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)

The cardiovascular effects of bradykinin require additional vasoactive mediators for a fully balanced response. This includes arachidonic acid (eicosatetraenoic acid) and its metabolites, the eicosanoids (prostaglandins, leukotrienes, thromboxanes, and others). Eicosanoid generation by bradykinin is started by binding of the peptide to specific B2 receptors at the plasma membrane. This initiates G-protein coupled stimulation of phospholipase C, IP3-induced increases in cytosolic Ca2+, and stimulation of protein kinase C. Arachidonic acid is liberated from membrane phospholipids primarily via Ca(2+)-induced stimulation of phospholipase A2 and converted into tissue-specific eicosanoids by enzymes in the vicinity. In vascular tissue, most of the available arachidonic acid is converted into vasodilator prostaglandins, i.e., prostacyclin (PGI2) and prostaglandin E2 (PGE2). These prostaglandins are involved in vasodilator actions of the kinins. There is also some evidence for generation of vasoconstrictor eicosanoids, such as thromboxane A2, under certain conditions. The biological significance of kinin-related prostaglandin formation becomes apparent after inhibition of kinin breakdown by ACE inhibitors. These compounds prevent generation of vasoconstrictor angiotensin II and stimulate endothelial eicosanoid formation via local kinin accumulation. There is evidence suggesting that kinin-induced prostaglandin generation contributes to anti-ischemic, inotropic, and blood pressure-lowering effects of the compounds. This also includes inhibition of polymorphonuclear leukocyte (PMN) accumulation in injured myocardial tissue, which is antagonized by PGI2-related pathways, stimulated by ACE inhibition and/or bradykinin.
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PMID:Role of prostaglandins in the cardiovascular effects of bradykinin and angiotensin-converting enzyme inhibitors. 128 33

Renin-angiotensin (RA) system plays an important role in cardiovascular homeostasis. Here, we have described the recent progress in our study of renin release as well as the cellular action of angiotensin II. (1) Microdissection of an isolated afferent artery with or without macula densa (MD) has revealed that renin release is regulated by NaCl exposure to MD. Furosemide, prostaglandins (PGE2 and PGI2) and adenosine modulate its function. (2) Angiotensin (ang) II increases cytosolic free calcium and induces the formation of inositolphosphates in vascular smooth muscle cells. Deduced protein structure of ang II receptor (AT1-R) cDNA has indicated the presumed link of AT1-R with phospholipase C. Through the cellular action, ang II has been reported to regulate gene expression.
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PMID:[Mechanism of renin release and cellular action of angiotensin II]. 129 35

Thrombin is thought to stimulate responsive cells by cleaving cell-surface receptors coupled to intracellular second-messenger-generating enzymes via G-proteins. In order to understand this process better, we have examined the regulation of adenylate cyclase by thrombin in the megakaryoblastic HEL cell line and compared it with platelets. A notable difference was found. In HEL-cell membrane preparations, thrombin inhibited cyclic AMP (cAMP) formation by a pertussis-toxin-sensitive mechanism comparable with that observed in platelets. In contrast, when added to intact HEL cells, thrombin activated adenylate cyclase and caused an increase in cAMP formation synergistic with that produced by forskolin and prostaglandin I2. This increase, which was not seen with platelets, was accompanied by an increase in cAMP metabolism by phosphodiesterase. Like other responses to thrombin, the increase in cAMP formation required proteolytically active thrombin and was subject to homologous desensitization. An equivalent response could be evoked by the addition of a polypeptide, derived from the N-terminus of the thrombin receptor, that has been shown to activate the receptor. The effects of thrombin could not, however, be reproduced by the addition of phorbol ester and the Ca2+ ionophore, A23187, nor be prevented with inhibitors of arachidonate metabolism. Preincubation of the cells with adrenaline, which inhibited Gs-mediated activation of adenylate cyclase, or pertussis toxin, which inhibited phospholipase C activation, had no effect on thrombin-induced cAMP formation. These results suggest that thrombin can regulate cAMP formation by two different mechanisms. First, thrombin can inhibit adenylate cyclase in a Gi-dependent manner. This effect predominates in HEL-cell membrane preparations, as it does in platelets, but is not detectable when thrombin is added to intact HEL cells. Instead, in intact HEL cells thrombin activates adenylate cyclase. Although clearly receptor-mediated, this response does not appear to involve Gi, Gs, protein kinase C, eicosanoid formation or changes in the cytosolic Ca2+ concentration.
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PMID:Dual regulation of cyclic AMP formation by thrombin in HEL cells, a leukaemic cell line with megakaryocytic properties. 131 10

