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)

Endothelial cells can produce contracting factors; endothelin, a 21-amino acid peptide that can control local vascular tone, is the most potent of these factors. Of the three isoforms of endothelin, endothelial cells appear to release primarily endothelin-1. The peptide is formed from its precursor big endothelin via the activity of the endothelin converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1, and the calcium ionophore A23187. In vascular smooth muscle cells, endothelin binds to a specific receptor that activates phospholipase C and leads to the formation of inositol trisphosphate, diacylglycerol, and increased intracellular calcium levels. In certain blood vessels, the endothelin receptor is linked to a voltage-operated calcium channel via a Gi protein. This may explain why calcium antagonists inhibit endothelin-induced contractions only in certain blood vessels. In the human forearm circulation, calcium antagonists of different classes prevent endothelin-induced contractions. In hypertension, the circulating endothelin levels appear to be normal, whereas the vascular sensitivity to the peptide is reduced in most vascular tissues, but normal and enhanced responses have also been reported. In atherosclerosis and other forms of vascular disease, circulating endothelin levels are augmented, a phenomenon that may be related to an increased formation of the peptide induced by modified forms of low-density lipoproteins.
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PMID:Endothelin. 172 99

Platelet-activating factor (PAF), a unique phospholipid mediator, possesses potent proinflammatory, smooth-muscle contractile and hypotensive activities, and appears to be crucial in the pathogenesis of bronchial asthma and in the lethality of endotoxin and anaphylactic shock. Despite this, little is known of the molecular properties of the PAF receptor and related signal transduction systems. Although several lines of evidence suggest that activation of the PAF receptor stimulates phospholipase C and subsequent inositol trisphosphate formation through G protein(s), the PAF receptor and calcium channel are reported to show a close relation. As a first approach to cloning lipid autacoid receptors, we have isolated complementary DNA for the PAF receptors. Our strategy involved gene expression in Xenopus laevis oocytes and electrophysiological detection of PAF-induced responses. Sequence analysis indicates that the receptor belongs to the superfamily of G protein-coupled receptors.
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PMID:Cloning by functional expression of platelet-activating factor receptor from guinea-pig lung. 184 31

In the rat vasculature, a single alpha 1-adrenoceptor may be coupled to two distinct G proteins, one of which regulates phospholipase C activity and is insensitive to pertussis toxin, and another which regulates calcium channel function and is highly sensitive to inhibition by pertussis toxin. alpha 1-Adrenoceptor agonists may in theory activate both pathways, but the efficiency of alpha 1-adrenoceptor coupling to the pertussis-toxin-insensitive pathway is low relative to the other pathway that couples the alpha 1-adrenoceptor to calcium channels. As such, only full agonists with high intrinsic efficacy can activate both pathways, whereas partial agonists, by virtue of their lower intrinsic efficacies, are less able to activate the pertussis-toxin-insensitive pathway, thereby rendering partial alpha 1-adrenoceptor agonists more sensitive than full alpha 1-adrenoceptor agonists to inhibition by calcium channel blockers and pertussis toxin.
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PMID:Interaction of vascular alpha-1 adrenoceptors with multiple signal transduction pathways. 184 21

1. We have investigated the modification of catecholamine efflux and inositol phosphate formation in cultured adrenal chromaffin cells by tetradecanoyl phorbol acetate (TPA) and inhibitors of diacylglycerol kinase (R 59,022) and diacylglycerol lipase (RG 80267), the two principal pathways of diacylglycerol metabolism. 2. TPA (1 nM to 1 microM) elicited a slow, calcium-dependent, sustained release of noradrenaline, which was partially blocked by the dihydropyridine calcium channel blocker (-)-202,791 and potentiated by the channel enhancer (+)-202,791. 3. R 59,022 enhanced noradrenaline efflux at 30 and 50 microM, while the lipase inhibitor RG 80267 failed to elicit release. 4. Neither R 59,022 nor RG 80267 affected bradykinin- or histamine-stimulated release, but both drugs substantially attenuated nicotine- and high K(+)-stimulated release. 5. Pretreatment for 10 min with TPA (but not the relatively inactive 4-methoxy TPA) or the non-phorbol protein kinase C stimulator mezerein potently inhibited bradykinin- and histamine-stimulated accumulation of total [3H]-inositol phosphate; inhibition of [3H]-inositol phosphate formation was also seen with 24 h TPA treatment. 6. Neither R 59,022 nor RG 80267, separately or together, affected bradykinin-stimulated [3H]-inositol phosphate formation. 7. Thus while the mechanism exists for inhibition of formation of inositol phosphates by stimulation of protein kinase C, these studies failed to show that this mechanism is activated by agonists acting on phospholipase C linked receptors.
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PMID:Influence of phorbol esters, and diacylglycerol kinase and lipase inhibitors on noradrenaline release and phosphoinositide hydrolysis in chromaffin cells. 196 97

