Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.1 (hexokinase)
 5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transduction pathways regulate various aspects of mammalian sperm function. When human sperm were incubated in a medium supporting capacitation, proteins became tyrosine-phosphorylated in a time-dependent manner. This phosphorylation was inhibited by genistein, a protein tyrosine kinase inhibitor. Phosphorylation was also reduced when sperm were incubated either in the presence of increasing concentrations of extracellular Ca2+ or in a medium containing the Ca2+ ionophore A23187. This Ca2+-induced dephosphorylation was calmodulin-dependent, suggesting that calcineurin was involved. In this regard, the calcineurin inhibitor deltamethrin inhibited the Ca2+ ionophore-induced dephosphorylation. A limited number of Mr 80,000-105,000 polypeptides were the most prominent phosphotyrosine-containing proteins present in human sperm. Unlike mouse sperm, which contains a tyrosine-phosphorylated isoform of hexokinase, a phosphotyrosine-containing hexokinase in human sperm was not detected. Most of the tyrosine-phosphorylated proteins were Triton X-100-insoluble and were localized to the principal piece of the flagellum, the region where the cytoskeletal fibrous sheath is found. Prominent phosphotyrosine-containing proteins of Mr 82,000 and 97,000 were identified as the human homologues of mouse sperm AKAP82, the major fibrous sheath protein, and pro-AKAP82, its precursor polypeptide, respectively. These proteins are A Kinase Anchor Proteins, polypeptides that sequester protein kinase A to subcellular locations. Taken together, these results suggest that protein tyrosine phosphorylation may be part of a signal transduction cascade(s) regulating events pertaining to capacitation and/or motility in mammalian sperm and that an interrelationship between tyrosine kinase and cAMP signaling pathways exists in these cells.
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PMID:Regulation of protein tyrosine phosphorylation in human sperm by a calcium/calmodulin-dependent mechanism: identification of A kinase anchor proteins as major substrates for tyrosine phosphorylation. 894 91

Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased MHC Ibeta mRNA levels and significantly increased MHC IIX, MHC IIB, embryonal MHC and perinatal MHC mRNA levels when compared to control. In addition, U0126 treatment significantly increased lactate dehydrogenase, creatine kinase, hexokinase, malate dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase activities above control values while a significant reduction in the percentage of pyruvate dehydrogenase in the active form was also observed. Calcineurin blockade significantly decreased both MHC Ibeta and embryonal mRNA levels below control and significantly increased MHC IIX mRNA levels. Significant increases in the activities of both lactate dehydrogenase and creatine kinase above control values were also seen following cyclosporin A treatment. In conclusion, the results suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre genes. Similarly, the ERK1/2 pathway upregulates slow-fibre MHC and suppresses fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre-type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in the active form suggests that the ERK1/2 pathway may also be involved in regulation of the phosphorylation state of this enzyme.
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PMID:Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture. 1246 48

Trk, encoded by the partially redundant genes TRK1 and TRK2, is the major potassium transporter of Saccharomyces cerevisiae. This system is specific for potassium and rubidium but, by reducing the electrical membrane potential of the plasma membrane, Trk decreases the uptake of toxic cations such as lithium, calcium, aminoglycosides and polyamines, which are transported by other systems. Gain- and loss-of-function studies indicate that TPS1, a gene encoding trehalose-6-phosphate synthase and known to modulate glucose metabolism, activates Trk and reduces the sensitivity of yeast cells to many toxic cations. This effect is independent of known regulators of Trk, such as the Hal4 and Hal5 protein kinases and the protein phosphatase calcineurin. Mutants defective in isoform 2 of phosphoglucomutase (pgm2) and mutants defective in isoform 2 of hexokinase (hxk2) exhibit similar phenotypes of reduced Trk activity and increased sensitivity to toxic cations compared with tps1 mutants. In all cases Trk activity was positively correlated with levels of glucose phosphates (glc-1-P and glc-6-P). These results indicate that Tps1, like Pgm2 and Hxk2, increases the levels of glucose phosphates and suggest that these metabolites, directly or indirectly, activate Trk.
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PMID:The trehalose pathway and intracellular glucose phosphates as modulators of potassium transport and general cation homeostasis in yeast. 1516 60

