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)

We have characterized a membrane-bound phosphatidylcholine (PC) specific phospholipase C (PC-PLC) in plasma membranes from rat cardiac muscle, and have investigated the role of PC-PLC and PC-specific phospholipase D (PC-PLD) activities in the mechanism of action of atrial natriuretic factor (ANF). In purified sarcolemma, ANF stimulated over a wide range of concentrations with a maximum at 10(-11) M the hydrolysis of phosphatidylcholine through PC-PLD giving phosphatidate and choline, whereas higher concentrations of ANF (10(-10) M) preferentially stimulated PC breakdown through PC-PLC to form diacylglycerol and phosphocholine. To confirm the involvement of the PC-PLD in the mechanism of ANF action, we measured the transphosphatidylation reaction, a specific assay for this phospholipase which in the presence of ethanol catalyses the phosphatidylethanol formation from PC. ANF stimulated phosphatidylethanol formation with the same dose-response behavior as phosphatidate formation. The significant diacylglycerol increase at 10(-10) M ANF, in the presence of propranolol, a potent inhibitor of phosphatidate phosphatase which can hydrolyse phosphatidate to give diacylglycerol, suggested a direct involvement of PC-PLC. The use of GTP-gamma-S, a non hydrolysable analog of GTP, and of pertussis toxin showed the involvement of a pertussis toxin insensitive G protein in PC-PLC mediated ANF signal transduction. We suggest a differential effect of ANF on PC breakdown by phospholipases C and D depending on the concentration of the peptide.
J Mol Cell Cardiol 1994 Dec
PMID:Selective activation by atrial natriuretic factor of phosphatidylcholine-specific phospholipase activities in purified heart muscle plasma membranes. 773 Oct 62

In the heart, alpha-adrenergic, angiotensin II and endothelin signaling pathways modulate short-term changes in chronotropy and inotropy, and participate in the long-term control of cardiac growth. A shared feature of these signaling pathways is the stimulation of phosphatidylinositol (PI) turnover, which is thought to occur via G protein-mediated regulation of phospholipase C (PLC) activity. However, G protein subunits capable of regulating PLC activity have not been identified in different regions and cell types of the heart and members of the G protein-regulated PLC-beta isozyme family have not been documented in the heart. Using a battery of antipeptide specific antisera directed against the G protein alpha q, beta and gamma subunit families and against members of the PLC-beta, PLC-gamma and PLC-delta families, we demonstrated that heart tissues express the G protein alpha subunits alpha q and alpha 11, multiple G protein beta and gamma subunits, and PLC-beta 3, a phospholipase C isozyme regulated by either G protein alpha or beta gamma subunits. The degree of expression and distribution of these subunits differed between regions of the heart (atria versus ventricle) and changed with development. These data lay the ground work for future studies to determine the functional coupling of specific subsets of these components involved in receptor activation of PI turnover in the heart.
J Mol Cell Cardiol 1995 Jan
PMID:Subunit expression of signal transducing G proteins in cardiac tissue: implications for phospholipase C-beta regulation. 776 Mar 67

Diverse and distinct hormonal stimuli arriving at the cardiomyocyte engage specific surface receptors to initiate hydrolysis of inositol phospholipids by phospholipase C whereby information flows from changes in intracellular levels of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate, 1,2-diacylglycerol and Ca2+ to the specific phosphorylation of cellular proteins by various protein kinases such as the protein kinase C family, Ca(2+)-calmodulin-dependent kinase and mitogen activated kinases. The phosphorylation products are potential regulators of the inotropic and chronotropic state, hypertrophic growth and specific gene expression and ischemic preconditioning of the myocardium. This review summarizes the current state of knowledge concerning the phosphatidylinositol cycle and its potential role in mediating various functional responses in myocardium. The multiplicity of receptor types, G-proteins, phospholipases C and protein kinases raises fundamental questions about the mechanisms that assure the precision and timing of the myocardial response to hormonal stimuli.
J Mol Cell Cardiol 1995 Jan
PMID:Signal transduction by the phosphatidylinositol cycle in myocardium. 776 Mar 91

