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 Ca2+ channel antagonists nifedipine and verapamil each significantly inhibited (50-100%) the smooth muscle contraction induced in response to either 5-hydroxytryptamine (1 microM, 5-HT) or 20 mM K+ (K(+)-physiological salt solution) in the basilar artery. Simultaneous measurements of smooth muscle membrane potential showed that changes in potential were not modified at this time. A similar inhibitory action against the smooth muscle contraction but not the depolarization to 5-HT was obtained with the putative protein kinase C and phospholipase C inhibitors, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (10 microM, H7) and 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (70 microM, NCDC). These data indicate that 5-HT-induced Ca2+ influx through voltage sensitive channels is important for smooth muscle contraction but not depolarization in the rabbit basilar artery.
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PMID:Ca2+ channel antagonists and inhibition of protein kinase C each block contraction but not depolarization to 5-hydroxytryptamine in the rabbit basilar artery. 851 72

The intracellular pathways responsible for maintenance of tone in the lower esophageal sphincter (LES) are not well understood. We show that the protein kinase C (PKC) antagonists (1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride) and calphostin C reduce spontaneous resting tone in LES muscle strips, whereas the calmodulin antagonist N-(6-aminohexyl-5-chloro-1-naphthalenesulfonamide hydrochloride) has no effect, which suggests that LES tone is maintained by a PKC-mediated mechanism. In addition, U73122, an inhibitor of phosphatidylinositol-4,5-bisphosphate (PIP2)-specific phospholipase C, and D609, an inhibitor of phosphatidylcholine-specific phospholipase C, reduced diacylglycerol formation and LES tone in a concentration-dependent manner. Finally diacylglycerol levels and PKC activity were reduced during relaxation of the LES induced by the inhibitory neurotransmitter vasoactive intestinal peptide. These data suggest that resting LES tone is associated with elevated diacylglycerol levels and PKC activity, which are reduced during relaxation. Diacylglycerol is derived from at least two different sources. Hydrolysis of PIP2 by PIP2-specific phospholipase C produces equimolar amounts of inositol 1,4,5-triphosphate and diacylglycerol, which may interact synergistically to activate PKC and develop tone. Furthermore, PKC-mediated contraction may be augmented by additional diacylglycerol production arising from the hydrolysis of phosphatidylcholine by phosphatidylcholine-specific phospholipase C.
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PMID:Protein kinase C mediates spontaneous tone in the cat lower esophageal sphincter. 861 11

We examined the intracellular mechanisms of substance P-induced superoxide anion (O2-) production in human neutrophils. Addition of substance P (30 microM) caused O2- production and biphasic increases in intracellular Ca2+ concentrations ([Ca2+]i) (early transient and subsequent sustained components) associated with the formation of inositol 1,4,5-trisphosphate (IP3). O2- and [Ca2+]i were assayed by using ferricytochrome C and fura 2-AM, respectively. These responses were abolished by tachykinin NK1 receptor antagonists, [D- Pro9[spiro-gamma-lactam],Leu10,Trp11]physalaemin-(1-11) (GR82334) or [D-Arg1,D-Trp7,9,Leu11]substance P (spantide), and an intracellular Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). Inhibition of IP3 formation by GTP-binding protein (G-protein) inactivators such as guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) and islet-activating protein (IAP), or a phospholipase C inhibitor, 1-[6-[[17 beta-3-methoxyestra-1,3,5(10)- trien-17-yl]amino]hexyl]1 H-pyrrole-2,5-dione (U-73122), blocked the substance P-induced O2- production and biphasic increases in [Ca2+]i. An IP3 receptor antagonist, heparin, reduced both the substance P-induced O2- production and the transient increase in [Ca2+]i without any significant effects on the sustained increase in [Ca2+]i. Protein kinase C inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) and calphostin C, only slightly suppressed O2- production, and abolished the sustained increase in [Ca2+]i without any significant effects on the transient increase in [Ca2+]i. A Ca2+ entry blocker, nicardipine, completely inhibited the sustained increase in [Ca2+]i without affecting O2- production and the transient increase in [Ca2+]i. These results suggest that the tachykinin NK1 receptor/G-protein-linked IP3 formation with the resulting IP3-induced transient increase in [Ca2+]i is the main signal transduction pathway for substance P-stimulated O2- production in neutrophils.
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PMID:Intracellular signaling pathway of substance P-induced superoxide production in human neutrophils. 890 Oct 22

