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 mitogenic effects of angiotensin II on cardiac fibroblasts are mediated by membrane receptors that are classified as AT1. These receptors are prototypical of the seven transmembrane group of receptors that couple, via G-proteins, to phospholipase C, thereby generating the endogenous activator of protein kinase C, diacylglycerol. Phorbol ester activators of protein kinase C exhibit growth-promoting effects in many cell types, suggesting that this enzyme may be responsible for the growth effects of angiotensin II on cardiac fibroblasts. Both kinase assays and Western analysis demonstrated that angiotensin II does induce translocation of protein kinase C to the detergent-soluble, membrane compartment of cardiac fibroblasts. Although translocation is commonly interpreted to mean activation of protein kinase C, in situ assays on permeabilized cells failed to detect increased enzymatic activity in response to angiotensin II. Nonetheless, this hormone did activate protein kinase C, leading to activation of mitogen-activated protein (MAP) kinases. However, a PKC-independent pathway for activation of MAP kinases exists as well. Downregulation and inhibitor studies indicated that protein kinase C is not critically involved in angiotensin II-induced thymidine incorporation into DNA. Furthermore, phorbol esters that activate protein kinase C do not elicit a mitogenic response in these cells. In conclusion, the mitogenic effects of angiotensin II on cardiac fibroblasts are not simply explained by activation of protein kinase C.
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PMID:Protein kinase C in angiotensin II signalling in neonatal rat cardiac fibroblasts. Role in the mitogenic response. 775 55

Stimulation of Jurkat E6 cells with anti-CD3 antibody results in a characteristic rise in [Ca2+]i which is due to both the release of Ca2+ from intracellular stores and the entry of external Ca2+. Individual components of the [Ca2+]i increase were investigated by measuring intracellular Ca2+ release in the absence of external Ca2+ and determining influx of bivalent cations by following the entry of Mn2+. The increase in [Ca2+]i induced by anti-CD3 antibody in the presence or absence of extracellular Ca2+ could be inhibited by the non-selective kinase inhibitor staurosporine, which also inhibits anti-CD3-stimulated phospholipase C activity. Staurosporine also inhibits the influx of bivalent cations induced by anti-CD3 antibody, but not that induced by depletion of intracellular Ca2+ stores using thapsigargin. The effect of staurosporine was compared with that of Ro 31-8425, a potent and selective inhibitor of protein kinase C (PKC). Ro 31-8425, at concentrations up to 10 microM, has no inhibitory effect on the anti-CD3 antibody-induced [Ca2+]i increase or phospholipase C activity. These studies are consistent with the concept that augmentation of [Ca2+]i by stimulated T-cell receptors requires activation of a kinase, probably a tyrosine kinase such as p56lck, ZAP-70 or p59fyn, and is independent of PKC. Phorbol esters inhibit the anti-CD3-stimulated [Ca2+]i increase and phospholipase C activity, showing that this can be negatively regulated by PKC. A small potentiation of the anti-CD3 antibody-induced [Ca2+]i rise in the presence of extracellular Ca2+ was detected in the presence of Ro 31-8425; this suggests that T-cell-receptor ligation can also limit the increase in [Ca2+]i via PKC activation.
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PMID:Regulation of T-cell-receptor-stimulated bivalent-cation entry in Jurkat E6 cells: role of protein kinase C. 798 Apr 31

