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)

Insulin causes the activation of phosphatidylinositol 3-kinase (PI 3-kinase) through complexation of tyrosine-phosphorylated YMXM motifs on insulin receptor substrate 1 with the Src homology 2 domains of PI 3-kinase. Previous studies with inhibitors have indicated that activation of PI 3-kinase is necessary for the stimulation of glucose transport in adipocytes. Here, we investigate whether this activation is sufficient for this effect. Short peptides containing two tyrosine-phosphorylated or thiophosphorylated YMXM motifs potently activated PI 3-kinase in the cytosol from 3T3-L1 adipocytes. Introduction of the phosphatase-resistant thiophosphorylated peptide into 3T3-L1 adipocytes through permeabilization with Staphylococcus aureus alpha-toxin stimulated PI 3-kinase as strongly as insulin. However, under the same conditions the peptide increased glucose transport into the permeabilized cells only 20% as well as insulin. Determination of the distribution of the glucose transporter isotype GLUT4 by confocal immunofluorescence showed that GLUT4 translocation to the plasma membrane can account for the effect of the peptide. These results suggest that one or more other insulin-triggered signaling pathways, besides the PI 3-kinase one, participate in the stimulation of glucose transport.
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PMID:Effect of the activation of phosphatidylinositol 3-kinase by a thiophosphotyrosine peptide on glucose transport in 3T3-L1 adipocytes. 759 91

Insulin is the only known hormone which rapidly stimulates glucose uptake in target tissues, mainly by translocation to the cell surface of the intracellular insulin-regulatable glucose transporter (glucose transporter type 4, GLUT4). We have developed a cell line for direct, sensitive detection of GLUT4 on the cell surface. We have suggested that insulin-activated phosphatidylinositol (PI) 3-kinase may be involved in the signaling pathway of insulin-stimulated GLUT4 translocation. We report that platelet-derived growth factor (PDGF), which stimulates PI 3-kinase activity, triggers GLUT4 translocation in Chinese hamster ovary (CHO) cells stably overexpressing the PDGF receptor and in 3T3-L1 mouse adipocytes. Using mutant PDGF receptors that cannot bind to Ras-GTPase-activating protein, phospholipase C-gamma, and PI 3-kinase, respectively, we obtained evidence that PI 3-kinase binding sites play a key role in the signaling pathway of PDGF-stimulated GLUT4 translocation in the CHO cell system.
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PMID:Platelet-derived growth factor triggers translocation of the insulin-regulatable glucose transporter (type 4) predominantly through phosphatidylinositol 3-kinase binding sites on the receptor. 786 37

The contribution of extrapancreatic effects of sulfonylureas to the blood glucose-decreasing activity was reevaluated in vivo and in vitro with several conventional sulfonylureas and with the new one glimepiride. In vivo, in dogs, after single approximately equipotent blood glucose-decreasing doses, the sulfonylureas were tested for a ranking in the ratios of mean plasma insulin-increasing and blood glucose-decreasing activity. Studies were also performed in hyperglycemic hyperinsulinemic KK-Ay mice under once daily treatment for 8 weeks. In vitro, glimepiride and glibenclamide were tested for the ranking of their extrapancreatic activity with respect to the stimulation of glucose transport and glucose metabolizing processes in normal and insulin-resistant fat cells as well as in the isolated diaphragm. Furthermore, in vitro studies were performed, especially with glimepiride, in order to characterize the molecular mechanism for the extrapancreatic activity. The dog studies revealed a marked ranking in the ratios of plasma insulin-increasing and blood glucose-decreasing activity between the different sulfonylureas (glimepiride < glipizide < gliclazide < glibenclamide). In the hyperglycemic hyperinsulinemic KK-Ay mice, glimepiride reduced blood glucose by 40%, plasma insulin by 50% and HBA1c by 33%, whereas glibenclamide and gliclazide had no effect on these parameters. In vitro, glimepiride and glibenclamide had extrapancreatic effects within the lower microM range, with glimepiride exhibiting 2-3-fold lower ED50 values than glibenclamide. In the absence of insulin, both stimulated glucose transport--up to 60% of the maximum insulin response in the rat diaphragm and up to 35% in 3T3 adipocytes. Glycogenesis was stimulated in the rat diaphragm--up to 55% of the maximum insulin effect; lipogenesis in 3T3 adipocytes--up to 40%. The studies on the molecular mechanism of extrapancreatic activity with rat adipocytes and diaphragm suggest that these direct insulin-mimetic effects rely on the induction of GLUT4 translocation from internal stores to the plasma membrane and on the activation of the key metabolic enzymes, glycogen synthase and glycerol-3-phosphate acyltransferase. These processes occur within the same drug concentration range and with the same ranking between glimepiride and glibenclamide as observed for glucose utilization and transport. The direct effects of sulfonylureas may ultimately be regulated by a glycosyl-phosphatidylinositol-specific phospholipase C, shown to be activated by glimepiride in rat adipocytes. Lipolytic cleavage products thereby generated from glycolipidic structures may in turn stimulate specific protein phosphatases which activate key regulatory proteins/enzymes of glucose and lipid metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Extrapancreatic effects of sulfonylureas--a comparison between glimepiride and conventional sulfonylureas. 852 4