Recent studies have shown that mastoparan, an amphiphilic peptide derived from wasp venom, accelerates guanine nucleotide exchange and GTPase activity of purified GTP-binding proteins. In the present study we have examined the functional consequences of exposure of intact human platelets to mastoparan. Mastoparan promoted rapid (less than or equal to 1 min) dose-dependent increases in 5-hydroxy[14C]tryptamine and beta-thromboglobulin release from dense-granule and alpha-granule populations respectively. The exocytotic response did not result from a lytic effect of mastoparan and occurred in the complete absence of platelet shape change and aggregation. Liberation of [3H]arachidonate and increases in cytosolic [Ca2+] (detected with fura 2) were not observed in platelets stimulated with mastoparan. Similarly, in platelets preloaded with [3H]inositol during reversible electroporation, mastoparan did not cause the accumulation of [3H]inositol phosphates. Mastoparan-induced secretion was unaffected by preincubation with either the protein kinase C inhibitor staurosporine (10 nM-10 microM) or prostacyclin (PGI2; 100 ng/ml) and was not accompanied by phosphorylation of the 45 kDa protein kinase C substrate or the 20 kDa protein normally associated with platelet activation. The G-protein inhibitor guanosine 5'-[beta-thio]diphosphate (GDP[S]; 1 mM) attenuated the secretion induced by mastoparan in both intact and saponin-permeabilized platelets. Encapsulation of GDP[S] during reversible permeabilization inhibited mastoparan-induced secretion, providing evidence for an intracellular action of GDP[S]. In all these studies thrombin (0.05-0.2 unit/ml) elicited characteristic responses, and thrombin-induced secretion was inhibited by staurosporine, PGI2 and GDP[S]. Mastoparan also increased intra-platelet cyclic AMP in a dose-dependent manner. Mastoparan and PGI2 increased 32P incorporation into a protein of approx. 24 kDa, whereas phosphorylation of a 50 kDa substrate was only seen in PGI2-stimulated platelets. These results indicate that mastoparan promotes secretion by a mechanism which does not involve stimulation of phospholipase C and suggest that the secretory event may result either from a direct fusogenic action of mastoparan and/or from stimulation of the putative exocytosis-linked G-protein, Ge.
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PMID:Mastoparan promotes exocytosis and increases intracellular cyclic AMP in human platelets. Evidence for the existence of a Ge-like mechanism of secretion. 131 May 99

Extracellular ATP and UTP caused increases in the concentration of cytoplasmic free calcium ([Ca2+]i) and the intracellular level of inositol 1,4,5-trisphosphate (IP3), a second messenger for calcium mobilization, prior to the release of prostacyclin (PGI2) from cultured bovine pulmonary artery endothelial (BPAE) cells. The agonist specificity and dose-dependence were similar for nucleotide-mediated increases in IP3 levels, [Ca2+]i and PGI2 release. An increase in [Ca2+]; and PGI2 release was observed after addition of ionomycin, a calcium ionophore, to BPAE cells incubated in a calcium-free medium. The addition of ATP to the ionomycin-treated cells caused no further increase in [Ca2+]i or PGI2 release. The inability of ATP to cause an increase in [Ca2+]i or PGI2 release in ionomycin-treated cells was apparently due to the ionomycin-dependent depletion of intracellular calcium stores since the subsequent addition of extracellular calcium caused a significant increase in both [Ca2+]i and PGI2 release. Introduction of BAPTA, a calcium buffer, into BPAE cells inhibited ATP-mediated increases in [Ca2+]i and PGI2 release, further evidence that PGI2 release is dependent upon an increase in [Ca2+]i. The increase in [Ca2+]i elicited by ATP apparently caused the activation of a calmodulin-dependent phospholipase A2 since trifluoperazine, an inhibitor of calmodulin, and quinacrine, an inhibitor of phospholipase A2, prevented the stimulation of PGI2 release by ATP. Furthermore, ATP caused the specific hydrolysis of [14C]arachidonyl-labeled phosphatidylcholine and the generation of free arachidonic acid, the rate-limiting substrate for PGI2 synthesis, prior to the release of PGI2 from BPAE cells. These findings suggest that the increase in PGI2 release elicited by ATP and UTP is at least partially dependent upon a phospholipase C-mediated increase in [Ca2+]i and the subsequent activation of a phosphatidylcholine-specific phospholipase A2. ATP analogs modified in the adenine base or phosphate moiety caused PGI2 release with a rank order of agonist potency of adenosine 5'-O-(2-thiodiphosphate) (ADP beta S) greater than 2-methylthioATP (2-MeSATP) greater than ATP, whereas alpha, beta methyleneATP and beta, gamma methyleneATP had no effect on PGI2 release.
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PMID:Mechanisms by which extracellular ATP and UTP stimulate the release of prostacyclin from bovine pulmonary artery endothelial cells. 131 59

