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)

We used polyclonal antisera raised in rabbits against membrane-bound rat lung and human lung carbonic anhydrase (CA) IV in immunofluorescence studies to stain cryosections of rat soleus and extensor digitorum longus (EDL) and several human skeletal muscles. There was strong specific staining of capillaries in all muscles investigated. Several techniques were applied to verify this result. (a) Serial sections were either incubated with anti-CA IV/FITC or processed for endothelial ATPase reaction. There was precise co-localization of antibody marked structures and ATPase stained capillaries. (b) Human muscle sections were double stained with anti-CA IV/TRITC and anti-von Willebrand factor (vWF)/FITC. vWF, a capillary marker, and CA IV were localized at identical sites. (c) The CAIV was released from capillaries by treatment with phosphatidylinositol specific phospholipase C, suggesting that the enzyme is anchored to the endothelial cell membrane via a phosphatidylinositolglycan anchor. (d) A rat hindlimb was perfused with diluted antiserum. Cryosections of perfused soleus and EDL processed for anti-rabbit IgG/FITC staining showed clear fluorescence associated with capillaries, indicating that the antigen was accessible from the capillary lumen. (e) Immune complexes formed during antiserum perfusion as described in d were precipitated from muscle homogenates. SDS-PAGE followed by immunoblotting showed that the predominant portion of total muscle CA IV was bound in these complexes and therefore must be located intravascularly.
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PMID:Immunohistochemical localization of carbonic anhydrase IV in capillaries of rat and human skeletal muscle. 806 30

The effect of the putative inhibitor of phospholipase C activity, U73122, on the Ca2+ sequestering and releasing properties of internal Ca2+ stores was studied in both permeabilized and intact rabbit pancreatic acinar cells. U73122 dose dependently inhibited ATP-dependent Ca2+ uptake in the inositol (1,4,5)-trisphosphate-[Ins(1,4,5)P3]-sensitive, but not the Ins(1,4,5)P3-insensitive, Ca2+ store in acinar cells permeabilized by saponin treatment. In a suspension of intact acinar cells, loaded with the fluorescent Ca2+ indicator, Fura-2, U73122 alone evoked a transient increase in average free cytosolic Ca2+ concentration ([Ca2+]i,av), which was largely independent of external Ca2+. Addition of U73122 to cell suspensions prestimulated with either cholecystokinin octapeptide or JMV-180 revealed an inverse relationship in size between the U73122- and the agonist-evoked [Ca2+]i,av transient. Moreover, thapsigargin-induced inhibition of intracellular Ca(2+)-ATPase activity resulted in a [Ca2+]i,av transient, the size of which was not different following maximal prestimulation with either U73122 or agonist. These observations suggest that U73122 selectively affects the Ins(1,4,5)P3- casu quo agonist-sensitive internal Ca2+ store, whereas thapsigargin affects both the Ins(1,4,5)P3-sensitive and -insensitive Ca2+ store. Digital-imaging microscopy of Fura-2-loaded acinar cells demonstrated that U73122, in contrast to thapsigargin, evoked sustained oscillatory changes in [Ca2+]i. The U73122-evoked oscillations were abolished in the absence of external Ca2+. The ability of U73122 to generate external Ca(2+)-dependent Ca2+ oscillations suggests that depletion of the agonist-sensitive store leads to an increase in Ca2+ permeability of the plasma membrane and that the Ins(1,4,5)P3-insensitive Ca2+ pool is necessary for the Ca2+ oscillations.
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PMID:Induction of Ca2+ oscillations by selective, U73122-mediated, depletion of inositol-trisphosphate-sensitive Ca2+ stores in rabbit pancreatic acinar cells. 807 41

