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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin resistance seen in diabetes mellitus has been attributed partly to impaired autophosphorylation of the insulin receptor. It has been suggested that the phosphorylation of serine and/or threonine residues of the insulin receptor may reduce tyrosine autophosphorylation in streptozotocin-induced diabetic rats (STZ-D rats). To elucidate the mechanisms of decreased autophosphorylation of the insulin receptor in diabetic rats, we have investigated the effect of dephosphorylation of the insulin receptor by alkaline phosphatase on the insulin- and protein kinase-stimulating incorporation of 32P into the receptor of the liver from STZ-D rats. Both basal and insulin-stimulated autophosphorylations of the insulin receptor from STZ-D rats were significantly impaired to those from normal rats. Dephosphorylation of the insulin receptor by alkaline phosphatase resulted in an increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats (43 +/- 13% to 66 +/- 14%, P less than 0.05), but not from normal rats (100% to 109 +/- 12%, NS). Although maximal autophosphorylation of the dephosphorylated insulin receptor was still lower in STZ-D rats than in normal rats, the increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats by dephosphorylation was higher than that from normal (159.2 +/- 27.2% vs 108.0 +/- 12.4%, p less than 0.01), supporting the idea that the residues of the insulin receptor of STZ-D rats was highly phosphorylated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dephosphorylation of the insulin receptor partially restores the decreased autophosphorylation in streptozotocin induced diabetic rats. 181 77

Human monocytes obtained by counter-current centrifugal elutriation released arachidonic acid when challenged in vitro with Con A, as well as with other soluble (PMA or ionomycin) or particulate stimuli (serum-treated zymosan). Cyclo-oxygenase metabolites were the principal eicosanoids detected in the supernatants of Con A-stimulated, [3H]arachidonate-labeled monocytes, 5-Lipoxygenase (5-LO) products, such as leukotriene B4 (LTB4), were conspicuously absent. Release of arachidonate and its metabolites in response to Con A was dependent on the presence of extracellular Ca2+, but not Mg2+. In contrast to serum-treated zymosan challenge, which resulted in increased inositol trisphosphate and LTB4 release, Con A-induced inositol phospholipid hydrolysis in monocytes was limited to phosphatidylinositol or phosphatidylinositol monophosphate. Despite an inability to augment LTB4 release, Con A or PMA induced a loss of 5-lipoxygenase from a cytosolic compartment that was similar to that achieved with a calcium ionophore (ionomycin), a potent stimulus for LTB4 generation. When cell-associated LTB4 was evaluated, evidence for increased LTB4 production was obtained in response to either stimulus (PMA greater than Con A). In combination, however, PMA and Con A treatment resulted in monocyte LTB4 release comparable with that observed with the calcium ionophore or STZ. LTB4 release in response to all stimuli tested was inhibited by MK-886, a drug that binds to 5-lipoxygenase-activating protein. These results indicate the following: 1) Phospholipase A2 activation and attendant arachidonic acid release induced by agents that increase intracellular Ca2+ and/or generate diacylglycerol results in increased synthesis and release of PG and increased synthesis of leukotrienes, but not necessarily leukotriene release. 2) 5-LO translocation, which may occur independently of increased intracellular Ca2+, may be necessary for LTB4 generation but is insufficient for its release. 3) 5-Lipoxygenase-activating protein activity is necessary for 5-LO activation and LTB4 release in response to all stimuli investigated here. 4) Phorbol ester, an activator of protein kinase C, may synergize with agents such as Con A (which by themselves induce a minimal intracellular Ca2+ rise), so as to result in the release of LTB4. Thus, Con A may represent a class of surface receptor-aggregating agents that initiates inflammatory changes or immunomodulation associated with liberation of PG and might predispose to release of other inflammatory mediators, such as leukotrienes, in the presence of additional signals including protein kinase activation.
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PMID:Calcium-dependent eicosanoid metabolism by concanavalin A-stimulated human monocytes in vitro. Synergism with phorbol ester indicates separate regulation of leukotriene B4 synthesis and release. 184 60