We explored the effect of glucose-free hypoxia/reoxygenation of cultured neonatal rat ventricular myocytes on endothelin-1 and alpha 1-adrenoceptor induced activity of the phosphoinositide cycle. At the same time the influence of these agonists on depletion of energy-rich phosphates and cellular damage was assessed. Glucose-free hypoxia did not lead to an increase in basal phospholipase C activity. However, endothelin-1 (10(-8) M) and phenylephrine (10(-5) M) evoked activation of phospholipase C was attenuated after 60 min of hypoxia and declined to 38% and 30% respectively of normoxic values after 90 min of hypoxia. During glucose-free hypoxia, phosphatidylinositol 4,5-bisphosphate, the substrate for phospholipase C, but not phosphatidylinositol or phosphatidylinositol 4-monophosphate was seen to decline to 59% of normoxic values which was independent of activation of phospholipase C by agonists. ATP levels decreased after 30 min of hypoxia and declined to 29% relative to normoxic control after 90 min of hypoxia. Total adenine nucleotide levels showed a similar pattern. The presence of 10(-8) M endothelin-1 during hypoxia did not influence the magnitude of ATP depletion. However, after 15 min of reoxygenation, by itself not significantly leading to recovery of ATP levels, ATP levels were decreased by endothelin-1 as compared to hypoxia/reoxygenation without phospholipase C agonist. Cellular damage as determined by lactate dehydrogenase leakage was not observed during 90 min hypoxia. Reoxygenation resulted in a three-fold increase in enzyme release relative to normoxic control. In the presence of endothelin-1 or phenylephrine this reoxygenation-induced damage was respectively 1.7 and 3.0-fold increased. We conclude that the agonist-induced activity of the phosphoinositide cycle is decreased in time during glucose-free hypoxia, partially through a decrease in phosphatidylinositol 4,5-bisphosphate level. However, the remaining activity may give rise to increased cellular damage. As endothelin-1 and alpha 1-adrenergic amines are known to be released during myocardial ischemia, stimulation of the phosphoinositide cycle by these agonists might be an important factor in determining the magnitude of myocardial injury.
J Mol Cell Cardiol 1994 Nov
PMID:Endothelin-1 and phenylephrine-induced activation of the phosphoinositide cycle increases cell injury of cultured cardiomyocytes exposed to hypoxia/reoxygenation. 789 74

A comprehensive review of the literature has revealed that endothelins belong to a family of vasoactive peptides which are formed and released from the endothelium. By producing constriction of the coronary arteries and peripheral blood vessels, endothelins are known both to reduce coronary bloodflow and increase blood pressure and thus can be seen to affect heart function adversely. On the other hand, endothelins are capable of producing positive inotropic and chronotropic effects by directly affecting both the myocardium and nodal tissues. Prolonged actions of high concentrations of endothelins can be seen to induce relative hypoxia in the myocardium which will eventually result in heart dysfunction. The mechanisms of actions of endothelin on smooth muscle cells and cardiomyocytes include interaction with endothelin receptors on the cell surface, activation of phospholipase C through G-proteins, and increase in the intracellular concentration of Ca2+ through the increase in phosphoinositol turnover. Endothelins were found to exert no effects on sarcolemmal Na+,K(+)-ATPase, Na(+)-Ca2+ exchange and Ca2+ pump systems nor on the sarcoplasmic reticular Ca2+ pump system and myofibrillar ATPase activities in the rat heart. Marked elevation in the levels of plasma endothelins and down-regulation of endothelin receptors in ischemia-reperfusion injury, hypertension and chronic diabetes indicate a significant role of endothelins in the genesis of heart dysfunction under different pathological conditions.
Can J Cardiol 1993 Sep
PMID:Role of endothelin in heart function in health and disease. 822 63

