guanine nucleotides and cyclic nucleotides on calcium stores in single patch-clamped smooth muscle cells from rabbit portal vein. 254 94

Angiogenin transiently depresses the cAMP level of rat aortic smooth muscle cells. The dose response is similar to angiogenin activation of the inositol-specific phospholipase C in this cell line [Moore, F. & Riordan, J.F. (1989) Biochemistry. Submitted]. The time course showed a maximal depression (28%) in cAMP at 2 min, followed by a return to that of unstimulated cells by 3.5 min. Angiogenin also inhibited isoproterenol stimulated cAMP formation, but the percentage depression in cAMP (9%) was less than that in cells treated with angiogenin alone (28%). In contrast angiogenin enhanced forskolin stimulation of adenylate cyclase, an effect previously linked with agonist activation of protein kinase C. The effect of angiogenin on cellular cAMP was abolished by pre-incubation with pertussis toxin. Angiogenin had no effect on cellular cGMP. These results are consistent with activation of adenylate cyclase Gi following exposure of the cells to angiogenin and provide further evidence for interaction between cellular signalling pathways.
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PMID:Angiogenin depresses aortic smooth muscle cell cAMP by a pertussis toxin sensitive mechanism. 255 Dec 76

The effects of adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP) and phorbol 12,13 dibutyrate (PDBu) on the Ca2+ sensitivity of the contractile elements in the rat mesenteric artery were investigated, using a method of permeabilizing smooth muscle with Staphylococcal alpha-toxin. Both cAMP and cGMP relaxed the permeabilized rat mesenteric artery at the intracellular Ca2+ concentrations [( Ca2+]i) held constant with Ca2+ EGTA buffer and Ca2+ ionophore, ionomycin. In addition, forskolin and sodium nitroprusside which activate adenylate and guanylate cyclases, respectively, also induced relaxation at a fixed [Ca2+]i. In contrast PDBu which stimulates protein kinase C caused an increase in force at a constant [Ca2+]i which could be partially reversed by cAMP or cGMP. These results indicate that second messengers exert direct control over smooth muscle Ca2+ sensitivity of the contractile elements, which is of physiologic and pharmacologic importance.
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PMID:Direct regulation of smooth muscle contractile elements by second messengers. 255 Dec 77


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