The current understanding of the cellular mode of action of PTH has undergone deep changes during the last decade and the major acquisitions can be summarized as follows. First, results from biochemical and cell biology studies suggest the existence of at least two receptor types coupled to two distinct intracellular signaling pathways by G proteins: the phospholipase C-calcium-protein kinase C pathway would be coupled to high-affinity receptors, whereas the adenylate cyclase-cAMP-protein kinase A pathway would be coupled to low-affinity receptors. Until now, only one type of PTH receptor has been identified at the molecular level. It is very likely that additional PTH receptor types will be evidenced. Second, both PTH receptor-coupled transduction pathways are involved in the inhibitory effect of the hormone on the activity of two transport systems of the apical membrane of proximal tubular cells: Na-Pi cotransport and Na-H exchanger. These effects are the cellular basis for PTH inhibition of Pi and bicarbonate reabsorption. Which proteins are the targets of the different protein kinases remains to be established. Concerning the other effects of PTH on the proximal tubule (stimulation of neoglucogenesis and of calcitriol synthesis, and Na, K-ATPase inhibition), protein kinase C seems to play a major role. Third, in Henle's loop, PTH stimulates reabsorption of divalent cations through a dual effect under the dependence of protein kinase A, i.e., enhanced epithelial potential difference and opening of paracellular pathway. Finally, stimulation of distal calcium reabsorption results from multiple events: membrane insertion of apical calcium channels, opening of basolateral chloride channels resulting in cellular hyperpolarization, and modulation of Ca-ATPase. Again, while it is commonly acknowledged that both transduction systems are involved, their precise molecular targets remain to be identified (Table 1). The elucidation of the cellular mode of action of PTH, some examples of which have been reviewed, holds major interest far beyond the field of cell or organ physiology. It is the basis for understanding and, ultimately, for comprehensive treatment of genetic diseases characterized by functional abnormalities of molecules involved in the cascade of events leading to the effect of PTH on its cellular targets (hormone receptors, G proteins, and kinases). The second perspective is pharmacologic: molecular and structural identification of PTH-receptor interactions will be a prelude to design and synthesis of new selective, nonpeptidic hormonal analogs and antagonists that are easier to handle. The high incidence and severity of secondary hyperparathyroidism during chronic renal failure highlights the importance of this research.
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PMID:Cellular mode of action of parathyroid hormone. 815 58

The mechanisms by which the generation and frequency of cytoplasmic Ca2+ oscillations are controlled were investigated in pituitary gonadotrophs. In these cells, two Ca(2+)-mobilizing receptors, the gonadotropin-releasing hormone and endothelin receptors, induce frequency-modulated Ca2+ spiking at the rate of up to 30 min-1. The cytoplasmic oscillator is also activated by discharge of luminal Ca2+ (initiated by ionomycin, thapsigargin, or thimerosal) but not by increased voltage-sensitive Ca2+ influx or treatment with caffeine. The basic difference between these two types of Ca2+ oscillations is related to their requirement for inositol-1,4,5-triphosphate (InsP3). Thapsigargin-, thimerosal-, and ionomycin-induced spiking occurs without the rise in InsP3 production that is essential for the generation of receptor-controlled oscillatory responses. The differential requirement for InsP3 in the two types of Ca2+ spiking is indicated by two lines of evidence. First, agonist-induced Ca2+ spiking of frequency similar to that of non-receptor-mediated oscillations was accompanied by a significant increase in InsP3, whereas none of the non-receptor-mediated oscillations was associated with measurable changes in inositol phosphate production. Second, agonist-induced InsP3 formation and Ca2+ spiking were abolished by treatment with the phospholipase C inhibitors U73122 and neomycin sulfate, whereas non-receptor-mediated Ca2+ spiking was not affected by these agents. When the oscillator was activated by agents that do not increase InsP3 formation, it operated only at the basal rate of approximately 5 min-1 and spiking frequency did not rise with increasing drug concentrations, in contrast to the situation in agonist-stimulated gonadotrophs. However, both types of oscillations were affected by depletion of luminal Ca2+ and by changes in the intracellular Ca2+ concentration ([Ca2+]i) but were not inhibited by ryanodine. These findings are consistent with the operation of a single-pool Ca2+ oscillator that is responsible for generation of both types of Ca2+ oscillations. The oscillator is controlled by the coagonist actions of InsP3 and Ca2+ on the InsP3 receptor channels and by the activation of Ca(2+)-ATPase by rising [Ca2+]i. It can be induced to operate at low frequency without an increase in InsP3 production by agents that reduce intraluminal [Ca2+]i, and it exhibits a dose-dependent increase in spiking frequency during agonist stimulation.
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PMID:Control of calcium spiking frequency in pituitary gonadotrophs by a single-pool cytoplasmic oscillator. 819 91