The [(3)H]inositol incorporation into the membrane fraction of A-431 human epidermoid carcinoma cells was markedly increased by stimulation of the cells with either epidermal growth factor (EGF), ATP, bradykinin, or a calcium ionophore A23187 in the presence of 1 mM extracellular calcium ions; most incorporated [(3)H]inositol was found to have accumulated as phosphatidylinositol (PI). The EGF- and ATP-stimulated PI synthesis was inhibited by two protein kinase C inhibitors, staurosporine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), and an intracellular calcium chelator, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA/AM), but not by the calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7). Pretreatment of cells with pertussis toxin (IAP, islet-activating protein) inhibited the PI synthesis, [Ca(2+)]i elevation, and inositol trisphosphate (IP(3)) production by ATP, suggesting that the phospholipase C(PLC) system coupled with IAP-sensitive G protein is involved in the ATP-stimulated PI synthesis. On the other hand, the ATP stimulation increased the release of [(3)H]choline and [(32)P)phosphatidic acid (PA) from radiolabeled cells, and such release was not inhibited by IAP. In the presence of n-butyl alcohol, which prevents the production of PA by generation of phosphatidylbutanol, the ATP-stimulated PI synthesis was reduced. Because n-butyl alcohol did not inhibit IP(3) production and [Ca(2+)]i elevation, this fact suggests that the lAP-insensitive PLD system is involved in the ATP-stimulated PI synthesis. In A-431 cells, the stimulation of P(2)-purinergic receptors appears to activate the IAP-sensitive PLC system and IAP-insensitive PLD system, both of which are essential for the stimulation of PI synthesis. The present results imply the general prospect that ligand stimulation, which mobilizes second messengers and consumes their precursors, simultaneously provokes the pathway to synthesize and salvage the second messenger precursors as well.
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PMID:ATP- and EGF-stimulated phosphatidulinositol synthesis by two different pathways, phospholipase D and diacylglycerol kinase, in A-431 epidermoid carcinoma cells. 921 28

Using the fluorescent Ca2+ indicator fura-2, we demonstrated that, in a single NG108-15 cell, acute repetitive challenge with leucine-enkephalin (EK) results in a gradual reduction of the increase of the cytosolic Ca2+ concentration ([Ca2+]i) at agonist exposure times of 90 s or less; increasing the EK exposure time of each challenge from 30 to 90 s results in greater desensitization, with complete desensitization occurring at 90 s exposure. Similar results are seen with ATP. In opioid-desensitized cells, bradykinin can still induce a marked [Ca2+]i increase, while exposure of desensitized cell to 50 mM K+ restores the response EK-induced, suggesting a role of intracellular Ca2+ stores in the desensitization process. Pretreatment of cells with certain protein kinase inhibitors, including N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004) and staurosporine, prevented desensitization, while others, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) and {1-[N, O-bis-(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenyl-piperazine (KN-62), had no effect. In contrast, activation of protein kinase C by phorbol 12-myristate 13-acetate promoted desensitization. Thus, the desensitization is dependent on protein phosphorylation. HA1004 alone did not alter EK- or bradykinin-induced inositol 1,4, 5-trisphosphate (IP3) generation; however, the inhibitory effect of calyculin A on EK- or bradykinin-induced IP3 generation was reversed by HA1004. In addition, in the presence of HA1004, the blockade of Ca2+ influx by either verapamil or removal of extracellular Ca2+ or the depletion of Ca2+ pools by thapsigargin still led to desensitization, suggesting that phosphorylation does not alter the activity of the Ca2+ transporters involved in Ca2+ influx and Ca2+ release. Our results imply that emptying of intracellular Ca2+ stores and protein phosphorylation in the phospholipase C signaling pathway play roles in the process of desensitization.
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PMID:Phosphorylation promotes the desensitization of the opioid-induced Ca2+ increase in NG108-15 cells. 1008 17

