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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotransmitters and hormones such as somatostatin, galanin, and adrenalin reduce insulin secretion. Their inhibitory action involves direct interference with the exocytotic machinery. We have examined the molecular processes underlying this effect using high resolution measurements of cell capacitance. Suppression of exocytosis was maximal at concentrations that did not cause complete inhibition of glucose-stimulated electrical activity. This action was dependent on activation of G proteins but was not associated with inhibition of the voltage-dependent Ca2+ currents or adenylate cyclase activity. The molecular processes initiated by the agonists culminate in the activation of the Ca(2+)-dependent protein phosphatase calcineurin, and suppression of the activity of this enzyme abolishes their action on exocytosis. We propose that mechanisms similar to those we report here may contribute to adrenergic and peptidergic inhibition of secretion in other neuroendocrine cells and in nerve terminals.
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PMID:Neurotransmitter-induced inhibition of exocytosis in insulin-secreting beta cells by activation of calcineurin. 881 14

Yeast respond to a variety of stresses through a global stress response that is mediated by a number of signal transduction pathways and the cis-acting STRE DNA sequence. The CYC7 gene, encoding iso-2-cytochrome c, has been demonstrated to respond to heat shock, glucose starvation, approach-to-stationary phase, and, as we demonstrate here, to osmotic stress. This response was delayed in a the hog1-delta 1 strain implicating the Hog1 mitogen-activated protein kinase cascade, a known component of the global stress response. Deletion analysis of the CYC7 regulatory region suggested that three STRE elements were each capable of inducing the stress response. Mutations in the ROX3 gene prevented CYC7 RNA accumulation during heat shock and osmotic stress. ROX3 RNA levels were shown to be induced by stress through a novel regulatory element. A selection for high-copy suppressors of a ROX3 temperature-sensitive allele resulted in the isolation of RTS1, encoding a protein with homology to the B' regulatory subunit of protein phosphatase 2A0. Deletion of RTS1 caused temperature and osmotic sensitivity and increased accumulation of CYC7 RNA under all conditions. Over-expression of this gene caused increased CYC7 RNA accumulation in rox3 mutants but not in wild-type cells.
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PMID:Rox3 and Rts1 function in the global stress response pathway in baker's yeast. 884 89

It has been shown that okadaic acid (OA) diminishes insulin secretion of rat pancreatic islets in response to glucose, glyceraldehyde and KCl. Glucose, glyceraldehyde and KCl cause release of insulin by depolarization and subsequent opening of L-type calcium channels. Calcium entry into cells is thought to be related to protein phosphorylation. To evaluate whether or not OA mediated inhibition of insulin secretion in response to depolarization might be due to an interference with calcium uptake, we studied its effect on KCl (30 mM)-induced increases of cytosolic calcium and discharge of insulin in the insulin secreting clonal tumor cell line RINm5F. OA inhibited KCl-stimulated insulin release in concentrations > or = 1 microM. In intact RINm5F cells similar concentrations of OA decreased the activity of protein phosphates PP-1/PP-2A and inhibited the depolarization-induced rise of cytosolic calcium ([Ca2+]i). The latter action could also be achieved with the protein phosphatase inhibitor calyculin A, whereas the OA analogue 1-nor-okadaone, which is without effect on phosphatases, did not affect [Ca2+]i or insulin release. It is concluded that depression of depolarization-induced insulin secretion by OA is due to inhibition of calcium entry along voltage dependent calcium channels. The data also suggest that in RINm5F cells protein phosphatases PP-1/PP-2A are related to the function of voltage-dependent calcium channels.
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PMID:The phosphatase inhibitor okadaic acid blocks KCl-depolarization-induced rise of cytosolic calcium of rat insulinoma cells (RINm5F). 885 85