1. We have previously demonstrated that although rats with streptozotocin-induced diabetes (STZ-D) have decreased behavioral mechanical nociceptive thresholds (hyperalgesia), their C-fiber primary afferent mechanical (von Frey hair) thresholds are not altered. Instead, when stimulated with a standardized sustained suprathreshold mechanical stimulus, C-fibers from STZ-D rats were found to have an increased number of spikes (hyperexcitability). We suggested that this C-fiber hyperexcitability contributes to the behavioral hyperalgesia and that agents that reverse the hyperalgesia may act by decreasing this hyperexcitability. Because protein kinase C activity contributes to C-fiber afferent excitability, we examined the effect of agents that inhibit protein kinases on behavioral mechanical nociceptive thresholds and on the response of C-fiber afferents to sustained mechanical stimulation. 2. The effects of intradermal injection of two protein kinase inhibitors, staurosporine and protein kinase C pseudosubstrate inhibitor peptide [PKC(19-36)], on behavioral mechanical nociceptive thresholds were determined using the Randall-Selitto paw-withdrawal device. These agents increased the mechanical nociceptive threshold of STZ-D rats in a dose-dependent manner but did not alter nociceptive threshold in control rats. 3. The same agents were tested for their effects on single C-fiber mechanical thresholds and excitability in response to suprathreshold (445 g) mechanical stimulation. Intradermal injection of staurosporine or PKC(19-36) significantly reduced the response of C-fibers from STZ-D rats to sustained suprathreshold mechanical stimulation but did not alter the response of C-fibers from control rats to the same stimulation. Neither agent altered mechanical threshold in C-fibers from either STZ-D or control rats. 4. In this study we found that both the mechanical behavioral hyperalgesia and the C-fiber hyperexcitability to mechanical stimuli seen in STZ-D rats are reduced by agents that inhibit protein kinase C. This evidence supports our hypothesis that C-fiber hyperexcitability, in part mediated by PKC activity, contributes to hyperalgesia in this model of diabetic neuropathy.
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PMID:Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat. 798 28

N-Myristoyl transferase (NMT) is the enzyme that covalently modifies several proteins important in signal transduction. Streptozotocin-induced diabetes resulted in a 2-fold increase in NMT activity from rat liver as compared to control animals. Administration of sodium orthovanadate to the diabetic rats reduced the activity of the NMT to 75-120% of the control values. Elevated NMT activity was observed with both cAMP-dependent protein kinase-derived and pp60src-derived peptide substrates. No significant change in the apparent Km was observed with the cAMP-dependent protein kinase-derived peptide substrate. Unlike in rat brain, in all conditions highest NMT activity was observed in the particulate fraction of rat liver.
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PMID:Elevated N-myristoyl transferase activity is reversed by sodium orthovanadate in streptozotocin-induced diabetic rat. 841 83

Streptozotocin-induced diabetes caused a profound increase in the steady-state level of phosphorylation of the alpha-subunit of the adenylate cyclase inhibitory protein Gi2 in hepatocytes. Unlike hepatocytes from control animals, those from streptozotocin-diabetic animals showed no increase in the phosphorylation of Gi2 alpha in response to a challenge with the protein kinase C activator phorbol myristate acetate. However, a stimulatory effect of 8-bromo-cAMP on Gi2 alpha phosphorylation was evident in hepatocytes from diabetic animals but this was severely reduced compared with that observed in hepatocytes from normal animals. Two-dimensional tryptic phosphopeptide mapping showed that Gi2 alpha in resting hepatocytes from diabetic animals was phosphorylated exclusively at the protein kinase C site (C-site) but no labelling was evident at the protein kinase A-regulated site (AN-site). Treatment of hepatocytes from diabetic animals with phorbol myristate acetate did not change this pattern of labelling. In contrast, challenge of hepatocytes from diabetic animals with 8-bromo-cAMP led to the appearance of a new labelled phosphopeptide that was consistent with labelling at the AN-site. Analysis of the C-site and AN-site phosphopeptides from hepatocytes of diabetic animals treated with 8-bromo-cAMP showed that the increase in labelling of Gi2 alpha caused by this ligand could be attributed almost entirely to labelling at the AN-site. Thus streptozotocin diabetes appears to cause enhanced labelling of hepatocyte Gi2 alpha by exclusively increasing phosphorylation at the C-site. It is suggested that the increased labelling at the C-site reflects an augmentation of the protein kinase C signalling system in hepatocytes from streptozotocin-induced diabetic animals. This may have wide-spread functional consequences for these cells and may result either from an increased protein kinase C activity and/or a reduction in protein phosphatase 1 and/or 2A activity.
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PMID:Streptozotocin-induced diabetes elicits the phosphorylation of hepatocyte Gi2 alpha at the protein kinase C site but not at the protein kinase A-controlled site. 861 8