Influence of the protein kinase C activator phorbol 12,13-dibutyrate on the alpha 1- and beta-adrenoceptor-mediated positive inotropic effect was studied in the rabbit ventricular myocardium. Phorbol 12,13-dibutyrate (10(-8)-10(-6) M) inhibited the positive inotropic effect mediated by alpha 1-adrenoceptors in a concentration-dependent manner, while the positive inotropy mediated by beta-adrenoceptors was not affected by phorbol 12,13-dibutyrate up to 3 x 10(-7) M. Phorbol 12,13-dibutyrate at 10(-6) M decreased the beta-mediated effect, but the extent of inhibition was less than that of alpha 1-mediated effect produced by 10(-8) M phorbol 12,13-dibutyrate. Thus, the inhibition induced by phorbol 12,13-dibutyrate was 100-fold more selective for alpha 1- than for beta-mediated inotropy. Phorbol 12,13-dibutyrate at 10(-7) M increased the basal force of contraction in some preparations, but decreased it at 3 x 10(-7) M and higher in a concentration-dependent manner. In membrane fractions derived from the rabbit ventricular muscle, phorbol 12,13-dibutyrate did not affect the specific binding of [3H]prazosin. A nonhydrolyzable GTP analogue GTP gamma S shifted the epinephrine-induced displacement curve of [3H]prazosin to the right, but phorbol 12,13-dibutyrate did not affect the curve. Accumulation of [3H]inositol monophosphate induced by alpha 1 stimulation was inhibited by phorbol 12,13-dibutyrate. These findings indicate that phorbol 12,13-dibutyrate may induce the selective uncoupling of the myocardial alpha 1-receptor stimulation to activation of phospholipase C, and inhibit selectively the alpha 1-mediated positive inotropy.
Int J Cardiol 1993 Jul 15
PMID:Selective inhibition by phorbol 12,13-dibutyrate of the alpha 1-receptor-mediated positive inotropic effect. 822 54

There are multiple mechanisms whereby ACE inhibitors could be beneficial during myocardial ischemia and reperfusion, including: i) reduced formation of angiotensin II, ii) decreased metabolism of bradykinin, iii) antioxidant activity, and iv) possibly other unknown mechanisms. Reduced formation of angiotensin II should be beneficial because this peptide exerts several actions that are potentially detrimental to the ischemic/reperfused myocardium, including vasoconstriction, increased release of norepinephrine, stimulation of phospholipase C and/or A2, and increased afterload with an attendant increase in oxygen demands. Reduced metabolism of bradykinin could be beneficial by increasing myocardial glucose uptake, by causing vasodilation, and by stimulating production of endothelium-derived relaxing factor and prostacyclin. Although earlier studies suggested that sulfhydryl-containing ACE inhibitors scavenge superoxide anions, recent data have shown that these drugs scavenge hydroxyl radical and hypochlorous acid with no effect on superoxide anion. Studies in isolated hearts have demonstrated that ACE inhibitors attenuate the metabolic, arrhythmic, and contractile dearrangements associated with ischemia and reperfusion, and have suggested that such beneficial effects are mediated by potentiation of bradykinin and/or increased synthesis of prostacyclin. Studies in models of myocardial stunning after brief (15-min) ischemia in vivo (anesthetized dogs) suggest that ACE inhibitors enhance the recovery of contractile function after a single brief ischemic episode. No data are available regarding the effect of these drugs on myocardial stunning after a prolonged, partly reversible episode, after multiple consecutive brief ischemic episodes, and after global ischemia. The mechanism for the salutary effects of ACE inhibitors on stunning remains a mystery. It may involve an antioxidant action (in the case of thiol-containing molecules) or potentiation of prostaglandins (in the case of non-thiol-containing molecules). What is clear is that the enhanced recovery of function effected by these drugs is not due to hemodynamic effects, inhibition of the converting enzyme per se, or an "antischemic" action (since the drugs were effective when given at the time of reperfusion). The effects of ACE inhibitors on myocardial infarct size remain controversial. Further studies will be necessary to conclusively establish whether ACE inhibitors can protect against the detrimental effects of myocardial ischemia and reperfusion. Nevertheless, the evidence provided thus far is encouraging and warrants an in-depth assessment of the role of these drugs in attenuating myocardial ischemia/reperfusion injury.
Basic Res Cardiol 1993
PMID:Effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury: an overview. 835 31

