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:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The heart is known for its ability to produce energy from fatty acids (FA) because of its important beta-oxidation equipment, but it can also derive energy from several other substrates including glucose, pyruvate, and lactate. The cardiac ATP store is limited and can assure only a few seconds of beating. For this reason the cardiac muscle can adapt quickly to the energy demand and may shift from a 100% FA-derived energy production (after a lipid-rich food intake) or any balanced situation (e.g., diabetes, fasting, exercise). These situations are not similar for the heart in terms of oxygen requirement because ATP production from glucose is less oxygen-consuming than from FA. The regulation pathways for these shifts, which occur in physiologic as well as pathologic conditions (ischemia-reperfusion), are not yet known, although both insulin and pyruvate dehydrogenase activation are clearly involved. It becomes of strategic importance to clarify the pathways that control these shifts to influence the oxygen requirement of the heart. Excess FA oxidation is closely related to myocardial contraction disorders characterized by increased oxygen consumption for cardiac work. Such an increased oxygen cost of cardiac contraction was observed in stunned myocardium when the contribution of FA oxidation to oxygen consumption was increased. In rats, an increase in n-3 polyunsaturated FA in heart phospholipids achieved by a fish-oil diet improved the recovery of pump activity during postischemic reperfusion. This was associated with a moderation of the ischemia-induced decrease in mitochondrial palmitoylcarnitine oxidation. In isolated mitochondria at calcium concentrations close to that reported in ischemic cardiomyocytes, a futile cycle of oxygen wastage was reported, associated with energy wasting (constant AMP production). This occurs with palmitoylcarnitine as substrate but not with pyruvate or citrate. The energy wasting can be abolished by CoA-SH and other compounds, but not the oxygen wasting. Again, the calcium-induced decrease in mitochondrial ADP/O ratio was reduced by increasing the n-3 polyunsaturated FA in the mitochondrial phospholipids. These data suggest that in addition to the amount of circulating lipids, the quality of FA intake may contribute to heart energy regulation through the phospholipid composition. On the other hand, other intervention strategies can be considered. Several studies have focused on palmitoylcarnitine transferase I to achieve a reduction in beta-oxidation. In a different context, trimetazidine was suggested to exert its anti-ischemic effect on the heart by interfering with the metabolic shift, either at the pyruvate dehydrogenase level or by reducing the beta-oxidation. Further studies will be required to elucidate the complex system of heart energy regulation and the mechanism of action of potentially efficient molecules.
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PMID:Fatty acid oxidation in the heart. 889 66