We have described the pertussis toxin (PTX)-sensitive potentiation of P2-purinergic agonist-induced phospholipase C activation, Ca2+ mobilization and arachidonic acid release by an adenosine receptor agonist, N6-(L-2-phenylisopropyl)adenosine (PIA), which alone cannot influence any of these cellular activities [Okajima, Sato, Nazarea, Sho and Kondo (1989) J. Biol. Chem. 264, 13029-13037]. In the present study we have found that arachidonic acid release was associated with lysophosphatidylcholine production, and conclude that arachidonic acid is produced by phospholipase A2 in FRTL-5 thyroid cells. This led us to assume that PIA augments P2-purinergic arachidonic acid release by increasing [Ca2+]i which, in turn, activates Ca(2+)-sensitive phospholipase A2. The arachidonic acid-releasing response to PIA was, however, always considerably higher (3.1-fold increase) than the Ca2+ response (1.3-fold increase) to the adenosine derivative. In addition, arachidonic acid release induced by the [Ca2+]i increase caused by thapsigargin, an endoplasmic-reticulum Ca(2+)-ATPase inhibitor, or calcium ionophores was also potentiated by PIA without any effect on [Ca2+]i and phospholipase C activity. This action of PIA was also PTX-sensitive, but not affected by the forskolin- or cholera toxin-induced increase in the cellular cyclic AMP (cAMP), suggesting that a PTX-sensitive G-protein(s) and not cAMP mediates the PIA-induced potentiation of Ca(2+)-generated phospholipase A2 activation. Although acute phorbol ester activation of protein kinase C induced arachidonic acid release, P2-purinergic and alpha 1-adrenergic stimulation of arachidonic acid release was markedly increased by the protein kinase C down-regulation caused by the phorbol ester. This suggests a suppressive role for protein kinase C in the agonist-induced activation of arachidonic acid release. We conclude that PIA (and perhaps any of the G1-activating agonists) augments an agonist (maybe any of the Ca(2+)-mobilizing agents)-induced arachidonic acid release by activation of Ca(2+)-dependent phospholipase A2 in addition to enhancement of agonist-induced phospholipase C followed by an increase in [Ca2+]i.
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PMID:Permissive stimulation of Ca(2+)-induced phospholipase A2 by an adenosine receptor agonist in a pertussis toxin-sensitive manner in FRTL-5 thyroid cells: a new 'cross-talk' mechanism in Ca2+ signalling. 819 75

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.
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PMID:Role of endothelin in heart function in health and disease. 822 63

1. We have studied whether a nucleotide receptor mediates the effects of extracellular ATP and UTP on phosphatidylcholine metabolism in rat cultured glomerular mesangial cells. 2. ATP and UTP stimulated a biphasic 1,2-diacylglycerol (DAG) formation in [3H]-arachidonic acid-labelled mesangial cells. In contrast, in cells labelled with [3H]-myristic acid, a tracer that preferentially marks phosphatidylcholine, both nucleotides induced a delayed monophasic production of DAG with a concomitant increase in phosphatidic acid and choline formation. 3. A phospholipase D-mediated phosphatidylcholine hydrolysis was further suggested by the observation that ATP and UTP stimulate the accumulation of phosphatidylethanol, when ethanol was added to mesangial cells. 4. The rank order of potency of a series of nucleotide analogues for stimulation of phosphatidylethanol formation was UTP = ATP > ITP > ATP gamma S > beta gamma-imido-ATP = ADP > 2-methylthio-ATP = beta gamma-methylene-ATP = ADP beta S, while AMP, adenosine, CTP and GTP were inactive, indicating the presence of a nucleotide receptor. 5. Elevation of cytosolic free Ca2+ by the calcium ionophore A23187 (1 microM) or the Ca(2+)-ATPase inhibitor, thapsigargin (200 nM) slightly increased phosphatidylethanol formation. However, chelation of cytosolic Ca2+ with high concentrations of Quin 2 did not attenuate ATP- and UTP-induced phosphatidylethanol production, thus suggesting that Ca2+ is not crucially involved in agonist-stimulated phospholipase D activation. 6. The protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), but not the biologically inactive 4 alpha-phorbol 12,13-didecanoate, increased phospholipase D activity in mesangial cells, suggesting that PKC may mediate nucleotide-induced phosphatidylcholine hydrolysis. 7. Down-regulation of PKC-alpha and -delta isoenzymes by 8 h PMA treatment still resulted in full phospholipase D activation. In contrast, a 24 h treatment of mesangial cells with PMA, a regimen that also causes depletion of PKC-epsilon, markedly attenuated nucleotide-evoked phosphatidylethanol formation. In addition, the selective PKC inhibitor, calphostin C attenuated ATP- and UTP-induced phosphatidylethanol production.8. In summary, these data suggest that extracellular ATP and UTP use a common nucleotide receptor to activate phospholipase D-mediated phosphatidylcholine hydrolysis. Stimulation of phospholipase D appears to involve the PKC-epsilon isoenzyme, activated by DAG derived from phosphoinositide hydrolysis by phospholipase C.
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PMID:Extracellular ATP and UTP activation of phospholipase D is mediated by protein kinase C-epsilon in rat renal mesangial cells. 824 60

