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 have investigated the putative role of nitric oxide (NO) as a modular of islet hormone release, when stimulated by the muscarinic receptor agonist phospholipase C activator, carbachol, with special regard to whether the IP3-Ca2+ or the diacylglycerol-protein kinase C messenger systems might be involved. It was observed that the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methylester (L-NAME) markedly potentiated insulin release and modestly inhibited glucagon release induced by carbachol. Similarly, insulin release induced by the phorbol ester TPA (protein kinase C activator) was markedly potentiated. Glucagon release, however, was unaffected. Dynamic perifusion experiments with 45C2+ -loaded islets revealed that the inhibitory action of L-NAME on carbachol-stimulated NO-production was reflected in a rapid and sustained increase in insulin secretion above carbachol controls, whereas the 45Ca2+ -efflux pattern was similar in both groups with the exception of a slight elevation of 45C2+ in the L-NAME-carbachol group during the latter part of the perifusion. No difference in either insulin release or 45Ca2+ -efflux pattern between the carbachol group and L-NAME-carbachol group was seen in another series of experiments with identical design but performed in the absence of extracellular Ca2+. However, it should be noted that in the absence of extracellular Ca2+ both 45Ca2+ -efflux and, especially, insulin release were greatly reduced in comparison with experiments in normal Ca2+. Further, in the presence of diazoxide, a potent K+ ATP-channel opener, plus a depolarizing concentration of K+ the NOS-inhibitor L-NAME still markedly potentiated carbachol-induced insulin release and inhibited glucagon release. The enantiomer D-NAME, which is devoid of NOS-inhibitory properties, did not affect carbachol-induced hormone release. TPA-induced hormone release in depolarized islets was not affected by either L-NAME or D-NAME. The pharmacological intracellular NO donor hydroxylamine dose-dependently inhibited insulin release stimulated by TPA. Furthermore, a series of perifusion experiments revealed that hydroxylamine greatly inhibited carbachol-induced insulin release without affecting the 45Ca2+ -efflux pattern. In summary, our results suggest that the inhibitory effect of NO on carbachol-induced insulin release is not to any significant extent exerted on the IP3-Ca2+ messenger system but rather through S-nitrosylation of critical thiol-residues in protein kinase C and/or other secretion-regulatory thiol groups. In contrast, the stimulating action of NO on carbachol-induced glucagon release was, at least partially, connected to the IP3-Ca2+ messenger system. The main effects of NO on both insulin and glucagon release induced by carbachol were apparently exerted independently of membrane depolarization events.
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PMID:Evidence for nitric oxide mediated effects on islet hormone secretory phospholipase C signal transduction mechanisms. 987 33

We previously demonstrated that vascular endothelial growth factor (VEGF)-elicited increase in the permeability of coronary venules was blocked by the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). The aim of this study was to delineate in more detail the signaling pathways upstream from NO production in VEGF-induced venular hyperpermeability. The apparent permeability coefficient of albumin (Pa) and endothelial cytosolic Ca2+ concentration ([Ca2+]i) were measured in intact perfused porcine coronary venules using fluorescence microscopy. VEGF (10(-10) M) induced a two- to threefold increase in Pa, which was blocked by a monoclonal antibody directed against the VEGF receptor Flk-1/KDR, the phospholipase C (PLC) antagonist U-73122, or the protein kinase C (PKC) antagonist bisindolylmaleimide (BIM). In 12 venules that displayed the [Ca2+]i response to bradykinin (10(-6) M) and ionomycin (10(-6) M), only 4 vessels responded to VEGF with a transient increase in [Ca2+]i. Furthermore, Western blot analysis of cultured human umbilical vein endothelial cells showed that VEGF increased tyrosine phosphorylation of PLC-gamma and serine phosphorylation of endothelial constitutive NO synthase (ecNOS). The hyperphosphorylation of PLC-gamma was greatly attenuated by the KDR receptor antibody and U-73122, but not by BIM or L-NMMA. In contrast, U-73122 and BIM were able to inhibit VEGF-elicited serine phosphorylation of ecNOS. The results suggest that VEGF induces venular hyperpermeability through a KDR receptor-mediated activation of PLC. In turn, ecNOS is activated by PLC-mediated PKC and/or cytosolic Ca2+ elevation stimulation.
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PMID:Role of phospholipase C, protein kinase C, and calcium in VEGF-induced venular hyperpermeability. 995 Aug 55