1. In the present study we examined whether interleukin-1 beta (IL-1 beta) increases the activity of adenylyl cyclase in vascular smooth muscle cells and determined its role in the cytokine-induced expression of the inducible nitric oxide synthase (iNOS) and activation of nuclear transcription factor-kappa B (NF-kappa B). In addition the interaction between cyclic AMP- and cyclic GMP-elevating agonists on the IL-1 beta-stimulated expression of iNOS was examined. 2. Exposure of vascular smooth muscle cells to IL-1 beta stimulated the formation of cyclic AMP but not of cyclic GMP. The intracellular level of cyclic AMP reached a maximum within 1 h and then gradually declined over the next 5 h. This IL-1 beta (60 u ml-1)-stimulated formation of cyclic AMP was modest (about 3 fold at 60 u ml-1 for 1 h) compared to that evoked by isoprenaline (about 9 fold at 3 x 10(-6) M for 2 min). 3. The IL-1 beta (60 u ml-1 for 24 h)-stimulated accumulation of nitrite, which was taken as an index of NO production, was concentration-dependently increased by preferential inhibitors of cyclic AMP-dependent phosphodiesterases (rolipram and trequinsin). This effect was reproduced by a specific activator of the cyclic AMP-dependent protein kinase(s) A, Sp-8-CPT-cAMPS (10(-4) M) but was prevented by a specific inhibitor of cyclic AMP-dependent protein kinase(s) A, Rp-8-CPT-cAMPS (10(-4) M). These compounds alone [rolipram (10(-6) M), trequinsin (3 x 10(-6) M) and Sp-8-CPT-cAMPS (10(-4) M)] slightly but significantly increased the release of nitric oxide while Rp-8-CPT-cAMPS elicited no such effect. 4. Inducible NOS protein was expressed in IL-1 beta (30 u ml-1, 24 h)-stimulated smooth muscle cells as assessed by Western blot analysis. The level of iNOS protein was markedly increased in smooth muscle cells which had been exposed to IL-1 beta in combination with either rolipram (3 x 10(-6) M) or Sp-8-CPT-cAMPS (10(-4) M) but was reduced in those exposed to IL-1 beta and Rp-8-CPT-cAMPS (10(-4) M). A weak expression of iNOS protein was found in smooth muscle cells which had been exposed to either Sp-8-CPT-cAMPS or rolipram alone for 24 h while Rp-8-CPT-cAMPS elicited no such effect. 5. Exposure of smooth muscle cells to IL-1 beta (30 u ml-1) for 30 min increased the level of NF-kappa B-DNA complexes in nuclear extracts as detected by electrophoretic mobility shift assay. Similar levels of NF-kappa B-DNA complexes were found in cells which had been exposed to IL-1 beta in combination with either Sp-8-CPT-cAMPS (10(-4) M), trequinsin (10(-6) M) or rolipram (10(-6) M). None of the modulators alone affected the basal level of NF-kappa B binding activity. 6. NO-donors [sodium nitroprusside (SNP) 10(-4) M; dinitrosyl-iron-di-L-cysteine-complex (DNIC), 10(-4) M; 3-morpholino-sydnonimine (SIN-1), 10(-4) M] and atrial natriuretic factor (10(-6) M) significantly increased the IL-1 beta (30 or 60 u ml-1, 24 h)-stimulated expression of iNOS protein and activity as assessed indirectly by the conversion of oxyhaemoglobin to methaemoglobin. In the absence of IL-1 beta, SNP (10(-4) M, 24 h) but not the other cyclic GMP-dependent vasodilators caused a modest expression of iNOS protein. No such effect was found in smooth muscle cells exposed to SNP in combination with Rp-8-CPT-cAMPS (10(-4) M) while an increased level of iNOS protein was found in those exposed to SNP in combination with either Sp-8-CPT-cAMPS (10(-4) M) or rolipram (3 x 10(-6) M). 7. Exposure of vascular smooth muscle cells to either S-nitroso-L-cysteine (Cys-SNO, 10(-4) M), SNP (10(-4) M) or SIN-1 (10(-4) M) for 35 min affected minimally the basal activation of NF-kappa B but abolished that evoked by IL-1 beta (30 u ml-1 added during the last 30 min). However, addition of Cys-SNO following the stimulation with IL-1 beta (during the last 5 min of the 30 min exposure period) reduced the level of NF-kappa B-DNA complexes only slightly. 8. These data indicate that the cyclic AMP-dependent pathway plays a decisi
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PMID:Effect of cyclic GMP-dependent vasodilators on the expression of inducible nitric oxide synthase in vascular smooth muscle cells: role of cyclic AMP. 890 45

The effects of two cell-permeable cyclic AMP analogues, 8-chloro cyclic AMP (8-Cl cAMP) and 8-(4-chlorophenylthio) cyclic AMP (8-CPT cAMP), on cholesterol esterification, cholesteryl ester hydrolysis and bile acid synthesis were compared in cultured rat and hamster hepatocytes. Cholesterol esterification, as measured by the incorporation of [3H]oleate into cholesteryl ester, was increased by 58-88% by the analogues in rat hepatocytes and by 33-43% in hamster cells. The response in rat hepatocytes, however, was observed after a relatively short incubation time (28% increase after 1 hr), whereas that in hamster cells required a longer period (36% after 12 hr) to become apparent. The activity of the cytosolic neutral cholesteryl ester hydrolase in rat hepatocytes was also stimulated by both cyclic AMP analogues (31-37%, but the microsomal activity was unaffected. In hamster hepatocytes, however, microsomal cholesteryl ester hydrolase activity was increased (47-80%) in the presence of 8-Cl cAMP or 8-CPT cAMP. Bile acid synthesis was increased by 8-CPT cyclic AMP in rat cells (approximately 25%) but was unchanged by both analogues in hamster hepatocytes. These results indicate significant differences in the way in which cholesterol metabolism responds to cyclic AMP in cultured rat and hamster hepatocytes.
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PMID:Comparison of the effects of cyclic AMP analogues on cholesterol metabolism in cultured rat and hamster hepatocytes. 893 53

The involvement of cyclic AMP in the settlement of the cypris larva of Balanus amphitrite amphitrite Darwin has been examined through the use of compounds that affect intracellular cyclic AMP levels. The activation of adenylate cyclase with forskolin, and the inhibition of phosphodiesterase with 3-isobutyl-1-methylxanthine, caffeine and theophylline, significantly increased the settlement of cyprids. Although the analogue dibutyryl cyclic AMP appeared to increase settlement, the effect was not significant. No marked increase in settlement resulted from the incubation of cyprids with dibutyryl cyclic GMP, 8-(4-chlorophenylthio) (CPT) cyclic AMP or papaverine (a phosphodiesterase inhibitor). Miconazole nitrate, an adenylate cyclase inhibitor, prevented settlement, but this effect appeared to be physico-chemical rather than pharmacological. Radioimmunoassay did not clearly show whether cyclic AMP levels changed following exposure of cyprids to a pulse of crude barnacle extract. However, exposure to forskolin significantly increased the cyclic AMP titre of cyprids. We conclude that compounds that alter intracellular cyclic AMP levels alter normal patterns of cyprid settlement. Whether this is because of an alteration in signal transduction is unclear.
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PMID:Evidence for the involvement of cyclic AMP in the pheromonal modulation of barnacle settlement 931 89