The goal of the present study was to identify the molecular mechanism underlying desensitization of endothelin-1 receptor-mediated phosphoinositide response in cultured neonatal rat heart cells. Endothelin elicited a concentration-dependent (EC50 = 2.2 x 10(-9) M) increase of inositol-phosphate production with a much higher potency than phenylephrine (EC50 = 1.4 x 10(-6) M). Endothelin-1 (10(-8) M) evoked phosphoinositide turnover in the presence of 10 mM LiCl, which was greatly attenuated after 30-45 min of continuous stimulation with agonist, apparently resulting in a total absence of further inositol-phosphate accumulation. However, when the uncompetitive inositol monophosphatase inhibitor Li+ was only present during the last 30 min of 150 min incubation, the inositol-phosphate accumulation was decreased to a steady state of 33% of the initial rate. The loss of responsiveness of cardiomyocytes to endothelin-1 was not brought about by a limiting supply of phospholipase C substrate phosphatidylinositol 4,5-bisphosphate. A very rapid resynthesis of this substrate took place as its level remained almost constant during 45 min stimulation with 10(-8) M endothelin-1 while the accumulation of inositol-phosphates was at least 15-fold higher than the initial cellular phosphatidylinositol 4,5-bisphosphate content. After 120 min preincubation of cells with 10(-9) M endothelin-1 the activation of phospholipase C by a second higher dose (10(-8) M) was severely (67%) inhibited at the same time leaving the induction of phosphoinositide turnover by phenylephrine (10(-4) M) virtually intact. Preincubation with phenylephrine (3 x 10(-6) M) also led to inhibition of the phenylephrine (10(-4) M)-mediated inositol-phosphate response (36% inhibition) while the endothelin-1 (10(-8) M) response was not affected. Addition of a direct activator of protein kinase C, phorbol 12-myristate 13-acetate, led to inhibition of the endothelin-1 evoked phosphoinositide turnover but the rate of desensitization was not affected. Inhibition of protein kinase C with staurosporine did not alter the time course of desensitization. In conclusion, the activity of the phosphoinositide cycle in cardiomyocytes is homologously desensitized after stimulation with endothelin-1. The desensitization is not likely to be due to either depletion of phospholipase C substrate or to the activation of protein kinase C by inositol 1,4,5-trisphosphate-mobilized Ca2+ and elevated 1,2-diacylglycerol levels.
J Mol Cell Cardiol 1993 Jan
PMID:Homologous desensitization of the endothelin-1 receptor mediated phosphoinositide response in cultured neonatal rat cardiomyocytes. 838 49

alpha 1-Adrenoceptors in most tissues couple with the heterotrimeric GTP-binding protein Gq, the alpha subunit of which activates the beta-isoforms of phospholipase C. However, in heart (and in liver) alpha 1-adrenoceptors have been reported to couple to a high molecular weight GTP-binding protein. Gh, which functions both as a type II transglutaminase and as a receptor coupling protein. Gh activates a phospholipase isoform distinct from phospholipase C-beta. Here we report that isolation and culture of neonatal cardiomyocytes decreased the expression of Gh without reducing the content of Gq or Gi. Gh was readily detected in extracts from intact neonatal and adult heart tissues. The expression of Gh thus appears to be a feature of intact cardiac tissue.
J Mol Cell Cardiol 1995 Oct
PMID:Isolation of neonatal cardiomyocytes reduces the expression of the GTP-binding protein, Gh. 857 53

The Na+/Ca2+ exchanger plays an important role in the maintenance of calcium homeostasis in the heart. Therefore, factors which regulate the exchanger have a significant impact on cardiac function. Previously, we showed that the non-hydrolysable GTP analog, 5'guanylyl imidodiphosphate [Gpp(NH)p], stimulates Na+/Ca2+ exchange activity, implying the involvement of a G protein in exchanger regulation. In this study, we examined the effect of G protein agonists on Na+/Ca2+ exchanger activity. Isoproterenol, a Gs agonist, had no effect on exchanger activity. Likewise, the Gi agonist, carbachol, did not influence Na+/Ca2+ exchanger activity. Since these G proteins couple to the adenylate cyclase system, it would appear that cAMP-linked events do not regulate the Na+/Ca2+ exchanger. We next examined the influence of Gq-linked agonists on exchanger activity. Phenylephrine, an alpha 1-adrenergic agonist, increased Na+/Ca2+ exchanger activity up to 111% with an EC50 of 21 microM. Moreover, the Na+/Ca2+ exchanger activity was enhanced by angiotensin II and endothelin 1, which caused maximal stimulation of exchanger activity up to 125% and 211%, respectively. The selective protein kinase C inhibitor chelerythrine significantly attenuated the ability of phenylephrine and angiotensin II to stimulate the Na+/Ca2+ exchanger. In addition, the protein kinase C activator, phorbol 12-myristate 13-acetate, stimulated exchanger activity by 32%, raising the possibility that all three Gq agonists mediate their actions in part through the promotion of phospholipase C activity and the subsequent activation of protein kinase C. The contribution of Na+/Ca2+ exchange to the actions of phenylephrine, angiotensin II, and endothelin 1 is discussed.
J Mol Cell Cardiol 1996 Jan
PMID:Stimulation of the Na+/Ca2+ exchanger by phenylephrine, angiotensin II and endothelin 1. 874 10


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