In glomerular hypertension, mesangial cells (MC) are subjected to at least two physical forces: mechanical stretch and high transmural pressure. Increased transmural pressure, as well as mechanical stretch, promotes MC proliferation, which may enhance glomerulosclerosis. The exact mechanism of this effect is not fully understood. We examined the effects of transmural pressure alone on cell proliferation and DNA synthesis and investigated the role of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), candidates for mediation of glomerular diseases, in the pressure-induced events. Pressure was applied to cultured MC placed in a sealed chamber using compressed helium gas. Application of pressure resulted in a time-dependent ( approximately 2 h) and pressure level-dependent (approximately 80 mmHg) increase in cell number (1.4-fold) and [(3)H]thymidine incorporation (2.7-fold). Pressure-induced DNA synthesis was significantly suppressed by inhibitors of phospholipase C (2-nitro-4-carboxyphenyl-N, N-diphenylcarbamate), protein kinase C [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine and chelerythrine], or tyrosine kinases (genistein). Pressure caused a rapid but transient formation of inositol 1,4,5-trisphosphate, which was blocked by the phospholipase C inhibitor. Pressure also promoted a rapid increase in tyrosine kinase activity. Pressure increased mRNA levels of PDGF-B, with a peak at 6 h, but not those of PDGF-A or bFGF. Pressure-induced DNA synthesis was partially inhibited by a neutralizing anti-PDGF antibody but not by an antibody against bFGF or nonimmune IgG. Our results indicated that pressure by itself increases DNA synthesis and proliferation of cultured rat MC possibly through activation of protein kinase C and tyrosine kinases, and PDGF-B could be partially involved in these pathways.
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PMID:Involvement of PDGF in pressure-induced mesangial cell proliferation through PKC and tyrosine kinase pathways. 1040 3

In normal subjects and in patients with cardiovascular disease, plasma triglycerides are positively correlated with plasminogen activator inhibitor type 1 (PAI-1) levels. Moreover, in vitro studies indicate that VLDLs induce PAI-1 synthesis in cultured cells, ie, endothelial and HepG2 cells. However, the signaling pathways involved in the effect of VLDL on PAI-1 synthesis have not yet been investigated. We report that VLDLs induce a signaling cascade that leads to an enhanced secretion of PAI-1 by HepG2 cells. In myo-[(3)H]inositol-labeled HepG2 cells, VLDL (100 microg/mL) caused a time-dependent increase in [(3)H]inositol phosphates, the temporal sequence being tris>bis>monophosphate. VLDL brought about a time-dependent stimulation of membrane-associated protein kinase C (PKC) activity and arachidonate release. Finally, VLDL stimulated mitogen-activated protein (MAP) kinase, and this effect was reduced by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), which suggests that PKC plays a pivotal role in MAP kinase phosphorylation. VLDL-induced PAI-1 secretion was completely prevented by U73122, a specific inhibitor of phosphatidylinositol-specific phospholipase C, by H7 or by PKC downregulation, and by mepacrine (all P<0.01 versus VLDL-treated cells). 3,4,5-Trimethoxybenzoic acid 8-(diethylamino)-octyl ester, which prevents Ca2+ release from intracellular stores, inhibited VLDL-induced PAI-1 secretion by 60% (P<0.05), and the MAP kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059 completely suppressed both basal and VLDL-induced PAI-1 secretion. These data demonstrate that VLDL-induced PAI-1 biosynthesis results from a principal signaling pathway involving PKC-mediated MAP kinase activation.
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PMID:Very low density lipoprotein-mediated signal transduction and plasminogen activator inhibitor type 1 in cultured HepG2 cells. 1041 3