We characterized norepinephrine (NE)-activated Ca2+ influx in the rat medullary thyroid carcinoma (rMTC) 6-23 cell line using fura-2. NE caused a sustained increase in the intracellular Ca2+ concentration ([Ca2+]i), which was completely reversed by addition of nifedipine or removal of extracellular Ca2+. Bay K8644, KCl-induced depolarization, and ATP also increased [Ca2+]i in rMTC 6-23 cells, effects that were also reversed by nifedipine. Release of intracellular Ca2+ by thapsigargin was not blocked by nifedipine, and NE caused nifedipine-sensitive increases in [Ca2+]i even in the presence of thapsigargin. NE-stimulated increases in [Ca2+]i were mimicked by the alpha 1-adrenergic receptor (AR) agonist phenylephrine but not by the beta-AR agonist isoproterenol. The response to NE was blocked by the alpha-AR antagonist phentolamine and by pretreatment with the alpha 1B-selective alkylating agent chloroethylclonidine (CEC) but was not blocked by alpha 1A-selective concentrations of the subtype-selective antagonist 5-methylurapidil. alpha 1-AR binding sites labeled by 125I-BE 2254 in membranes from this cell line were highly sensitive to inactivation by CEC (> 80%), and competition with subtype-selective antagonists suggested the presence of a homogeneous population of alpha 1B-ARs. NE, epinephrine, and phenylephrine, but not KCl, ATP, or isoproterenol, caused large increases in [3H]inositol phosphate (InsP) formation in these cells. This [3H]InsP response was greatly reduced by CEC pretreatment, and competitive antagonists blocked this response with an alpha 1B-like pharmacology. Northern blots of poly(A)+ RNA from rMTC 6-23 cells showed single transcripts hybridizing to the hamster alpha 1B-AR (2.2-kilo-base) and less prominently to the rat alpha 1D-AR (4.0-kilobase) cDNAs but no detectable hybridization to the bovine alpha 1C-AR cDNA. The phospholipase C inhibitor U-73122 reduced the [3H] InsP response to NE in a concentration-dependent manner but had little or no effect on the NE-induced increases in [Ca2+]i. Phorbol myristate acetate also increased [Ca2+]i in rMTC 6-23 cells, although this response was not blocked by nifedipine. We conclude that activation of alpha 1B-like ARs (including possibly both alpha 1B- and alpha 1D-ARs) increases voltage-dependent Ca2+ influx in rat rMTC 6-23 cells. This effect appears to be independent of release of intracellular Ca2+, activation of phospholipase C, and/or activation of protein kinase C. This cell line should be very useful in defining the mechanisms underlying the known effects of alpha 1-ARs on voltage-gated Ca2+ influx, which plays an important functional role in vascular smooth muscle.
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PMID:Increased voltage-dependent calcium influx produced by alpha 1B-adrenergic receptor activation in rat medullary thyroid carcinoma 6-23 cells. 818 37

Evidence for the modulation of the P2z-purinoceptor for extracellular ATP in dissociated rat parotid cells is presented in studies using compounds that inhibit protein kinases. Preincubation of acinar cells with the protein kinase catalytic-site inhibitors K-252a and staurosporine, as well as with the regulatory-domain inhibitor sphingosine, specifically potentiates the elevation in cytosolic Ca2+ concentration ([Ca2+]i) mediated by extracellular ATP, but has no effect on the [Ca2+]i elevation mediated by muscarinic receptors through phospholipase C activation. Phorbol dibutyrate (PDBu), which activates protein kinase C (PKC), has no modulatory effect on ATP-mediated [Ca2+]i elevation. Further, pretreatment with PDBu does not reverse or block the effects of K-252a or sphinogosine, arguing against the involvement of PKC. Other pharmacological manipulations indicate that neither calmodulin-dependent nor cyclic-AMP-dependent kinases are involved. Neither the peak intracellular Ca2+ mobilization nor the sustained Ca2+ entry in response to carbachol or to a Ca2+ ionophore (4-bromo-A23187) is altered by the kinase inhibitors that potentiate the [Ca2+]i response to ATP, indicating that effects on the ATP response are not due to non-specific permeability changes, nor to decreased Ca2+ removal from the cytosol. ATP-mediated influx of Mn2+ as well as ATP-induced membrane depolarization are potentiated in cells preincubated with K-252a, directly demonstrating that cation influx is enhanced through a P2z-specific route. These results show that P2z responses (or purinoceptors) can be modulated and suggest that phosphorylation events are involved.
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PMID:Modulation of extracellular ATP-induced Ca2+ responses: role of protein kinases. 821 26