The present study characterizes cellular calcium stores that are sensitive to norepinephrine and caffeine in arteries from deoxycorticosterone acetate hypertensive rats. Mesenteric arteries from normotensive and hypertensive rats were excised and cut into helical strips for isometric force recording. In calcium-free solution, phasic contractile responses to norepinephrine (5.9 x 10(-9) to 5.9 x 10(-6) M), but not caffeine (0.3-30 mM), were greater in hypertensive arteries. D-600, a calcium channel blocker, or removal of the endothelium did not alter phasic contractions to norepinephrine or caffeine. In contrast, contractions to both norepinephrine and caffeine were inhibited by ryanodine, a drug that depletes calcium from intracellular stores. An inhibitor of phospholipase C (2-nitro-4-carboxyphenyl N,N-diphenylcarbamate) attenuated contractions to norepinephrine but not those to caffeine. The augmented response to norepinephrine in hypertensive rats did not occur early after implantation of the mineralocorticoid, suggesting that this vascular change may not play a role in the development of high blood pressure in this experimental model. The augmented response to norepinephrine was reduced in mineralocorticoid-treated rats maintained on a low sodium diet, and these rats had blood pressures in the normotensive range. Because contractile responses to caffeine were not enhanced in arteries from hypertensive rats, we conclude that the cellular store for calcium is not enlarged compared with that in normotensive arteries. In contrast, the mobilization of calcium from cellular stores by norepinephrine is augmented in mineralocorticoid hypertension. This augmented response may be linked to altered phospholipase C activity and thus to an augmented action of inositol trisphosphate that releases calcium from intracellular sites.
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PMID:Agonist-sensitive calcium stores in arteries from steroid hypertensive rats. 202 5

The carboxy terminal homologue of angiotensin II (Ang II), Ang-(3-8) or hexapeptide, was used as a model peptide to examine the types of receptor mechanisms involved in calcium mobilization in cultured vascular smooth muscle cells. Hexapeptide did not produce tachyphylaxis but did produce a sustained increase in intracellular calcium. Differences in the increase in intracellular calcium [( Ca2+]i) and the pattern of inositol phosphate production indicate that Ang-(3-8) and maximal concentrations of Ang II mobilize calcium through different mechanisms. The calcium-mobilizing mechanisms that predominate appear to depend on the concentration of angiotensin. Concentrations of Ang II greater than 10(-8) M produce sharp calcium transients in which the [Ca2+]i returns close to baseline within 1 minute after stimulation, but concentrations of Ang II equal to or less than 3 x 10(-9) M result in a plateau increase in calcium. Pretreatment with Bordetella pertussis toxin does not abolish either the calcium transient induced by Ang II or the plateau phase induced by Ang-(3-8), indicating that the GTP-transducing protein that couples the receptor to phospholipase C or, possibly, a receptor-operated calcium channel is not Bordetella pertussis toxin sensitive.
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PMID:Regulation of cytosolic calcium by angiotensins in vascular smooth muscle. 211 11

Cultured aortic smooth muscle cells from SHR proliferate more actively than cells normotensive control animals. This experimental data may be related to the hypertensive arteriopathy which mainly proceeds from media dystrophy made of hypertrophy, hyperplasia and excessive protein secretion of the smooth muscle cells. In order to precise the molecular cause of the phenomenon and the eventual action of calcium channel blockers on the development of this organic characteristic of hypertension, we have compared the responses of cultured cells from both SH and WKY rats to various agents in the absence or presence of verapamil. Cell proliferation, phospholipase C activation, and c-jun and c-fos oncogene expressions were measured in both cultures under the same conditions. The mitogenic actions of both foetal calf serum (FCS) and angiotensin II are two times more important on SH than on WKY rat cells. However, while inositol phosphate production elicited by angiotensin in also doubled in SHR cultures versus WKY ones. FCS-induced PLC activation is equivalent in both types of cells. The proto-oncogenes are more intensively expressed when WKY cells are stimulated by FCS than in the presence of angiotensin, but, contrarily to angiotensin, serum is not more active upon this parameter in SHR cultures. Verapamil (from 10(-8) M to 10(-5) M) decreases by 30% the proliferative effect of serum in both SH and WKY rat cells but is not significantly active on angiotensin stimulation. It also depresses in the same proportion the serum-induced inositol phosphate production and oncogene expressions without altering the responses to angiotensin. Nicardipine is less active than verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Role of external calcium on the growth of aortic smooth muscle cells in SHR]. 212 55