The possibility of an insulin-independent blood glucose decreasing activity of sulfonylureas was re-evaluated. Single dose studies in dogs with different sulfonylureas revealed a ranking in the ratio of plasma insulin release/blood glucose decrease with glimepiride exhibiting the lowest and glibenclamide the highest ratio. This ranking suggests that sulfonylureas have extrapancreatic activity and that this is most pronounced for glimepiride. Further evidence for this was derived from single dose studies in rabbits, euglycemic hyperinsulinemic clamp studies in rats and subchronic studies in manifestly diabetic KK-AY mice. Extrapancreatic activity of sulfonylureas as deduced from the ranking in vivo between glimepiride and glibenclamide directly on peripheral tissues would imply a similar ranking between the two drugs in glucose utilizing processes in isolated muscle and fat cells. Indeed, glimepiride exhibits a higher potency compared to glibenclamide with respect to stimulation of glucose transport, glucose transporter isoform 4 (GLUT4) translocation and lipid and glycogen synthesis in normal and insulin-resistant adipocytes and in muscle cells, as well as of the potential underlying signalling processes examined at the molecular level. The molecular basis for the sulfonylurea-induced increase of glucose transport and non-oxidative glucose metabolism may rely on the dephosphorylation of key metabolic proteins/enzymes, like GLUT4 as demonstrated in isolated rat adipocytes. Activation of certain serine/threonine-specific protein phosphatases by insulin has been postulated to be mediated by the mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol (P1)-3'-kinase. However, there was no evidence that these pathways are involved in the regulation of protein phosphatase activity by sulfonylureas. Binding and photoaffinity studies showed that glimepiride associates in a time- and concentration dependent non-saturable manner with detergent-insoluble complexes of the plasma membrane which may correspond to caveolae. This association seems to be based on the interaction of glimepiride with glycosyl-phosphatidylinositol (GPI) lipids and membrane protein anchors. These were found to be enriched in detergent-insoluble complexes together with a GPI-specific phospholipase (PLC), the caveolae-specific coast protein, caveolin, and acylated tyrosine kinases of the src family. Sulfonylureas were found to stimulate the GPI-PLC and tyrosine phosphorylation of caveolin. This is presumably caused by direct interaction of the sulfonylurea into caveolar glycolipids and stimulation of a caveolar src tyrosine kinase, respectively. In accordance with the higher potency of glimepiride in vivo and in glucose transport/metabolism in vitro, the EC50 values for GPI-PLC activation and caveolin phosphorylation were lower for glimepiride than those for glibenclamide. The stimulation of protein tyrosine phosphorylation by sulfonylureas via this pathway not involving the insulin signaling cascade may be coupled to activation of specific protein phosphatases regulating glucose transport and metabolism. The concentrations required in vitro were higher than the reported therapeutic plasma concentrations. However, provided that the observed time-dependent accumulation of glimepiride in caveolae of peripheral cells were of functional relevance for stimulation of glucose transport/metabolism and would also occur in vivo, due to the longer exposure times even at lower drug concentrations the insulin-independent blood glucose decreasing activity of sulfonylureas might become effective in vivo.
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PMID:Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at adipocytes. 891 85

Effects of the immunosuppressant cyclosporin A (CsA), a specific inhibitor of Ca2+/calmodulin-dependent protein phosphatase (PP2B), were examined with regard to the induction of insulin secretion from MIN6 cells, a glucose-responsive cell line derived from mouse insulinoma. CsA had no effect on basal insulin secretion from MIN6 cells, but did increase glucose-, tolbutamide-, and KCl-induced insulin secretion. Treatment of the cells with CsA resulted in a dose-dependent increase in insulin secretion, which was maximal at 3 microM. CsA inhibited PP2B activity in a dose-dependent manner, and the increase in insulin secretion correlated with the decrease in PP2B activity. In 32P-labeled cells, treatment with CsA for 30 min increased phosphorylation of synapsin I-like protein by 50 +/- 5.7%. As revealed by one-dimensional phosphopeptide mapping of 32P-labeled synapsin I-like protein, treatment with CsA for 30 min increased phosphorylation of site II of synapsin I-like protein by 59 +/- 8%, which is phosphorylated by calmodulin kinase II. Messenger RNAs, which hybridize with complementary DNAs of calcineurin A and B subunits from rat brain, were detected in MIN6 cells. Western blot analysis showed a 61-kDa band, which interacts with rat brain calcineurin A antibody. Similar increases in secretagogue-induced insulin secretion with CsA were observed for HIT-T15 cells. These results suggest that CsA stimulates glucose-induced insulin secretion by inhibiting the activity of PP2B, an event that may be involved in mechanisms governing glucose-induced insulin secretion via dephosphorylation of synapsin I-like protein in MIN6 cells.
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PMID:Cyclosporin A stimulation of glucose-induced insulin secretion in MIN6 cells. 894 Mar 43