The receptor agonist-mediated hydrolysis of phosphoinositides and production of prostacyclin were studied in murine cerebral endothelial cells (MCEC). Of 11 neurotransmitters and neuromodulators examined, carbachol, noradrenaline (NE), bradykinin, and thrombin significantly increased 3H-inositol phosphate accumulation in the presence of LiCl (20 mM). The maximal stimulation of [3H]inositol monophosphate ([3H]IP1) reached approximately 11, 11, seven, and four times the basal levels for carbachol, NE, bradykinin, and thrombin, respectively. The EC50 values of IP1 accumulation for carbachol and NE were 34 and 0.16 microM, respectively. The muscarinic antagonists, atropine and pirenzepine, blocked the carbachol-induced IP1 accumulation with Ki values of 0.3 and 30 nM, respectively. The adrenergic antagonist, prazosin, blocked NE-induced IP1 accumulation with a Ki of 0.1 nM. The calcium ionophore A23187, histamine, glutamate, vasopressin, serotonin, platelet activating factor, and substance P did not stimulate IP1 accumulation. A23187, bradykinin, and thrombin stimulated prostacyclin release to approximately four, four, and two times the basal levels, respectively, whereas carbachol and NE had little effect upon prostacyclin release. These results suggest that the activation of phospholipase C and of phospholipase A2 in MCEC are regulated separately.
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PMID:Receptor-linked hydrolysis of phosphoinositides and production of prostacyclin in cerebral endothelial cells. 131 55

Eicosanoids (prostaglandins, leukotrienes, thromboxane A2 and other metabolites of C-20 polyunsaturated fatty acids) have numerous effects in the cardiovascular system. Direct inotropic actions have been repeatedly described, but appear in only very few cases to be due to direct modification of the inotropic state of the heart. Specific eicosanoid receptors have been identified on the surface of the sarcolemmal membrane. Signal transduction pathways in the cardiac myocyte involve the adenylate cyclase/cAMP system or stimulation of the phospholipase C/IP3 pathway. In general, concentrations of eicosanoids which affect myocardial contractility are higher as the response is less predictable than the effects on platelet function or vessel tone. Therefore, eicosanoid-induced extracardiac effects may be superimposed to more direct changes in the contractile state of the intact heart in vitro or in vivo. In contrast to non-failing hearts, there is a significant improvement of the contractile function in contractile failure ("stunning", ischemia, congestive heart failure) by vasodilating prostaglandins (e.g., PGI2). The mechanism of this action is still unknown.
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PMID:Inotropic actions of eicosanoids. 131 58

Endothelial cells produce the 21-amino acid peptide endothelin, which is formed from its precursor, big endothelin, via the activity of converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1, and hypoxia. In vascular smooth muscle, endothelin binds to a specific receptor (ETA-subtype), which activates phospholipase C, leads to the formation of inositol trisphosphate, diacylglycerol (which activates protein kinase C), and increased intracellular Ca2+. In certain blood vessels, the endothelin receptor on vascular smooth muscle is linked to a voltage-operated Ca2+ channel via a G-protein. This explains why Ca2+ antagonists inhibit endothelin-induced contractions in certain, but not all, blood vessels. In the human forearm circulation, Ca2+ antagonists do prevent endothelin-induced contractions and unmask endothelin-induced vasodilation mediated by endothelial prostacyclin production (via the ETB-receptor). The pulmonary circulation plays an important role in the metabolism of endothelin, as the lungs take up large quantities of the peptide during passage. Endothelin has profound vasoconstrictor effects in the pulmonary circulation (and also in bronchial tissue), and its production is augmented in pulmonary hypertension. In systemic hypertension, the circulating endothelin levels appear to be normal. In atherosclerosis and other forms of vascular disease, circulating endothelin levels are increased. Thus, endothelin is a potent mediator in the systemic and pulmonary circulation and, in particular, in diseases of the vasculature.
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PMID:Endothelin: systemic arterial and pulmonary effects of a new peptide with potent biologic properties. 133 60