The alpha 1-adrenergic receptor has been shown to mediate the release of arachidonic acid in FRTL5 thyroid cells and MDCK kidney cells. In primary cultures of spinal cord cells, norepinephrine stimulated release of arachidonic acid (from neurons only) and turnover of inositol phospholipids (from neurons and glia) via alpha 1-adrenergic receptors. These two responses were dissociated by treatment with phorbol ester and pertussis toxin, which inhibited production of inositol phosphates with no appreciable effect on release of arachidonic acid. Extracellular calcium was required for release of arachidonic acid, but not for production of inositol phosphates. The calcium channel blockers nifedipine and verapamil inhibited release of arachidonic acid only. However, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), a compound that blocks intracellular calcium release, diminished production of inositol phosphates, but had little effect on release of arachidonic acid. These results suggest that alpha 1-adrenergic receptors couple to release of arachidonic acid in primary cultures of spinal cord cells by a mechanism independent of activation of phospholipase C, possibly via the activation of phospholipase A2.
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PMID:Alpha 1-adrenergic receptor mediates arachidonic acid release in spinal cord neurons independent of inositol phospholipid turnover. 215 16

The effect of fluoride (NaF; 10 mM sodium fluoride plus deferoxamine to chelate contaminating aluminum) and fluoride plus aluminum fluorides (AlF; 10 mM sodium fluoride plus 20 microM aluminum chloride) on activation of rabbit femoral arteries was investigated. AlF and NaF produced large increases in stress (force/muscle cross-sectional area), but temporal changes were dissimilar, as were other indices of muscle activation. Stress produced by NaF developed slowly and only after a long delay of about 15 min, whereas stress produced by AlF developed rapidly after a delay of only about 5 min. NaF-induced contractions were more sustained than AlF-induced contractions. Both AlF and NaF increased the level of cross-bridge phosphorylation and the velocity of muscle shortening, but at comparable stresses, AlF produced greater increases than did NaF. AlF produced a large increase in lP production, whereas NaF produced a small increase. Also, AlF-induced stress was largely insensitive to inhibition by the calcium channel blocker, nifedipine (1 microM), whereas NaF-induced stress was largely inhibited by nifedipine. However, in tissues depleted of calcium, both agents produced potent contractions when CaCl2 was added back to the tissues (EC50 values for AlF, NaF, histamine, phenylephrine and KCl were, respectively, 0.057, 0.085, 0.11, 0.11 and 0.23 mM). AlF, but not NaF, strongly desensitized arteries to phenylephrine, causing a 73% reduction in the ability of phenylephrine to achieve maximum steady-state stress. These data suggest that fluoride contracted rabbit femoral arteries by stimulating L-type calcium channels, and that aluminum fluoride stimulated phospholipase C, producing additional muscle activation.
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PMID:Differential activation of rabbit femoral arteries by aluminum fluoride and sodium fluoride. 216 93

Cultured endothelial cells release a potent vasoconstrictor peptide, endothelin. Cumulative addition of synthetic endothelin to isolated rabbit aortic rings elicited a concentration-dependent increase in contractile tension which was endothelium-independent. In cultured rabbit vascular smooth muscle cells loaded with the fluorescent dye fura 2, endothelin induced a concentration-dependent increase in [Ca2+]i over the range of 0.01 to 100 nM. Moreover, in the absence of extracellular Ca2+, endothelin could still induce an increase in [Ca2+]i. In addition, endothelin stimulated 45Ca2+ efflux from preloaded vascular smooth muscle cells in the presence and absence of extracellular Ca2+, as well as stimulating 45Ca2+ influx in a concentration-dependent manner. Measurement of inositol phosphates in [3H]-myoinositol-labelled vascular vascular trisphosphate. Unlabelled endothelin inhibited (125I)-endothelin binding to cultured rabbit vascular smooth muscle cells in a concentration-dependent manner. Binding was not inhibited by other vasoactive hormones or calcium channel ligands, suggesting cell surface receptors specific for endothelin. We conclude that one of the initial membrane events in the action of endothelin is to induce phospholipase C-stimulated PIP2 hydrolysis and that this signalling mechanism is initiated by endothelin/receptor interaction at the plasma membrane.
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PMID:Endothelin action on vascular smooth muscle involves inositol trisphosphate and calcium mobilization. 253 80


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