In the rat, cytochrome P4501A1 gene expression is thought to be regulated by several trans-acting factors including the 4 S polycyclic aromatic hydrocarbon (PAH)-binding protein. Phosphorylation and dephosphorylation have been suggested to influence the function of many cytosolic receptors and transcription factors. The ATP level within H4IIE rat hepatoma cells could be depleted by treatment with sodium azide or 2,4-dinitrophenol; restoration of the original ATP levels occurred with addition of glucose to the cell culture. ATP depletion reduced the phosphate content of the 4 S protein by approximately 25-30%, which lowered the binding of benzo[a]pyrene (B[a]P) to the 4 S protein by >60%. This effect could not be reversed by the addition of ATP to the binding reaction mixtures. Alkaline phosphatase treatment of the purified 4 S protein in a cell-free system also reduced the B[a]P binding to the protein. Cells treated with a protein phosphatase inhibitor, okadaic acid, and a protein kinase inhibitor, staurosporin, affected the B[a]P binding of the 4 S protein positively and negatively, respectively. These data suggested that phosphorylation is involved in the interaction of the 4 S protein with the PAH. The nuclear translocation of the predominantly cytosolic binding protein has been investigated after ligand binding. Western blots with the immunopurified 4 S PAH-binding protein from cytosolic and nuclear lysates showed significant differences in the distribution of the 4 S receptor between cytosolic and nuclear compartments in control and ATP-depleted cells. Ligand binding stimulated the movement of the receptor into the nucleus, which was completely blocked by reducing the intracellular ATP concentration. These findings provide new information on the role of ATP and phosphorylation on the interaction of B[a]P with 4 S PAH-binding protein and its nuclear translocation.
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PMID:ATP depletion affects the phosphorylation state, ligand binding, and nuclear transport of the 4 S polycyclic aromatic hydrocarbon-binding protein in rat hepatoma cells. 895 80

FK506 (tacrolimus) is an immunosuppressive drug which interrupts Ca2+-calmodulin-calcineurin signaling pathways in T lymphocytes, thereby blocking antigen activation of T cell early activation genes. Regulation of insulin gene expression in the beta cell may also involve Ca2+-signaling pathways and FK506 has been associated with insulin-requiring diabetes mellitus during clinical use. The purpose of this study was to characterize the effects of FK506 on human insulin gene transcription, insulin mRNA levels, and insulin secretion using as a model the HIT-T15 beta cell line. FK506 had no acute effect on insulin secretion in the HIT cell, but caused a reversible time- and dose-dependent (10(-9)-10(-6) M) decrease in HIT cell insulin secretion. Decreased insulin secretion in the presence of FK506 was also accompanied by a dose-dependent decrease in HIT cell insulin content, insulin mRNA levels, and expression of a human insulin promoter-chloramphenicol acetyl transferase (CAT) reporter gene. FK506 decreased HIT cell expression of the human insulin promoter-CAT reporter gene by 40% in the presence of both low (0.4 mM) at high (20 mM) glucose concentrations. Western blot analysis of HIT cell proteins gave evidence for the presence of calcineurin in the HIT cell. These findings suggest that FK506 may have direct effects to reversibly inhibit insulin gene transcription, leading to a decline in insulin mRNA levels, insulin synthesis, and ultimately insulin secretion.
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PMID:Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells. 898 25

