Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The hypoglycemic sulfonylurea drugs cause reduction of blood glucose predominantly via stimulation of insulin release from pancreatic beta cells. In addition, during long-term treatment, an insulin-independent blood glucose-decreasing mechanism is assumed to operate. This may include insulin-sensitizing and insulin-mimetic activity in muscle and adipose tissue. This review summarizes our current knowledge about the putative modes of action of the sulfonylurea compound, Amaryl, in pancreatic beta cells and, in particular, peripheral target cells that form the molecular basis for its characteristic pharmacological and clinical profile. The analysis was performed in comparison with the conventional and the "golden standard" sulfonylurea, glibenclamide. I conclude: (I) The blood glucose decrease provoked by Amaryl can be explained by a combination of stimulation of insulin release from the pancreas and direct enhancement, as well as potentiation of the insulin response of glucose utilization in peripheral tissues only. (II) The underlying molecular mechanisms seemed to rely on beta cells on a sulfonylurea receptor protein, SURX, associated with the ATP-sensitive potassium channel (K(ATP)) and different from SUR1 for glibenclamide, and in muscle and adipose cells on: (a) the increased production of diacylglycerol and activation of protein kinase C; (b) the enhanced expression of glucose transporter isoforms; and (c) the insulin receptor-independent activation of the insulin receptor substrate/phosphatidylinositol-3-kinase pathway. (III) The latter mechanism involved a nonreceptor tyrosine kinase and a number of components, such as caveolin and glycosylphosphatidylinositol structures, which are assembled in caveolae/detergent-insoluble glycolipid-enriched rafts of the target cell plasma membrane. Since hyperinsulinism and permanent K(ATP) closure are supposed to negatively affect the pathogenesis and therapy of non-insulin-dependent diabetes mellitus, the demonstrated higher insulin-independent blood glucose-lowering activity of Amaryl may be therapeutically relevant.
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PMID:The molecular mechanism of the insulin-mimetic/sensitizing activity of the antidiabetic sulfonylurea drug Amaryl. 1114 70

In the rat, dexamethasone treatment during late pregnancy leads to intrauterine growth retardation and is used as a model of early programming of adult onset disease. The present study investigated whether pre-natal dexamethasone treatment modifies cardiac glucose transporter (GLUT) protein expression in adulthood and identified signalling pathways involved in the response. Dexamethasone (100 microg/kg body wt per day) administered via an osmotic pump to pregnant rats (day 15 to day 21; term=22 to 23 days) reduced fetal weight at day 21 and caused hypertension, hyperinsulinaemia and elevated corticosterone levels in the adult (24-week-old) male offspring. Cardiac GLUT1 protein expression was selectively up-regulated (2.5-fold; P<0.001), in the absence of altered cardiac GLUT4 protein expression, in adult male offspring of dexamethasone-treated dams. Maternal dexamethasone treatment did not influence cardiac GLUT1 protein expression during fetal or early post-natal life. We examined potential regulatory signalling proteins that might mediate up-regulation of cardiac GLUT1 protein expression in adulthood. We observed marked (2.2-fold; P<0.01) activation of Akt/protein kinase B (PKB), together with modest activation of the anti-apoptotic protein kinase C (PKC) isoforms PKC alpha (88%, P<0.05) and PKC epsilon (56%, P<0.05) in hearts of the early-growth-retarded male offspring. These effects were, however, observed in conjunction with up-regulation of cardiac protein expression of PKC beta(1) (191%, P<0.01), PKC beta(2) (49%, P<0.05) and PKC delta (35%; P<0.01), effects that may have adverse consequences. Maternal dexamethasone treatment was without effect on cardiac extracellular signal-related kinase (ERK) 1 or ERK2 activity in adulthood. In conclusion, our data demonstrate an effect of maternal dexamethasone treatment to up-regulate cardiac GLUT1 protein expression in early-growth-retarded, hypertensive, hyperinsulinaemic adult male offspring, an effect observed in conjunction with activation of Akt/PKB.
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PMID:Early growth retardation induced by excessive exposure to glucocorticoids in utero selectively increases cardiac GLUT1 protein expression and Akt/protein kinase B activity in adulthood. 1125 Jun 42