Exercise induces a rapid increase in expression of the GLUT4 isoform of the glucose transporter in skeletal muscle. One of the signals responsible for this adaptation appears to be an increase in cytosolic Ca(2+). Myocyte enhancer factor 2A (MEF2A) is a transcription factor that is involved in the regulation of GLUT4 expression. It has been reported that the Ca(2+)-regulated phosphatase calcineurin mediates the activation of MEF2 by exercise. It has also been shown that the expression of activated calcineurin in mouse skeletal muscle results in an increase in GLUT4. These findings suggest that increases in cytosolic Ca(2+) induce increased GLUT4 expression by activating calcineurin. However, we have obtained evidence that this response is mediated by a Ca(2+)-calmodulin-dependent protein kinase. The purpose of this study was to test the hypothesis that calcineurin is involved in mediating exercise-induced increases in GLUT4. Rats were exercised on 5 successive days using a swimming protocol. One group of swimmers was given 20 mg/kg body weight of cyclosporin, a calcineurin inhibitor, 2 h before exercise. A second group was given vehicle. GLUT4 protein was increased approximately 80%, GLUT4 mRNA was increased approximately 2.5-fold, MEF2A protein was increased twofold, and hexokinase II protein was increased approximately 2.5-fold 18 h after the last exercise bout. The cyclosporin treatment completely inhibited calcineurin activity but did not affect the adaptive increases in GLUT4, MEF2A, or hexokinase expression. We conclude that calcineurin activation does not mediate the adaptive increase in GLUT4 expression induced in skeletal muscle by exercise.
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PMID:Calcineurin does not mediate exercise-induced increase in muscle GLUT4. 1573 36

1. The present study was designed to examine the role of calcineurin in muscle metabolic components by the administration of the specific calcineurin inhibitor cyclosporine A (CsA) to rats. 2. Male Wistar rats were divided into either a CsA-treated group (CT) or a vehicle-treated group (VT). Cyclosporine A was administered subcutaneously to rats at a rate of 25 mg/kg bodyweight per day for 10 successive days. Thereafter, changes in muscle enzyme activities and glucose transporter (GLUT)-4 and monocarboxylate transporter (MCT)-1 and MCT-4 proteins in the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles were examined. 3. There was a significant increase in MCT-1 and MCT-4 proteins in the soleus muscle in the CT group, but not in the EDL muscle. The activities of hexokinase, pyruvate kinase and lactate dehydrogenase in the soleus muscle also increased significantly in the CT group, but a similar increase in enzyme activity was not seen in EDL muscle. The activities of citrate synthase or malate dehydrogenase and the GLUT-4 protein content were not altered by CsA treatment in either the soleus or EDL muscles. 4. These results seem to imply that calcineurin negatively regulates the components of glucose/lactate metabolism, except for GLUT-4, especially in slow-twitch muscle.
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PMID:Inhibition of calcineurin increases monocarboxylate transporters 1 and 4 protein and glycolytic enzyme activities in rat soleus muscle. 1574 6

Depletion of mitochondrial DNA (mtDNA) or treatment with mitochondrial poison CCCP initiates mitochondrial stress signaling, which operates through altered Ca2+ homeostasis. In C2C12 rhabdomyoblasts and A549 human lung carcinoma cells mitochondrial stress signaling activates calcineurin and a number of Ca2+ responsive factors including ATF, NFAT, CEBP/delta and CREB. Additionally, PKC and MAP kinase are also activated. A number of nuclear gene targets including those involved in Ca2+ storage/release (RyR1, calreticulin, calsequestrin), glucose metabolism (hexokinase, pyruvate kinase, Glut4), oncogenesis (TGFbeta1, cathepsin L, IGFR1, melanoma antigen) and apoptosis (Bcl-2, Bid, Bad, p53) are upregulated. Mitochondrial stress in both C2C12 myoblasts and A549 cells induced morphological changes and invasive phenotypes. These cells also showed markedly increased resistance to etoposide-induced apoptosis that is a hallmark of highly invasive tumors. Our results describe a new mechanism of altered nuclear gene expression and phenotypic changes triggered by mitochondrial dysfunction and mtDNA damage.
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PMID:Mitochondria-to-nucleus stress signaling in mammalian cells: nature of nuclear gene targets, transcription regulation, and induced resistance to apoptosis. 1597 49