The cascade of transmembrane signaling events that follow the occupancy of the interleukin 1 receptor remain poorly defined. We examined potential postreceptor transduction systems involved in human recombinant interleukin 1-beta-stimulated prostacyclin synthesis in human umbilical vein endothelium. Challenge of human umbilical vein endothelium monolayers with recombinant interleukin 1-beta resulted in dose- and time-dependent tritiated arachidonate release and prostacyclin synthesis consistent with phospholipase A2 activation. Prostacyclin synthesis after interleukin 1-beta (10 ng/ml) was detected 4 hours after stimulation and peaked at 16 to 24 hours. To examine whether interleukin 1-beta produced early activation of a phosphoinositide-specific phospholipase C, human umbilical vein endothelium monolayers were labeled with tritiated-2-myoinositol and inositol polyphosphates recovered after interleukin 1-beta stimulation. In contrast to the potent agonist, alpha-thrombin, interleukin 1-beta failed to significantly increase inositol phosphate production when examined for up to 4 hours. The absence of a significant increase in the Cai++ secretagogue, IP3, was confirmed in human umbilical vein endothelium monolayers loaded with the Ca++ photoprotein probe aequorin. Basal aequorin luminescence was unaltered after interleukin 1-beta (0 to 2 hours), whereas both alpha-thrombin and Ca++ ionophore A23187 produced rapid rises in Cai++. The intracellular Ca++ antagonist BAPTA and the extracellular Ca++ chelator EGTA produced significant inhibition of interleukin 1-beta-stimulated prostacyclin generation at 4 to 8 hours, suggesting either an indirect inhibitory effect of these agents on phospholipase A2 activity or that an increase in Ca++ may be a late event in the transduction scheme after interleukin 1 stimulation. Interleukin 1-beta-stimulated protein kinase C, phospholipase D, and adenylyl cyclase activities (0 to 4 hours) were unchanged from controls. Despite the absence of increased plasma membrane protein kinase C activity up to 4 hours after interleukin 1, pretreatment of human umbilical vein endothelium monolayers with staurosporine or phorbol myristate acetate (18 hours) to reduce protein kinase C activities, significantly attenuated the interleukin 1-stimulated prostanoid responses at 16 hours but not at 4 hours. Furthermore, short (5 minute) pretreatment with phorbol myristate acetate dramatically augmented interleukin 1-mediated prostacyclin responses in synergistic fashion, suggesting that protein kinase C may modulate interleukin 1 signal transducing pathways. In summary, these studies suggest that interleukin 1-beta-mediated endothelial cell phospholipase A2 activity and prostacyclin synthesis occur via a novel transducing pathway that does not involve early activation of phospholipase C, phospholipase D, or adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interleukin 1-stimulated prostacyclin synthesis in endothelium: lack of phospholipase C, phospholipase D, or protein kinase C involvement in early signal transduction. 133 14

The glomerular mesangial cell is a specialized pericyte with multiple functional capabilities including contraction. Mesangial contraction may reduce the glomerular filtration surface area and hence the ultrafiltration coefficient, Kf. Cultured mesangial cells convert arachidonic acid into biologically active eicosanoids which are either contractile (thromboxane A2 [TxA2], prostaglandin F2 alpha [PGE2 alpha]) or relaxant (PGE2, PGI2). The addition of TxA2 analogues, PGE2 or sulfidopeptide leukotrienes (LTC4 and LTD4) stimulated contraction of cultured mesangial cells with threshold responses at approximately 1 nM and maximum responses at 1 microM. PGE2 and PGI2 antagonized mesangial contraction induced by TxA2 analogues. Contraction was enhanced by inhibiting mesangial cyclooxygenase with nonsteroidal antiinflammatory drugs (NSAID). Contractile eicosanoids stimulated phospholipase C thereby elevating intracellular inositol trisphosphate and cytosolic free Ca2+ concentration ([Ca2+]i). Vasorelaxant prostanoids stimulated adenylate cyclase, increasing intracellular cyclic AMP. We conclude that eicosanoids control mesangial contractility by regulating [Ca2+]i and cAMP. NSAID increase mesangial reactivity by blocking the inhibitory effects of endogenous vasodilator eicosanoids, with potential consequences on glomerular hemodynamics.
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PMID:Eicosanoids, mesangial contraction, and intracellular signal transduction. 141 47


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