Histamine, a putative neuromodulator and neurotransmitter, can depolarize supraoptic neurons and enhance depolarizing afterpotentials that play a key role in determining the excitability of these neurons. This study investigated intracellular signal transduction involved in histamine-induced enhancement of depolarizing afterpotentials utilizing immunohistochemical and electrophysiological methods. Abundant inositol 1,4,5-trisphosphate receptor-related immunostaining was seen in all parts of the supraoptic nucleus, mainly within somata and proximal processes of the magnocellular neurons, but also in astrocytes of the ventral glial lamina. In supraoptic neurons displaying depolarizing afterpotentials, three brief depolarizations evoked a slow inward current. Bath application of histamine (1-2.5 microM) reversibly enhanced this slow inward current in almost all supraoptic neurons tested. Amplitudes and durations of the slow inward current were increased by 68.1% and 22.8%, respectively. Pretreatment of cells with a histamine receptor (subtype 1) antagonist (pyrilamine) or inhibitors of phospholipase C activation (neomycin or U73122) prevented histamine-induced enhancement of the slow inward current. When electrodes containing heparin, an inositol 1,4,5-trisphosphate receptor blocker, were used for recording, histamine had no effect on the slow inward current. Heparin, however, failed to abolish norepinephrine-induced enhancement of the slow inward current. After H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine], an inhibitor of protein kinase C, was infused into supraoptic neurons via the electrodes, histamine-induced enhancement of the slow inward current was also blocked. These results indicate the presence of, and functional roles for, inositol 1,4,5-trisphosphate receptor-sensitive Ca2+ stores in supraoptic neurons. Following activation of histamine receptors (subtype 1) and phospholipase C, Ca2+ mobilization from internal stores participates in mediating histamine-induced enhancement of depolarizing afterpotentials.
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PMID:Inositol 1,4,5-trisphosphate-sensitive Ca2+ stores in rat supraoptic neurons: involvement in histamine-induced enhancement of depolarizing afterpotentials. 1046 50

It has been known that endothelin-1 (ET-1) exerts important actions in gastrointestinal smooth muscle motility, but its precise mechanism remains unsolved. We investigated the intracellular mechanism of ET-1-induced circular smooth muscle cell contraction in cat esophagus. ET-1 produced contraction of smooth muscle cells isolated by enzymatic digestion. The contraction in response to ET-1 was concentration-dependent. Pertussis toxin (PTX) blocked contraction induced by ET-1 in intact cells. To identify the specific G protein involved in the contraction, muscle cells were permeabilized with saponin. The G(i3) or G(beta) protein antibody inhibited the contraction. Neomycin phospholipase C (PLC) inhibitor inhibited the contraction, but 7,7-dimethyleicosadienoic acid (phospholipase A(2) inhibitor) and p-chloromercuribenzoic acid (phospholipase D inhibitor) had no effects. Incubation of permeabilized cells with PLC-beta(3) isozyme antibody inhibited the contraction. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine, chelerythrine [protein kinase C (PKC) inhibitor], or genistein (protein tyrosine kinase inhibitor) inhibited the contraction, but not by diacylglycerol (DAG) kinase inhibitor, R59949. To test whether the contraction may be PKC isozyme-specific, we examined the effect of PKC isozymes antibodies on the contraction. PKC-epsilon antibody inhibited the contraction. To characterize further the specific PKC isozymes that mediate the contraction, we used, as an inhibitor, N-myristoylated peptides (myr-PKC) derived from the pseudosubstrate sequences of PKC-alphabetagamma, -alpha, -delta, or -epsilon. myr-PKC-epsilon inhibited the contraction, confirming that PKC-epsilon isozyme is involved in the contraction. To examine whether mitogen-activated protein kinases (MAPKs) mediate the contraction, specific MAPK inhibitors [MAPK kinase inhibitor, PD98059, (2'-amino-3'-methoxy-flavone), and p38 MAPK inhibitor, SB202190 (4-4-fluorophenyl) 2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole)] were used. PD98059 or SB202190 blocked the contraction. ET-1 increased the intensity of the detection bands identified by immunological methods as MAPK monoclonal p44/p42 peptides. PD98059 decreased the intensity of the detection bands compared with ET-1. In conclusion, ET-1-induced contraction in cat esophageal circular muscle cells depends on PTX-sensitive G(i3) protein and PLC-beta(3) isozyme, resulting in the activation of PKC-epsilon- or protein-tyrosine kinase-dependent pathway, subsequently mediating the activation of p44/p42 MAPK or p38 MAPK pathway.
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PMID:The signal transduction of endothelin-1-induced circular smooth muscle cell contraction in cat esophagus. 1218 48