The role of calcium signalling and specific intracellular calcium signalling pathways in regulating skeletal muscle tissue peroxisome proliferator-activated receptor gamma co-activator (PGC)-1alpha, hexokinase (HK)II and pyruvate dehydrogenase kinase (PDK)4 mRNA was examined. Cultured primary rat skeletal muscle cells were incubated for 6 h in caffeine or ionomycin. Because PGC-1alpha mRNA clearly showed greater induction with ionomycin, the latter was chosen for the main experiments, whereby cells were incubated for 6 h with either ionomycin alone or in combination with either cyclosporin A or KN-62. The PGC-1alpha mRNA level was increased (p<0.05) approximately six-fold and HKII mRNA content approximately two-fold by ionomycin relative to the corresponding controls, whereas the PDK4 mRNA content remained unaffected. Cyclosporin A abolished (p<0.05) and KN-62 reduced (p<0.1) the ionomycin-induced increase in PGC-1alpha mRNA. Electrical stimulation of in vitro incubated rat EDL muscle increased (p<0.05) PGC-1alpha mRNA by 2.2-fold after 4 h of recovery relative to a resting control, and this increase was absent when muscles were incubated with KN-62 or cyclosporin A. The present data strongly suggest that calcium signalling is involved in regulating the PGC-1alpha and HKII genes, but not PDK4. Both calcineurin and CaMK signalling seem to be involved in the calcium- and contraction-mediated PGC-1alpha up-regulation in skeletal muscle.
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PMID:Calcium signalling in the regulation of PGC-1alpha, PDK4 and HKII mRNA expression. 1751 43

Thymol is a major component of thyme, and it has been reported that thymol administration reduces body weight, plasma insulin and blood glucose in type-2 diabetes. Skeletal muscle is the most important metabolism organs in the body; however, to date, there is no report on the effect of thymol on skeletal muscle. Our goal was to determine whether thymol has an effect on the different types of skeletal muscle fibers and their metabolism characteristics. Hence, we performed in vivo and in vitro experiments. In vivo, SD rats (4 weeks old) were fed with different concentrations of thymol for 4 weeks, and in vitro C2C12 myotubes were directly treated with thymol for 2 days. The rats fed with 0.025% thymol showed a significantly lower body weight, subcutaneous white adipose tissue index and gastrocnemius muscle index (P < 0.05), while their proportion of brown adipose tissue significantly increased (P < 0.05). The protein and mRNA expression of MyHC I and MyHC IIa in the gastrocnemius muscle of the rats significantly increased (P < 0.05), while the protein level of MyHC II and mRNA expression of MyHC IIb decreased (P < 0.05). Furthermore, 0.025% thymol supplement significantly reduced (P < 0.05) the activity of lactate dehydrogenase (LDH) in the gastrocnemius muscle of the rats, but their succinate dehydrogenase (SDH) and hexokinase (HK) activities increased (P < 0.05). Also, the expression of the fatty acid oxidation-related genes in the gastrocnemius muscle of the rats decreased with the thymol supplement (P < 0.05). In vitro, similar results were obtained. Furthermore, the Ca2+-calcineurin-NFAT pathway, which is an important pathway to regulate the transformation of skeletal muscle fiber type, was studied. We found that the effects of thymol on the myosin heavy chain isoforms, genes related to metabolism and the activation of the Ca2+-calcineurin-NFAT pathway were all reversed by a Ca2+ chelator (P < 0.05). Thus, thymol can promote the oxidative metabolism and fiber type switch in skeletal muscle, and the Ca2+-calcineurin-NFAT pathway plays an important role in it.
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PMID:Ca2+-Calcineurin-NFAT pathway mediates the effect of thymol on oxidative metabolism and fiber-type switch in skeletal muscle. 3137 98