The vasoactive peptide, endothelin-1 (ET-1) has been implicated in the pathophysiology of various diseases. Recently, we have shown that human brain endothelial cells both secrete and express immunoreactive ET-1 high-affinity ETA receptors coupled to activation of phospholipase C (PLC). The present study demonstrates concentration-dependent stimulation of prostanoids [thromboxane B2 (TxB2), prostaglandin F2 alpha (PGF2 alpha), 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) prostaglandin E2 (PGE2), and prostaglandin D2 (PGD2)] production by ET-1 in capillary endothelial cells derived from human brain (HBCEC). The increase in the vasoconstrictive prostanoids TxA2 and PGF2 alpha temporally preceded that of the vasodilatory PGI2, PGE2 and PGD2, and was seen after 15 min of incubation with ET-1 (10 nM). Increased production of vasodilatory prostanoids was observed between 4-8 h of incubation, whereas normalization of both vasoconstrictive and vasodilatory prostaglandins occurred 24 h after addition of ET-1. Both ET-1-stimulated prostanoid and IP3 production were inhibited by BQ123, a specific antagonist of ETA receptors. ET-1-induced prostanoid secretion by HBCEC was also inhibited by dexamethasone (50 microM) and diminished by neomycin (50 microM) and verapamil (10 microM) but not by nifedipine. Phorbol myristate ester potentiated ET-1-stimulated prostanoid secretion, whereas it inhibited IP3 production. Data indicate that ET-1 activates phospholipase A2 (PLA2) and PLC in HBCEC by different intracellular mechanisms. The subsequently induced secretion of vasoactive prostanoids by HBCEC may contribute both qualitatively and temporally to the vasoactive actions of ET-1.
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PMID:Profile of prostaglandins induced by endothelin-1 in human brain capillary endothelium. 822 Jan 80

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.
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PMID:Selective inhibition by phorbol 12,13-dibutyrate of the alpha 1-receptor-mediated positive inotropic effect. 822 54

In murine keratinocytes, Ca(++)-induced terminal differentiation is accompanied by a rapid and sustained increase of inositol phosphates and diacylglycerol. Based on Western blotting analysis, basal keratinocytes cultured in 0.05 mM Ca++ medium express phospholipase C (PLC)-gamma 1 predominantly and no detectable PLC-beta 1. Differentiating keratinocytes cultured in 1.4 mM Ca++ express two- to threefold more PLC-gamma 1 protein and PLC-delta 1, but no detectable PLC-beta 1. Although the amount of PLC-gamma 1 and -delta 1 protein increased, PLC-gamma 1 and -delta 1 mRNA decreased in differentiating cells. Thus the sustained rise of PLC activity induced by Ca++ in differentiating keratinocytes may be associated with higher amounts of both PLC-gamma 1 and -delta 1 in maturing cells, determined by a posttranscriptional mechanism. Tyrosine phosphate content in PLC-gamma 1 was low in basal cells and did not change in cells exposed to 1.4 mM Ca++. However, genistein inhibited the increase in PLC activity induced by 1.4 mM Ca++. In contrast, transforming growth factor (TGF)alpha, which stimulates both PLC activity and growth in basal keratinocytes, increased tyrosine phosphorylation of PLC-gamma 1. These results suggest that tyrosine phosphorylation of PLC-gamma 1 by the epidermal growth factor (EGF) receptor is linked to stimulated proliferation, whereas stimulation of PLC activity by Ca++ is linked to keratinocyte differentiation and involves the action of a tyrosine kinase but not tyrosine phosphorylation of PLC-gamma 1. Based on studies using the intracellular free Ca++ chelator BAPTA, a rise in intracellular free Ca++ was not required for stimulation of PLC activity by raising extracellular Ca++. Phorbol esters inhibited PLC stimulation by 1.4 mM Ca++ medium and increased serine phosphorylation of PLC-gamma 1. Exogenous phosphatidylinositol-specific and phosphatidylcholine-specific bacterial PLC also inhibited endogenous inositol phosphate formation and increased endogenous diacylglycerol (DAG). Thus, direct serine phosphorylation of PLC-gamma 1 by protein kinase C is associated with the inhibition of Ca(++)-mediated PLC stimulation. These results show that keratinocytes have multiple mechanisms to regulate PLC activity in response to a specific signal.
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PMID:Keratinocyte differentiation is associated with changes in the expression and regulation of phospholipase C isoenzymes. 822 34