Cell injury frequently occurs in the setting of tissue destruction and inflammation and is associated with a rise in intracellular calcium (Cai) and increased NO production. The mechanisms that trigger rises in Cai and NO during cell injury are not fully defined, but they may involve activation of G protein-coupled receptors for substances such as bradykinin, Ang II, thromboxane, and thrombin. These receptors act through G proteins from different families that have distinct functions. Receptors for bradykinin and Ang II act through members of the G alpha i and G alpha q families, whereas receptors for thrombin and thromboxane act through members of the G alpha i, G alpha q, and G alpha 12/13 families. These G proteins cooperate to regulate Cai and NO in epithelial cells through distinct mechanisms. In a number of experimental settings, activators of the adenylyl cyclase system reduce the severity of cell injury. To understand the mechanisms by which G protein-dependent signaling systems may contribute to cell injury and to define the role of adenylyl cyclase in ameliorating cell injury, the effects of adenylyl cyclase on bradykinin-stimulated Ca influx and NO in cultured renal epithelial cells that stably overexpress G alpha q and G alpha 13 were studied. This system allowed for the separation of different components of the signals initiated by receptors for thromboxane and thrombin. G alpha 13 increased bradykinin-stimulated Ca influx by a mechanism that depends on NO and cGMP. The increased Ca influx was blocked by inhibitors of NO synthase and guanylyl cyclase and by activation of adenylyl cyclase. NO production was inhibited by activators of cAMP-dependent protein kinase, which indicated that cAMP blocks Ca influx by inhibiting NO production. Expression of G alpha q, the G protein that regulates phospholipase C, also increased bradykinin-stimulated Ca influx, but by an NO, cGMP-independent mechanism that was insensitive to inhibition by adenylyl cyclase. The authors conclude that Ca influx is modulated by NO-dependent and independent mechanisms, and that to the extent that increased NO production contributes to increased Ca influx and cell injury, cell injury may be reduced by agents that activate adenylyl cyclase.
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PMID:Inhibition of nitric oxide synthase activity and nitric oxide-dependent calcium influx in renal epithelial cells by cyclic adenosine monophosphate: implications for cell injury. 1049 85

We examined the effect of bradykinin (BK) on the accumulation of cGMP of the mesangial cell (MC), a smooth muscle-like cell of the renal glomerulus. BK caused a time- and concentration dependent reduction of the cGMP concentration. In addition, BK inhibited total protein tyrosine kinase (PTK) activity. Two tyrosine kinase inhibitors (TKI) genistein and tyrphostin also reduced the cGMP concentration. The inhibition of BK and TKI were not additive. The inhibition of PTK by BK, mediated through activation of the B2-receptor, was unaffected by inhibitors of Gi/o proteins, phospholipase C, protein kinase C, cyclooxygenase and Ca2+ release from intracellular stores. Only IBMX a broad spectrum inhibitor of phosphodiesterases (PDE) and 8-methoxymethyl IBMX a specific type-1 PDE inhibitor prevented the inhibitory effects of BK and TKI indicating the involvement of type-1 PDE. In addition, BK had no effect on soluble guanylate cyclase (sGC) and nitric oxide synthase activity. In freshly isolated glomeruli, which represent the physiological environment of MC, BK also reduced the cGMP concentration. Like in MC, the inhibitory effect was suppressed by IBMX. These data demonstrate that BK suppresses a PTK-dependent pathway of cGMP production in rat MC at a level downstream of NO synthase and sGC. It is suggested that BK and TKI inhibitors decrease cGMP levels by preventing tyrosine phosphorylation of type-1 PDE activity, thereby leading to enzyme activation.
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PMID:Inhibition of cGMP accumulation in mesangial cells by bradykinin and tyrosine kinase inhibitors. 1053 81