Overexpression of surrogate receptors [epidermal growth factor (EGF) receptor (EGFR) and platelet-derived growth factor receptor] in adipocytes has demonstrated that multiple signaling pathways may lead to GLUT4-mediated glucose uptake. These implicated pathways function independently of IRS-1 phosphorylation and PI3-kinase activation. In addition, we previously demonstrated that EGFR tyrosyl autophosphorylation is required to stimulate GLUT4-mediated glucose transport in 3T3-L1 adipocytes. This observation suggests that signaling molecules that are dependent on EGFR autophosphorylation, such as phospholipase C (PLC), may lie in the signaling pathway to glucose transport. As PLC has been implicated in glucose transport by several clinical and basic mechanistic studies, we investigated whether EGFR signaling may promote glucose transport via modulation of PLC activity. Activation of EGFR overexpressing 3T3-L1 adipocytes leads to a 3.4 +/- 1.2-fold stimulation of PLC activity over basal levels vs. only 1.06 +/- 0.01-fold stimulation by insulin. Pharmacological inhibition of PLC by 50 microM U73122 reduced phosphoinositide accumulation by 79.2 +/- 16.9% and resulted in a concomitant 56.0 +/- 12.7% decrease in EGF-induced glucose transport. This inhibition of glucose transport by U73122 was specific, because the inactive congener, U73343, failed to block EGF-induced glucose transport. Despite the low levels of insulin-induced PLC activity, insulin-stimulated glucose transport activity was similarly inhibited by U73122 (55.9 +/- 13.1% inhibition). Inhibition of PLC activation did not impair either EGF- or insulin-induced activation of glycogen synthase or incorporation of glucose into lipid, supporting the hypothesis that both EGF- and insulin-induced glucose disposal can be independent of GLUT4-mediated glucose transport. The diminution of glucose transport secondary to inhibition of PLC activity was reflected by a decrease in GLUT4 translocation to the plasma membrane upon either EGF or insulin stimulation. These results are consistent with either a permissive or an active role for PLC activity in the translocation of GLUT4 to the plasma membrane.
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PMID:A role for phospholipase C activity in GLUT4-mediated glucose transport. 938 97

Endothelin-1 (ET-1) can stimulate insulin-responsive glucose transporter (GLUT4) translocation in 3T3-L1 adipocytes (Wu-Wong, J. R., Berg, C. E., Wang, J., Chiou, W. J., and Fissel, B. (1999) J. Biol. Chem. 274, 8103-8110), and in the current study, we have evaluated the signaling pathway leading to this response. First, we inhibited endogenous Galpha(q/11) function by single-cell microinjection using anti-Galpha(q/11) antibody or RGS2 protein (a GTPase activating protein for Galpha(q)) followed by immunostaining to quantitate GLUT4 translocation in 3T3-L1 adipocytes. ET-1-stimulated GLUT4 translocation was markedly decreased by 70 or 75% by microinjection of Galpha(q/11) antibody or RGS2 protein, respectively. Pretreatment of cells with the Galpha(i) inhibitor (pertussis toxin) or microinjection of a Gbetagamma inhibitor (glutathione S-transferase-beta-adrenergic receptor kinase (GST-BARK)) did not inhibit ET-1-induced GLUT4 translocation, indicating that Galpha(q/11 )mediates ET-1 signaling to GLUT4 translocation. Next, we found that ET-1-induced GLUT4 translocation was inhibited by the phosphatidylinositol (PI) 3-kinase inhibitors wortmannin or LY294002, but not by the phospholipase C inhibitor U-73122. ET-1 stimulated the PI 3-kinase activity of the p110alpha subunit (5.5-fold), and microinjection of anti-p110alpha or PKC-lambda antibodies inhibited ET-stimulated GLUT4 translocation. Finally, we found that Galpha(q/11) formed immunocomplexes with the type-A endothelin receptor and the 110alpha subunit of PI 3-kinase and that ET-1 stimulation enhances tyrosine phosphorylation of Galpha(q/11). These results indicate that: 1) ET-1 signaling to GLUT4 translocation is dependent upon Galpha(q/11) and PI 3-kinase; and 2) Galpha(q/11) can transmit signals from the ET(A) receptor to the p110alpha subunit of PI 3-kinase, as does insulin, subsequently leading to GLUT4 translocation.
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PMID:Endothelin-1-induced GLUT4 translocation is mediated via Galpha(q/11) protein and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. 1055 59