Over the last decade, a debate has developed about the mechanism of the passive or 'diffusive' component of intestinal glucose absorption and, indeed, whether it even exists. Pappenheimer and colleagues have proposed that paracellular solvent drag contributes a passive component, which, at high concentrations of sugars similar to those in the jejunal lumen immediately after a meal, is severalfold greater than the active component mediated by the Na+-glucose cotransporter SGLT1. On the other hand, Ferraris & Diamond maintain that the kinetics of glucose absorption can be explained solely in terms of SGLT1 and that a passive or paracellular component plays little, if any, part. Recently, we have provided new evidence that the passive component of glucose absorption exists, but is in fact facilitated since it is mediated by the rapid, glucose-dependent activation and recruitment of the facilitative glucose transporter GLUT2 to the brush-border membrane; regulation involves a protein kinase C (PKC)-dependent pathway activated by glucose transport through SGLT1 and also involves mitogen-activated protein kinase (MAP kinase) signalling pathways. This topical review seeks to highlight the significant points of the debate, to show how our proposals on GLUT2 impact on different aspects of the debate and to look at the regulatory events that are likely to be involved in the short-term regulation of sugar absorption during the assimilation of a meal.
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PMID:The facilitated component of intestinal glucose absorption. 1125 Oct 42

Glucose serves as the major energy substrate and the main precursor for the synthesis of glycosaminoglycans in chondrocytes. Facilitated glucose transport represents the first rate-limiting step in glucose metabolism. This study examines molecular regulation of facilitated glucose transport in normal human articular chondrocytes by proinflammatory cytokines. IL-1beta and TNF-alpha, and to a lesser degree IL-6, accelerate facilitated glucose transport as measured by [(3)H]2-deoxyglucose uptake. IL-1beta induces an increased expression of glucose transporter (GLUT) 1 mRNA and protein, and GLUT9 mRNA. GLUT3 and GLUT8 mRNA are constitutively expressed in chondrocytes and are not regulated by IL-1beta. GLUT2 and GLUT4 mRNA are not detected in chondrocytes. IL-1beta stimulates GLUT1 protein glycosylation and plasma membrane incorporation. IL-1beta regulation of glucose transport in chondrocytes depends on protein kinase C and p38 signal transduction pathways, and does not require phosphoinositide 3-kinase, extracellular signal-related kinase, or c-Jun N-terminal kinase activation. IL-1beta-accelerated glucose transport in chondrocytes is not mediated by endogenous NO or eicosanoids. These results demonstrate that stimulation of glucose transport represents a component of the chondrocyte response to IL-1beta. Two classes of GLUTs are identified in chondrocytes, constitutively expressed GLUT3 and GLUT8, and the inducible GLUT1 and GLUT9.
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PMID:Cytokine regulation of facilitated glucose transport in human articular chondrocytes. 1173 20

In the rat liver epithelial cell line Clone 9, the V(max) for glucose uptake is acutely increased by inhibition of oxidative phosphorylation and by osmotic stress. By using a membrane-impermeant photoaffinity labelling reagent together with an isoform-specific antibody, we have, for the first time, provided direct evidence for the involvement of the GLUT1 glucose transporter isoform in this response. Transport stimulation was found to be associated with enhanced accessibility of GLUT1 to its substrate and with photolabelling of formerly 'cryptic' exofacial substrate binding sites in GLUT1 molecules. The total amount of cell surface GLUT1 remained constant. The precise mechanism for this binding site 'unmasking' is unclear but appears to involve AMP-activated protein kinase: in the current study, osmotic and metabolic stresses were found to result in activation of the alpha 1 isoform of AMP-activated protein kinase, and transport stimulation could be mimicked both by 5-aminoimidazole-4-carboxamide ribonucleoside and by infection of cells with a recombinant adenovirus encoding constitutively active AMP-activated protein kinase. The effect of 5-aminoimidazole-4-carboxamide ribonucleoside, as for metabolic stress, was on the V(max) rather than on the K(m) for transport and did not affect the cell-surface concentration of GLUT1. The relevant downstream target(s) of AMP-activated protein kinase have not yet been identified, but stimulation of transport by inhibition of oxidative phosphorylation or by 5-aminoimidazole-4-carboxamide ribonucleoside was not prevented by either inhibitors of conventional and novel protein kinase C isoforms or inhibitors of nitric oxide synthase. These enzymes, which have been implicated in stress-regulated pathways in other cell types, are therefore unlikely to play a role in transport regulation by stress in Clone 9 cells.
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PMID:Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK). 1200 27