Nebivolol is a recently developed beta-blocker provided with vasodilator properties. Because the mechanism of the putative endothelium-dependent effect of this beta-adrenoceptor blocker has not been completely elucidated, the aim of this study was to investigate the effects of nebivolol on an isolated resistance vascular bed and on cell messengers and constitutive nitric-oxide synthase activity (cNOS) in endothelial cells. Experiments were carried out using the rat mesenteric vascular bed and cultured bovine coronary postcapillary venular endothelial cells from bovine heart (CVEC). In mesenteric vascular bed preconstricted by 30 microM noradrenaline and 0.3 microM U46619, dl-nebivolol induced a concentration-dependent relaxing effect at concentrations between 3 and 30 microM; this effect was changed to a concentration-dependent vasoconstrictor response either in endothelium-denuded preparations or in intact preparations pretreated with 100 microM N(omega)-nitro-L-arginine methyl ester plus 3 microM indomethacin. The vasorelaxant effect of dl-nebivolol in preconstricted preparations was completely blocked by pretreatment either with the phospholipase C inhibitor U73122 (1 microM) or with the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin (1 microM) for 30 min. The cellular level of the inositol trisphosphate metabolite inositol monophosphate in coronary postcapillary venular endothelial cells was not affected by dl-nebivolol in the concentration range 100 nM to 1 microM, but it was concentration dependently increased after exposure for 15 min to 10 and 30 microM dl-nebivolol. The activity of cNOS was almost doubled after a 5-min exposure to 10 microM dl-nebivolol and was significantly impaired by thapsigargin and N(omega)-nitro-L-arginine methyl ester treatment, although it was unaffected by N(omega)-nitro-D-arginine methyl ester. These findings demonstrate that nebivolol, in micromolar concentrations, induces vasorelaxation through activation of inositol phosphate metabolism and stimulation of cNOS activity in endothelial cells.
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PMID:Inositol phosphate metabolism and nitric-oxide synthase activity in endothelial cells are involved in the vasorelaxant activity of nebivolol. 1064 Mar 8

The role of phospholipase C in the molecular mechanism of glutamate neurotoxicity was assessed in primary cultures of cerebellar neurons. It is shown that 1-[6-[[(17b)-3-methoxyestra-1,3, 5(10)-trien-17-yl]amino] hexyl]-1H-pyrrole-2,5-dione (U-73122) and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphorylcholine (Et-18-OCH(3)), two agents that inhibit phospholipase C, prevent glutamate and N-methyl-D-aspartic acid (NMDA) neurotoxicity. It is shown that both compounds prevent glutamate neurotoxicity at concentrations lower than those required to inhibit carbachol-induced hydrolysis of inositol phospholipids. In contrast, it was a good correlation between the concentrations of U-73122 and Et-18-OCH(3) required to inhibit NMDA-induced hydrolysis of phospholipids and those required to prevent glutamate and NMDA neurotoxicity. NMDA-induced hydrolysis of phospholipids is inhibited by nitroarginine, an inhibitor of nitric-oxide synthase, and is mimicked by the nitric oxide-generating agent S-nitroso-N-acetylpenicillamine. The results reported indicate that glutamate neurotoxicity would be mediated by activation of NMDA receptors, leading to activation of nitric-oxide synthase and increased formation of nitric oxide, which results in increased activity of phospholipase C. Inhibition of phospholipase C by U-73122 or Et-18-OCH(3) prevents glutamate-induced neuronal death.
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PMID:Inhibitors of phospholipase C prevent glutamate neurotoxicity in primary cultures of cerebellar neurons. 1068 99