We assessed the functional response and the mechanisms following receptor stimulation of endothelin-1 (ET-1) in the rat renal artery. In this study, isometric tension was recorded in renal artery rings without endothelium. Cumulative application of ET-1 from 0.1 to 100 nmol/l induced a sustained concentration-dependent contraction in the renal artery. Submaximal contraction induced by 10 nmol/l ET-1 in 2.5 mmol/l Ca(2+) and in the absence of inhibitors was used as control response (100%). The relative contribution of different sources of Ca(2+) in ET-1-induced contraction was evaluated. The contractile response to 10 nmol/l ET-1 in 2.5 mmol/l Ca(2+ )(1.2 +/- 0.2 g) was significantly inhibited either in Ca(2+)-free solution containing 100 micromol/l ethylene glycol bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (0.6 +/- 0.1 g) or after depletion of intracellular Ca(2+) stores (0.62 +/- 0.05 g). The contribution of phospholipase C and protein kinase C was evaluated by using their inhibitors 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (NCDC) and [1-(5-isoquinolinesulfonyl)-2-methylpiperazine] (H-7), respectively. The contractile response to 10 nmol/l ET-1 was inhibited by 10 micromol/l NCDC (to 80 +/- 6%) and 30 micromol/l H-7 (to 76.6 +/- 6.5%). We found that 1 micromol/l nifedipine inhibited the ET-1-induced contraction (to 48.7 +/- 6.9%), indicating the contribution of Ca(2+) influx through voltage-gated L-type Ca(2+) channels to this response. Further, the inhibitory effect of nifedipine was to a greater extent as compared with NCDC or H-7. Additive inhibition of ET-1-induced contraction was not observed in the presence of both nifedipine and NCDC. We also evaluated the role of the ionic transport system in the ET-1-induced response by using 20 nmol/l 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), an inhibitor of Na(+)-H(+) exchange, or 100 micromol/l ouabain, an inhibitor of Na(+)-K(+)-ATPase. The response to ET-1 was decreased by both EIPA (to 61.6 +/- 8.4%) and ouabain (to 62.1 +/- 8.6%). The contribution of Na(+)-Ca(2+) exchange to ouabain action was tested using the inhibitor dimethyl amiloride HCl (10 micromol/l). The decrease in ET-1-induced contraction by the combination of ouabain and dimethyl amiloride HCl was similar to that observed with ouabain alone. In view of these observations, both extra- and intracellular sources of Ca(2+) contribute to the contractile response induced by ET-1 in the renal artery. Our findings also revealed the importance of Ca(2+) influx through voltage-gated L-type Ca(2+) channels in mediating contraction to ET-1 in the renal artery, whereas a minor role of phospholipase C and protein kinase C was observed. Na(+)-H(+) exchange and Na(+)-K(+)-ATPase also play a role in the ET-1-induced contraction in renal artery. Moreover, the contribution of Na(+)-K(+)-ATPase in ET-1 contraction is not an Na(+)-Ca(2+) exchange-related process.
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PMID:Mechanisms underlying the contractile response to endothelin-1 in the rat renal artery. 1278 84


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