The incorporation of 32Pi into phosphatidylinositols and inositol trisphosphates was studied in Langendorff-perfused hearts from hypothyroid, euthyroid and hyperthyroid rats. The hearts were perfused with modified Krebs buffer containing [32P]orthophosphate and the degree of 32P-labeling of phosphatidylinositol, phosphatidylinositol 4-monophosphate, phosphatidylinositol 4,5-bisphosphate, inositol trisphosphates and phosphatidic acid was measured. Hyperthyroidism was associated with increases in rates of rise and fall of left ventricular systolic pressure, sarcoplasmic reticular Ca(2+)-ATPase activity and 32P-labeling of phosphatidylinositols, inositol trisphosphates and phosphatidic acid. These measurements were significantly decreased in hypothyroid hearts. The tissue levels of inositol 1,4,5-trisphosphate isoform were found to be significantly higher in hyperthyroid hearts and lower in hypothyroid hearts than in euthyroid ones. Examination of phosphoinositide-specific phospholipase C activity in the perfused hearts revealed that hyperthyroidism was associated with an increase in the membrane-associated enzymatic activity, assayed at physiological calcium concentrations, while hypothyroidism was associated with a decrease in this activity as compared with control hearts. These findings indicate that alterations in the thyroid state of the myocardium may be associated with changes in basal phosphoinositide turnover which may contribute to alterations in myocardial contraction.
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PMID:Effect of thyroid status on phosphatidylinositols in rat heart. 829 67

SHR (spontaneously hypertensive rat) is the most popular genetic hypertensive model rat. Using the F2 progeny obtained from SHR and normotensive rats, for example, WKY (Wistar-Kyoto rat), many cosegregation studies to find the genes responsible for blood pressure have been done. In this review, we present some studies using F2 rats concerning candidate genes, renin, kallikrein, sodium potassium-ATPase, heat shock protein 70, angiotensin converting enzyme, phospholipase C-delta 1 and SA gene to show whether these genes really associate with blood pressure. We discuss the signification of these genes in the process of producing SHR and stroke-prone SHR from WKY. We hope these studies will lead to identify the mechanism of human essential hypertension.
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PMID:[Cosegregation studies in spontaneously hypertensive rats]. 832 Aug 40

Cobra snake venom cardiotoxins and bee venom melittin share a number of pharmacological properties in intact tissues including hemolysis, cytolysis, contractures of muscle, membrane depolarization and activation of tissue phospholipase C and, to a far lesser extent, an arachidonic acid-associated phospholipase A2. The toxins have also been demonstrated to open the Ca2+ release channel (ryanodine receptor) and alter the activity of the Ca(2+)+Mg(2+)-ATPase in isolated sarcoplasmic reticulum preparations derived from cardiac or skeletal muscle. However, a relationship of these actions in isolated organelles to contracture induction has not yet been established. The toxins also bind to and, in some cases, alter the function of a number of other proteins in disrupted tissues. The most difficult tasks in understanding the mechanism of action of these toxins have been dissociating the primary from secondary effects and distinguishing between effects that only occur in disrupted tissues and those that occur in intact tissue. The use of cardiotoxin and melittin fractions contaminated with trace ('undetectable') amounts of venom-derived phospholipases A2 has continued to be common practice, despite the problems associated with the synergism between the toxins and enzymes and the availability of methods to overcome this problem. With adequate precautions taken with regard to methodology and interpretation of results, the cobra venom cardiotoxins and bee venom melittin may prove to be useful probes of a number of cell processes, including lipid metabolism and Ca2+ regulation in skeletal and cardiac muscle.
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PMID:Possible mechanisms of action of cobra snake venom cardiotoxins and bee venom melittin. 834 68


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