The SNF1 protein kinase is broadly conserved in eukaryotes and has been implicated in responses to environmental and nutritional stress. In yeast, the SNF1 kinase has a central role in the response to glucose starvation. SNF1 is associated with its activating subunit, SNF4, and other proteins in complexes. Using the two-hybrid system, we show that interaction between SNF1 and SNF4 is strongly regulated by the glucose signal. Moreover, this interaction is appropriately affected by mutations in regulators, including protein phosphatase 1. We show that SNF4 binds to the SNF1 regulatory domain in low glucose, whereas in high glucose the regulatory domain binds to the kinase domain of SNF1 itself. Genetic analysis further suggests that the SNF1 regulatory domain autoinhibits the kinase activity and that in low glucose SNF4 antagonizes this inhibition. Finally, these interactions have been conserved from yeast to plants, indicating that homologs of the SNF1 kinase complex respond to regulatory signals by analogous mechanisms.
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PMID:Glucose regulates protein interactions within the yeast SNF1 protein kinase complex. 898 80

The effects of isometric contraction (66% of maximal force) and recovery on glycogen synthase fractional activity (GSF) in human skeletal muscle have been studied. Biopsies were taken from the quadriceps femoris muscle at rest, at fatigue and 5 min postexercise on two occasions: after one of the contractions, the circulation to the thigh was occluded during the 5 min recovery (OCC), and after the other contraction, the circulation was intact (control, CON). During CON, GSF decreased from (mean +/- SE) 0.34 +/- 0.05 at rest to 0.24 +/- 0.02 at fatigue and then increased to 0.74 +/- 0.04 at 5 min postexercise; corresponding values for OCC were 0.37 +/- 0.04, 0.25 +/- 0.04 and 0.48 +/- 0.05 (P < 0.001 vs. CON for 5 min postexercise only). Compared with the value at fatigue, protein phosphatase activity (PP) increased by 79 +/- 16% during CON recovery (P < 0.01), whereas no change was observed during OCC recovery. Uridine diphosphate glucose increased by approximately 2.5-fold at fatigue, remained elevated during OCC recovery, but reverted to the preexercise level during CON recovery (P < 0.001 vs. OCC recovery). Glucose 6-P increased approximately 5-fold at fatigue and was higher at 5 min postexercise in OCC vs. CON recovery (8.6 +/- 1.5 vs. 4.1 +/- 0.9 mmol/kg dry wt; P < 0.01). It is concluded that the rapid increase in GSF after intense exercise with an intact circulation may be at least partly attributed to an increase in the specific activity of PP. The increase in GSF during recovery in OCC may be at least partly attributed to the high glucose 6-P content in vivo, which enhances the substrate suitability of GS for PP. Thus, separate mechanisms exist for the activation of PP and GS during recovery from intense short term exercise.
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PMID:Rapid activation of glycogen synthase and protein phosphatase in human skeletal muscle after isometric contraction requires an intact circulation. 902 87

It has been suggested that, in pancreatic beta-cells, acetyl-CoA carboxylase (ACC) is a key enzyme in glucose signal transduction leading to glucose-induced insulin secretion. The PII promoter is the only active promoter for the ACC gene in the beta-cell. Here we report that, in the pancreatic beta-cell, high glucose levels (above 20 mm) activate Sp1 binding to the glucose response element of the PII promoter, which leads to a dose-dependent increase in PII transcription. The expression of a gene coding protein kinase CK2 (CK2) alpha subunit, or the presence of okadaic acid (a serine/threonine protein phosphatase inhibitor), partially blocks the glucose activation of PII transcription. The inhibitory effect of CK2 alpha, or okadaic acid, was not observed in the absence of glucose or at low glucose concentrations. Phosphorylation of Sp1 by CK2 alpha leads to the inactivation of Sp1 binding to PII. Dephosphorylation of the phosphorylated Sp1 by protein phosphatase 1 (PP1) activates the binding of Sp1 to PII. Inhibition of PP1-catalyzed Sp1 dephosphorylation by okadaic acid, or PP1 specific inhibitor 2, decreases Sp1 binding to PII. These results suggest that the phosphorylation/dephosphorylation of Sp1 by CK2/PP1 may be the underlying mechanism by which the expression of the PII promoter of ACC is controlled in the process of glucose-mediated insulin secretion in pancreatic beta-cells.
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PMID:Protein kinase CK2 down-regulates glucose-activated expression of the acetyl-CoA carboxylase gene. 902 76


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