Changes in the protein levels and activity of Ca2+/Calmodulin dependent protein kinase II (CaM kinase II) level were studied in cytosolic and particulate fractions from cerebral hemisphere, cerebellum, brain stem, thalamus and hypothalamus regions of rat brain after 4 and 12 weeks of induction of diabetes. Streptozotocin induced diabetes, resulted in pronounced increase of CaM kinase II activity as determined by the kinase activity assay. The total amount of enzyme protein (alpha-subunit specific) also showed increase as revealed by western blotting. Parallel studies were also made in age matched control rats and insulin treated diabetic rats. The increase in CaM kinase II activity was more pronounced in the 12 weeks diabetic group. Insulin treatment of diabetic rats, resulted in recovery of enzyme activity near to control values from majority of the brain regions studied. The expression of alpha-subunit specific CaM kinase II correlates with the enzyme activity in the diabetic rat brain.
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PMID:Effect of diabetes on calcium/calmodulin dependent protein kinase-II from rat brain. 1048 53

We have previously shown that infection with Plasmodium yoelii malaria or injection of extracts from malaria-parasitized red cells induces hypoglycemia in normal mice and normalizes the hyperglycemia in mice made moderately diabetic with streptozotocin. Inositol phosphoglycans (IPGs) are released outside cells by hydrolysis of membrane-bound glycosylphosphatidylinositols (GPIs), and act as second messengers mediating insulin action. The C57BL/Ks-db/db and C57BL/6J-ob/ob mice offer good models for studies on human obesity and Type 2 diabetes. In the present study, we show that a single iv injection of IPG-A or IPG-P extracted from P. yoelii significantly (P < 0.02) lowers the blood glucose in STZ-diabetic, db/db, and in ob/ob mice for at least 4--6 h. Using rat white adipocytes, IPG-P increased lipogenesis by 20--30% in the presence and absence of maximal concentrations of insulin (10(-8) M) (P < 0.01) and stimulated pyruvate dehydrogenase (PDH) phosphatase in a dose-related manner. Both IPG-A and IPG-P inhibited c-AMP-dependent protein kinase (PKA) in a dose-related manner. Compositional analysis of IPGs after 24 h hydrolysis revealed the presence of myo-inositol, phosphorus, galactosamine, glucosamine, and glucose in both IPG-A and IPG-P. However, hydrolysis of IPGs for 4 h highlighted differences between IPG-A and IPG-P. There are some functional similarities between P. yoelii IPGs and those previously described for mammalian liver. However, this is the first report of the hypoglycemic effect of IPGs in murine models of Type 2 diabetes. We suggest that IPGs isolated from P. yoelii, when fully characterized, may provide structural information for the synthesis of new drugs for the management of diabetes mellitus.
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PMID:Reversal of type 2 diabetes in mice by products of malaria parasites. II. Role of inositol phosphoglycans (IPGs). 1146 Nov 92