Pancreastatin (PST), a chromogranin A-derived peptide, has counterregulatory effects on insulin in the hepatocyte and the adipocyte, suggesting a possible role in insulin resistance. The mechanism of PST action on glucose and lipid metabolism is typical of a calcium-mobilizing hormone and involves a receptor Gq/11 protein-phospholipase C (PLC)-beta pathway. In the rat adipocyte, PST inhibits insulin-mediated glucose transport, glucose utilization, and lipid synthesis, and it has a lipolytic effect but stimulates basal and insulin-stimulated protein synthesis. We have also recently studied the PST receptor-effector system in adipocyte membranes. To further investigate the mechanisms of PST effect on insulin action, we studied the cross-talk of PST with insulin signaling in the rat adipocyte. We found that PST inhibits insulin-stimulated GLUT4 translocation to the membrane, which may explain the reported inhibition of glucose transport. Tyrosine phosphorylation of the activated insulin receptor, insulin receptor substrate (IRS)-1, and p60-70 was also blunted, preventing their association with p85 phosphatidylinositol 3-kinase (PI3K) and their activity. The mechanism of this inhibition involves the activation of the "classical" protein kinase C isoforms and the serine phosphorylation of insulin receptor and IRS-1. On the other hand, PST activates the mitogen-activated protein kinase (MAPK) signaling module and enhances the effect of insulin. This pathway may account for the described effect of PST on protein synthesis. In conclusion, PST seems to inhibit the insulin-stimulated PI3K pathway in the adipocyte, whereas it activates the MAPK pathway. These data provide some clues to the PST cross-talk with insulin signaling that may explain the PST effects on glucose metabolism and protein synthesis.
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PMID:Pancreastatin modulates insulin signaling in rat adipocytes: mechanisms of cross-talk. 1092 27

In an attempt to know the functional role of alpha1A-adrenoceptors in adipose tissue, white adipocytes (WAT) of Wistar rats were used to investigate the change of glucose uptake after pharmacological activation of alpha1-adrenoceptors. Methoxamine enhanced the uptake of radioactive glucose into isolated WAT in a concentration-dependent manner. Translocation of glucose transporter (GLUT4) from cytosol to membrane was also stimulated with methoxamine. Action of methoxamine to raise glucose uptake was abolished in WAT pre-incubated with the antagonists, both tamsulosin and WB 4101, at concentrations sufficient to block alpha1A-adrenoceptors. However, chlorethylclonidine (CEC). the antagonist of alpha1B-adrenoceptors, showed the inhibition of methoxamine-induced action only at a higher concentration. Even under the treatment with maximal concentration of CEC, methoxamine can produce action about 80% of the vehicle-treated control. The major role of alpha1A-adrenoceptors in the stimulation of glucose uptake by methoxamine can thus be considered. In the presence of specific inhibitor of phospholipase C (PLC), U73312, methoxamine-stimulated glucose uptake into WAT was reduced in a concentration-dependent manner and U73343, the negative control of U73312, did not affect the action of methoxamine. Moreover, chelerythrine and GF 109203X diminished the methoxamine-stimulated glucose uptake at a concentration sufficient to inhibit protein kinase C (PKC). Inhibition of phosphoinositide-3 kinase (PI-3 kinase) by LY294002 also abolished methoxamine-stimulated glucose uptake. Therefore. the obtained data suggest that an activation of alpha1A-adrenoceptors, presence in WAT, by agonist and/or neurotransmitter may increase the glucose uptake via PLC-PKC pathway and the activation of PI-3 kinase.
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PMID:Role of alpha1A-adrenoceptor in the regulation of glucose uptake into white adipocyte of rats in vitro. 1111 46