There are many reports on acute renal failure (ARF) after ingestion of grass carp bile (CB; Ctenopharyngodon idellus). Renal dipeptidase (RDPase; EC 3.4.13.19) is a glycosylphosphatidylinositol-anchored ectoenzyme within the renal proximal tubules (PTs) and is proposed as a diagnostic enzyme of renal disease. We examined the release of RDPase following treatment with CB and various nitric oxide (NO) related compounds in porcine PTs. The RDPase release from PTs was inhibited by CB in a concentration-dependent manner and was also inhibited by sodium nitroprusside (direct NO donor) and L-arginine (NO synthase substrate) in the tested range (0-12 mM). CB-treated (0. 1 mg/ml) PTs showed a decreased RDPase activity in comparison with the control group. This inhibition was blocked by 2 mM L-NAME (NO synthase inhibitor) and U73122 (inhibitor of phosphatidylinositol-specific phospholipase C) in a concentration-dependent manner. Eel bile (0-0.1 mg/ml), used as the control, did not significantly affect the RDPase release from PTs. The NO concentration was observed as nitrite, the degradation product of the NO metabolism, increased in proportion to CB and L-arginine. The increase of nitrite to 151.5% by CB treatment (0.1 mg/ml) was blocked by 2 mM L-NAME (95.5%). When the phospholipase C pathway was blocked by 10 and 20 microM U73122, the nitrite generation decreased to 122.7 and 89.4%, respectively. These results strongly suggest that NO generation and the phospholipase C pathway affect the RDPase release from the PTs and that they may be involved in the development of ARF in vivo following CB ingestion. The release of RDPase from PTs could be a useful tool not only for this CB-caused ARF, but also for the elucidation of other biochemical mechanisms.
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PMID:Grass carp (Ctenopharyngodon idellus) bile may inhibit the release of renal dipeptidase from the proximal tubules by nitric oxide generation. 1076 13

The development of neuropathic pain involves a series of changes including primary and secondary hyperalgesia, peripheral and central sensitization, and wind-up phenomena. Neurotransmitters play a critical role in this process. For example, glutaminergic subtypes of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and neurokinin prime the N-methyl-D-aspartate (NMDA) receptor by triggering the release of intracellular calcium ions, thus unblocking the magnesium ion plug on the NMDA receptor and allowing Ca2+ influx into the cell. Ca2+ ions acting as secondary messengers initiate protein kinase C activation, phospholipase C and nitric oxide synthetase production, and proto-oncogene expression. The activation of the NMDA receptor thereby increases the responsiveness of the nociceptive system. Anticonvulsant drugs--including carbamazepine, phenytoin, and felbamate--have been used to treat neuropathic pain. Gabapentin is a novel anticonvulsant that may have a unique effect on voltage-dependent Ca2+ channel currents at postsynaptic dorsal horn neurons. Thus, gabapentin may interrupt an entire series of events, not just a single process, that lead to the development of neuropathic pain. Preclinical models of anti-inflammatory and neuropathic pain indicate that gabapentin effectively antagonizes the maintenance of this pain. Additionally, in preemptive surgical models, gabapentin has been shown to prevent the induction of pain. Gabapentin has been shown to be efficacious in numerous smaller clinical studies, case reports, and chart reviews in a variety of neuropathic pain syndromes. Two large multicenter studies, one in postherpetic neuralgia (PHN) and one in diabetic peripheral neuropathy (DPN), support preclinical findings. In the PHN study, patients treated with gabapentin demonstrated a significant difference (P<0.001) in their average daily pain score at endpoint compared to placebo patients. In the DPN trial, mean weekly pain was significantly (P<0.001) different for gabapentin-treated patients compared to placebo-treated patients at endpoint. Consistent with the known side-effect profile of gabapentin, the most common adverse events noted in both studies were dizziness and somnolence. Gabapentin should be considered an important addition to the management of neuropathic pain syndromes.
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PMID:Gabapentin use in neuropathic pain syndromes. 1087 51