Streptozotocin (STZ) is used to induce experimental diabetes in animals and is also applied for the treatment of patients with insulinoma. The aim of the present work was to investigate the direct effect of STZ on lipolysis in isolated rat adipocytes. After the isolation, the cells were incubated in a Krebs-Ringer buffer of pH 7.4, at the temperature 37 degrees C for 90 min with different concentrations of STZ: 0.5, 1 or 2 mmol/l. STZ caused a significant rise in basal values (99%, 199%, and 377%, respectively) and epinephrine-stimulated (1 micromol/l) lipolysis (15%, 24% and 46%, respectively). Augmentation of basal lipolysis by STZ was neither restricted by insulin (1 nmol/l) nor by H-89 (an inhibitor of protein kinase A, 50 micromol/l). These results indicate the stimulatory influence of STZ on the action of hormone-sensitive lipase in isolated cells of white adipose tissue. The obtained outcomes suggest that in studies employing STZ, it is necessary to consider its direct effect upon lipolysis in adipocytes.
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PMID:Streptozotocin induces lipolysis in rat adipocytes in vitro. 1223 17

The contribution of second messenger signaling, glucose level and sex hormones to sexual dimorphism in the streptozotocin model of diabetic painful peripheral neuropathy was evaluated. Streptozotocin induced elevation of blood glucose and mechanical hyperalgesia (measured by the Randall-Selitto paw-withdrawal test) were both greater in female rats. Ovariectomy abolished and estrogen implants reconstituted this sexual dimorphism; gonadectomy in males had no effect. An inhibitor of protein kinase Cepsilon attenuated hyperalgesia in males and ovariectomized females, but not in normal females or in ovariectomized females with estrogen implants, whereas inhibitors of protein kinase Cdelta attenuated hyperalgesia in females but not in males. Inhibitors of protein kinase A, protein kinase C (non-selective), protein kinase G and nitric oxide synthase attenuated hyperalgesia equally in both sexes. Higher blood glucose levels in diabetic females were also sex hormone dependent, and magnitude of hyperalgesia correlated with blood glucose level in diabetic male and female rats. These results demonstrate sexual dimorphism in diabetic hyperalgesia, mediated by sex hormone dependent differences in protein kinase Cepsilon and protein kinase Cdelta signaling and blood glucose levels and suggest that sex may be an important factor to be considered in the treatment of symptomatic diabetic neuropathy.
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PMID:Sexual dimorphism in the contribution of protein kinase C isoforms to nociception in the streptozotocin diabetic rat. 1292 97

We hypothesized that sepsis during hyperglycemia would activate left ventricular (LV) mitogen activated protein kinase (MAPK) signaling mechanisms and modulate generation of endothelin-1 (ET-1) and nitric oxide (NO) that can contribute to the progression of LV dysfunction. A single injection of streptozotocin (STZ, 60 mg/kg, via tail vein) was used to produce type 2 diabetes in male SD rats. Polymicrobial sepsis and sham-sepsis were induced using single i.p. injection of cecal inoculum and sterile 5% dextrose water, respectively, on the 13th and 27th day following STZ injection. Both 2-week (2-wk) and 4-wk diabetes groups were associated with hyperglycemia and weight loss. LV end diastolic pressure (LVEDP) was significantly increased in 4-wk diabetes but not in 2-wk diabetes group. Plasma concentration of tumor necrosis factor-alpha (TNF-alpha) was significantly increased in 4-wk diabetes+sepsis group as compared to sham, 2-wk diabetes+sepsis and sepsis groups. Elevated plasma and LV ET-1 and NO byproducts (NOx) along with LV preproET-1 and inducible nitric oxide synthase (iNOS) protein expression were observed in 4-wk but not in 2-wk diabetes group. Sepsis further elevated LV iNOS and preproET-1 in 4-wk diabetes group. Up-regulated phosphorylation of LV p38-MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and heat shock protein-27 (Hsp27) was observed in 4-wk diabetes group. Sepsis caused a factorial increase in LV p38-MAPK and Hsp27 phosphorylation and iNOS up-regulation but not ERK1/2 following progression from 2-wk to 4-wk diabetes. The study provides evidence that sepsis up-regulated LV iNOS, p38-MAPK phosphorylation and elevated LVEDP during 4-wk diabetes. We concluded that sepsis contributes in the development of LVEDP dysfunction and alteration in signaling mechanisms depending upon the progression from 2-wk to 4-wk diabetes in the rat.
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PMID:Left ventricular mitogen activated protein kinase signaling following polymicrobial sepsis during streptozotocin-induced hyperglycemia. 1533 69


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