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

Insulin-responsive aminopeptidase (IRAP) colocalizes with glucose transporter type 4 (GLUT4) in adipocytes and is recruited to the plasma membrane in response to insulin. Microinjection of peptides corresponding to the IRAP cytoplasmic domain sequences causes GLUT4 recruitment in adipocytes. Inhibitors of protein kinase C-zeta (PKC-zeta) abolish the insulin-induced GLUT4 recruitment in rat adipocytes. These findings suggest an interesting possibility that PKC-zeta may phosphorylate IRAP, playing a key role in GLUT4/IRAP recruitment. To test this possibility, here we studied the (32)P incorporation into IRAP catalyzed by PKC-zeta in insulin-stimulated cells. There was a small but significant (32)P incorporation into IRAP in rat adipocytes, which was partly abolished upon addition of a PKC-zeta pseudosubstrate, suggesting that PKC-zeta may be responsible in part for the IRAP phosphorylation in adipocytes. PKC-zeta also catalyzed the incorporation of (32)P not only into IRAP in GLUT4 vesicles isolated from rat adipocytes but also into the IRAP cytoplasmic domain inserts in glutathione S-transferase-fusion proteins, demonstrating direct IRAP phosphorylation by PKC-zeta. Reversed-phase HPLC, matrix-assisted laser desorption ionization mass spectrometry, and radiosequencing of the tryptic digests of the (32)P-labeled IRAP fusion proteins identified Ser-80 and Ser-91 as major phosphorylation sites. In GLUT4 vesicles, the (32)P incorporation into IRAP was exclusively localized at a 6.9-kDa tryptic fragment identified as IRAP(76-138) and the (32)P labeling at Ser-80 accounted for 80-90% of the total IRAP labeling, suggesting that Ser-80 is the major phosphorylation site in intact IRAP. These findings are consistent with the possibility that the IRAP cytoplasmic domain phosphorylation by PKC-zeta plays a key role in insulin-induced IRAP or GLUT4 recruitment in adipocytes.
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PMID:Protein kinase C-zeta phosphorylates insulin-responsive aminopeptidase in vitro at Ser-80 and Ser-91. 1206 4

We develop a mathematical model that explicitly represents many of the known signaling components mediating translocation of the insulin-responsive glucose transporter GLUT4 to gain insight into the complexities of metabolic insulin signaling pathways. A novel mechanistic model of postreceptor events including phosphorylation of insulin receptor substrate-1, activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-zeta is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation. A system of differential equations is defined by the structure of the model. Rate constants and model parameters are constrained by published experimental data. Model simulations of insulin dose-response experiments agree with published experimental data and also generate expected qualitative behaviors such as sequential signal amplification and increased sensitivity of downstream components. We examined the consequences of incorporating feedback pathways as well as representing pathological conditions, such as increased levels of protein tyrosine phosphatases, to illustrate the utility of our model for exploring molecular mechanisms. We conclude that mathematical modeling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signaling.
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PMID:A mathematical model of metabolic insulin signaling pathways. 1237 38

In the development of diabetic nephropathy, angiotensin (Ang) II is thought to exert numerous actions on the glomerulus, and especially on the mesangium. However, the role(s) played by Ang II in the glucose metabolism per se in mesangial cells remains unclear. Ang II, at least via its type 1 receptor (AT1-R)-mediated effect, phosphorylates extracellular signal regulated kinase (ERK) by transactivation of epidermal growth factor receptors (EGF-Rs) via the Ca2+ or protein kinase C (PKC) pathways. Our objective in the present study was to assess the effect of Ang II on glucose transporter 1 (GLUT1) gene expression and to clarify the involvement of EGF-R in Ang II-mediated GLUT1 mRNA expression in glomerular mesangial cells. The results showed that Ang II upregulated GLUT1 mRNA accumulation in a time- and dose-dependent manner (peaking at 12 h; approximately 3.8-fold vs. control), and this upregulation was completely inhibited by the PKC inhibitor calphostin-C. The Ang Il-induced GLUT1 expression was significantly inhibited by the EGF-R inhibitor AG1478 (approximately 80% inhibition), by inactivation of ERK by PD98059, and by pretreatment with heparin and the metalloproteinase (MMP) inhibitor batimastat. On the other hand, phorbol ester markedly upregulated GLUT1 mRNA (approximately 8.6-fold). Batimostat and AG1478 significantly reduced the phorbol ester-induced GLUT1 mRNA expression (approximately 72 and approximately 69% inhibition, respectively). In conclusion, PKC-mediated heparin-binding (HB)-EGF/EGF transactivation followed by ERK activation plays a predominant role in the induction of GLUT1 expression by Ang II.
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PMID:Regulation of glucose transporter (GLUT1) gene expression by angiotensin II in mesangial cells: involvement of HB-EGF and EGF receptor transactivation. 1266 15


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