Preceding the onset of type 1 diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1beta (IL-1beta) which induces beta-cell apoptosis and exerts inhibitory actions on islet beta-cell insulin secretion. IL-1beta seems to act chiefly through induction of nitric oxide (NO) synthesis. Hence, IL-1beta and NO have been implicated as key effector molecules in type 1 diabetes mellitus. In this paper, the influence of endogenously produced and exogenously delivered NO on the regulation of cell proliferation, cell viability and discrete parts of the stimulus-secretion coupling in insulin-secreting RINm5F cells was investigated. Because vitamin E may delay diabetes onset in animal models, we also investigated whether tocopherols may protect beta-cells from the suppressive actions of IL-1 and NO in vitro. To this end, the impact of NO on insulin secretory responses to activation of phospholipase C (by carbamylcholine), protein kinase C (by phorbol ester), adenylyl cyclase (by forskolin), and Ca(2+) influx through voltage-activated Ca(2+) channels (by K(+)-induced depolarization) was monitored in culture after treatment with IL-1beta or by co-incubation with the NO donor spermine-NONOate. It was found that cell proliferation, viability, insulin production and the stimulation of insulin release evoked by carbamylcholine and phorbol ester were impeded by IL-1beta or spermine-NONOate, whereas the hormone output by the other secretagogues was not altered by NO. Pretreatment with gamma-tocopherol (but not alpha-tocopherol) afforded a partial protection against the inhibitory effects of NO, whereas specifically inhibiting inducible NO synthase with N-nitro-L-arginine completely reversed the IL-1beta effects. In contrast, inhibiting guanylyl cyclase with ODQ (1H-[1,2, 4]oxadiazolo[4,3-alpha]-quinoxaline-1-one) or blocking low voltage-activated Ca(2+) channels with NiCl(2) failed to influence the actions of NO. In conclusion, our data show that NO inhibits growth and insulin secretion in RINm5F cells, and that gamma-tocopherol may partially prevent this. The results suggest that phospholipase C or protein kinase C may be targeted by NO. In contrast, cGMP or low voltage-activated Ca(2+) channels appear not to mediate the toxicity of NO in these cells. These adverse effects of NO on the beta-cell, and the protection by gamma-tocopherol, may be of importance for the development of the impaired insulin secretion characterizing type 1 diabetes mellitus, and offer possibilities for intervention in this process.
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PMID:gamma-tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide. 1103 27

Vascular endothelial growth factor (VEGF) induces adhesion molecules on endothelial cells during inflammation. Here we examined the mechanisms underlying VEGF-stimulated expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in human umbilical vein endothelial cells. VEGF (20 ng/ml) increased expression of ICAM-1, VCAM-1, and E-selectin mRNAs in a time-dependent manner. These effects were significantly suppressed by Flk-1/kinase-insert domain containing receptor (KDR) antagonist and by inhibitors of phospholipase C, nuclear factor (NF)-kappaB, sphingosine kinase, and protein kinase C, but they were not affected by inhibitors of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 or nitric-oxide synthase. Unexpectedly, the phosphatidylinositol (PI) 3'-kinase inhibitor wortmannin enhanced both basal and VEGF-stimulated adhesion molecule expression, whereas insulin, a PI 3'-kinase activator, suppressed both basal and VEGF-stimulated expression. Gel shift analysis revealed that VEGF stimulated NF-kappaB activity. This effect was inhibited by phospholipase C, NF-kappaB, or protein kinase C inhibitor. VEGF increased VCAM-1 and ICAM-1 protein levels and increased leukocyte adhesiveness in a NF-kappaB-dependent manner. These results suggest that VEGF-stimulated expression of ICAM-1, VCAM-1, and E-selectin mRNAs was mainly through NF-kappaB activation with PI 3'-kinase-mediated suppression, but was independent of nitric oxide and MEK. Thus, VEGF simultaneously activates two signal transduction pathways that have opposite functions in the induction of adhesion molecule expression. The existence of parallel inverse signaling implies that the induction of adhesion molecule expression by VEGF is very finely regulated.
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PMID:Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. 1110 18


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