Previously we have shown that the insulin receptor and phospholipase C-gamma1 physically interact in the 3T3-L1 adipocyte cell line. In this study, we investigated the ability of insulin and PDGF to stimulate PLC-gamma1 enzyme activity as measured by PI-(4,5)P(2) hydrolysis. Both insulin and PDGF caused a rapid (<1 min) increase in PLC activity associated with the respective receptor. PDGF treatment resulted in a higher and more sustained stimulation of PLC-gamma1 activity compared to insulin (0.95 pmol/min/mg vs 0.68 pmol/min/mg). Furthermore, insulin and PDGF promoted increases in total cellular DAG, one of the products of PI-(4,5)P(2) hydrolysis. Insulin-stimulated PLC activity appears to be downstream of PI-3Kinase as the DAG increase was partially blocked by Wortmannin and addition of PI-(3,4,5)P(3) activated PLC-gamma1 in vitro. Inhibition of PLC using U73122 or an inhibitory peptide caused a decrease in insulin-stimulated 2-deoxyglucose transport and GLUT4 translocation that was rescued by the addition of OAG, a cell-permeable synthetic DAG.
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PMID:Insulin activates phospholipase C-gamma1 via a PI-3 kinase dependent mechanism in 3T3-L1 adipocytes. 1140 5

Osmotic shock induces GLUT4 translocation and glucose uptake through a mechanism independent of PI 3-kinase, but dependent on tyrosine phosphorylation of cellular proteins. To identify the tyrosine phosphorylated proteins required for osmotic shock-stimulated glucose uptake, we examined tyrosine phosphorylation of candidate proteins, and found that the 60-80kDa species including paxillin and the 120-130kDa species including p130Cas, PYK2, FAK and Gab1 were tyrosine-phosphorylated in response to osmotic shock. Inhibition of actin polymerization by cytochalasin D significantly decreased the tyrosine phosphorylation of paxillin, p130Cas, PYK2 and FAK but not Gab1, but had no effect on 2-deoxyglucose (DOG) uptake, suggesting a role for Gab1 in osmotic shock-induced glucose transport. Also, we found that osmotic shock increases the association of phospholipase C-gamma (PLC-gamma) with Gab1 and stimulates tyrosine phosphorylation of PLC-gamma itself. The PLC inhibitor, U73122, inhibited osmotic shock-induced 2-DOG uptake. These results suggest that tyrosine phosphorylation of Gab1 and subsequent recruitment and activation of PLC-gamma may play a role in osmotic shock-induced glucose transport.
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PMID:Potential role of Gab1 and phospholipase C-gamma in osmotic shock-induced glucose uptake in 3T3-L1 adipocytes. 1150 76

Extracellular ATP acts as a signal that regulates a variety of cellular processes via binding to P2 purinergic receptors (P2 receptors). We herein investigated the effects and signaling pathways of ATP on glucose uptake in C(2)C(12) skeletal muscle cells. ATP as well as P2 receptor agonists (ATP-gamma S) stimulated the rate of glucose uptake, while P2 receptor antagonists (suramin) inhibited the stimulatory effect of ATP, indicating that P2 receptors are involved. This ATP-stimulated glucose transport was blocked by specific inhibitors of Gi protein (pertusiss toxin), phospholipase C (U73122), protein kinase C (GF109203X), and phosphatidylinositol (PI) 3-kinase (LY294002). ATP stimulated PI 3-kinase activity and P2 receptor antagonists blocked this activation. In C(2)C(12) myotubes expressing glucose transporter GLUT4, ATP increased basal and insulin-stimulated glucose transport. Finally, ATP facilitated translocation of GLUT1 and GLUT4 into plasma membrane. These results together suggest that cells respond to extracellular ATP to increase glucose transport through P2 receptors.
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PMID:ATP stimulates glucose transport through activation of P2 purinergic receptors in C(2)C(12) skeletal muscle cells. 1205 71


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