We examined the intracellular mechanisms for the release of motilin in a preparation of mucosal cells obtained from dog duodenum. Enzymatically dispersed cells were separated by counterflow elutriation to enrich motilin content. Postreceptor activation process was studied by comparing the release of motilin obtained with exogenous analogues or stimulants of the various intracellular signal pathways. Dibutyryl cyclic adenosine monosphate (10(-3) M) and forskolin (10(-5) M) induced a moderate response in motilin secretion. Phorbol ester beta-phorphol-12-myristate-13-acetate and phospholipase C were potent stimulants of motilin release. Raising intracellular calcium concentration by calcium ionophore A23187 or increasing calcium content in the incubation milieu failed to modify the secretion of motilin. Analogues of 8-bromoguanosine-3'5' cyclic monosphosphate were ineffective. Therefore, the motilin cell was very sensitive to protein kinase C activators and appeared moderately responsive to a stimulation of the adenylate cyclase pathway.
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PMID:Role of second messengers in the release of motilin from isolated canine intestinal cells. 823 23

The influence of protein kinase C (PKC) inhibitors, staurosporine, NA 0345 and H-7, on the alpha 1- and beta-adrenoceptor-mediated positive inotropic effect (PIE) was studied in rabbit ventricular myocardium. Staurosporine (1-10 nM), NA 0345 (10-100 nM) and H-7 (1-10 microM) selectively attenuated the PIE mediated by alpha 1-adrenoceptors at concentrations that did not affect the beta-mediated PIE and basal force of contraction. Staurosporine at higher concentrations (> 10 nM) decreased the basal force, while NA 0345 and H-7 did not. In membrane fractions derived from rabbit ventricular muscle, neither staurosporine, NA 0345 nor H-7 modified the specific [3H]prazosin binding at the concentrations that elicited the functional modulation. Accumulation of [3H]inositol monophosphate (IP1) induced by alpha 1-adrenoceptor stimulation was not affected by the PKC inhibitors. Phorbol 12,13-dibutyrate (PDBu), a PKC activator, also selectively attenuated the alpha 1-mediated PIE, but in association with the inhibition of the alpha 1-mediated IP1 accumulation. Staurosporine (1 nM), but not H-7, antagonized the PDBu-induced inhibitory action on the alpha 1-mediated PIE. These findings indicate that staurosporine, NA 0345 and H-7 produce a selective inhibition of the alpha 1-mediated PIE, probably through inhibition of the alpha 1-adrenoceptor-mediated activation of PKC. On the contrary, externally administered phorbol ester may act by uncoupling of alpha 1-adrenoceptors to activation of phospholipase C through a pathway different from endogenous diacylglycerol to lead to a selective inhibition of the alpha 1-mediated PIE.
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PMID:Inotropic effects of staurosporine, NA 0345 and H-7, protein kinase C inhibitors, on rabbit ventricular myocardium: selective inhibition of the positive inotropic effect mediated by alpha 1-adrenoceptors. 827 27

Nonhydrolyzable guanine nucleotide analogues were used to evaluate the role of guanine nucleotide binding (G) proteins in regulating pepsinogen secretion from streptolysin O-permeabilized chief cells from guinea pig stomach. In the presence of 100 nM calcium, 100 microM guanosine 5'-(beta,gamma-imido)triphosphate or guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) caused a 2- to 4-fold increase in pepsinogen secretion. GTP gamma S stimulated secretion in the absence of calcium (up to 10 mM EGTA). With or without added calcium, GTP analogues caused a 2- to 3-fold increase in cAMP, whereas guanosine 5'-O-2-(thio)diphosphate and calcium alone had no effect on cAMP levels. GTP analogue-induced activation of phospholipase C was evidenced by a calcium-independent increase in cytidine diphospho-1,2-diacylglycerol levels (50% above basal). Phorbol ester- and GTP gamma S-stimulated phosphorylation of a 72-kDa acidic protein was abolished by an inhibitor of protein kinase C (CGP 41251). However, GTP gamma S-induced pepsinogen secretion was only partially inhibited by adding CGP 41251 or a protein kinase C inhibitor peptide. These results indicate that guanine nucleotides activate major signaling pathways in gastric chief cells. Nevertheless, GTP gamma S can induce pepsinogen secretion independently of changes in calcium, cAMP, or activation of protein kinase C.
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PMID:Guanine nucleotides activate multiple signaling pathways in permeabilized gastric chief cells. Evidence for GTP gamma S-induced calcium-independent pepsinogen secretion. 838 61


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