Chronic salt stress in ducklings (Anas platyrhynchos) resulted in a sustained accumulation of cyclic AMP in the secretory cells of the nasal salt glands. Adaptive increases in the activity of the Na+/K+-ATPase, measured as ATP hydrolysis rates in freshly isolated tissue, were observed after 12 h of salt stress. This change in enzyme activity was associated with increases in protein abundance in the - as well as in the ss-subunit of Na+/K+-ATPase and an increase in ss-subunit glycosylation. We investigated whether the increase in the cytosolic cyclic AMP concentration and the adaptive changes in Na+/K+-ATPase activity were causally related. Using an organotypic tissue culture system for salt gland slices from unstressed (naive) ducklings, we produced similar changes in Na+/K+-ATPase activity and subunit abundance by treating cultured tissue with drugs that elevate cytosolic cyclic AMP levels (forskolin, 8-CPT-cAMP) during a 15 h culture period. Protein synthesis assays using cultured tissue revealed that elevations in cytosolic cyclic AMP level mediate increases in Na+/K+-ATPase subunit abundance by slowing down the degradation of ATPase subunits. This increase in the amount of enzyme protein was associated with a significant increase in Na+/K+-ATPase activity in tissue homogenates. The time course of these changes in cyclic-AMP-treated cultured tissue resembled that observed in salt-stressed intact animals, indicating that the elevation in cyclic AMP level in salt gland tissue may constitute a portion of the signalling events ultimately leading to the adaptive increase in Na+/K+-ATPase activity in vivo.
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PMID:Changes in Na+/K+-ATPase expression during adaptive cell differentiation in avian nasal salt gland 931 5

We have used an in vitro trauma model to examine the effects of modulation of group III metabotropic glutamate receptors (mGluR) on post-traumatic neuronal cell death. Rat cortical neuronal/glial cultures were subjected to standardized mechanical injury using a punch that delivers 28 parallel cuts to 96-well culture plates, resulting in approximately 50% neuronal cell loss in untreated cultures. RT-PCR demonstrated expression of mRNA for mGluR4, mGluR6, mGluR7, and mGluR8 in uninjured cultures as well as in adult rat brain. Treatment with the group III agonists L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) or L-serine-O-phosphate (L-SOP) resulted in dose-dependent neuroprotection. In contrast, treatment with the group III antagonists alpha-methyl-AP4 (MAP4) or (RS)-alpha-methylserine-O-phosphate (MSOP) caused dose-dependent exacerbation of injury, which was significantly attenuated by L-AP4 or L-SOP. The neuroprotective actions of L-AP4 or L-SOP were markedly reduced by the cyclic AMP analog 8-CPT-cAMP (500 microm), which by itself had no effects at this concentration. Moreover, treatment with L-AP4 or L-SOP reduced basal cyclic AMP levels. Treatment with the NMDA antagonist MK 801 decreased post-traumatic cell death by 45% at optimal concentrations; combined treatment with MK 801 and group III agonists showed a significant enhancement of neuroprotection as compared to treatment with the NMDA antagonist alone. Our findings indicate a clear neuroprotective action for group III agonists in this model and suggest that group III mGluR are endogenously activated in response to trauma. The neuroprotective effects of group III agonists appear to result in part from modulation of adenylyl cyclase activity and are additive to those of an NMDA receptor antagonist.
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PMID:Neuroprotective effects of group III mGluR in traumatic neuronal injury. 947 70

As muscle goes from a resting state to exercise, the following sequence of events occurs (Figure 5.5): (1) The rise in AMP accompanying contraction allosterically activates AMPK and an AMPK kinase; (2) The activated AMPK kinase phosphorylates and further activates AMPK; (3) The activated AMPK phosphorylates and inactivates ACC; and (4) The consequent decline in malonyl-CoA (product of ACC reaction) relieves inhibition of CPT-1 and allows an increased rate of fatty acid oxidation when fatty acids become available.
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PMID:Malonyl-CoA--regulator of fatty acid oxidation in muscle during exercise. 969 87

The role of carnitine palmitoyltransferase I (CPT-I) in the control of ketogenesis was studied in primary cultures of rat astrocytes. Ketone bodies were the major product of [14C]palmitate oxidation by cultured astrocytes, whereas CO2 made a minor contribution to the total oxidation products. Using tetradecylglycidate as a specific, cell-permeable inhibitor of CPT-I, a flux control coefficient of 0.77 +/- 0.07 was calculated for CPT-I over the flux of [14C]palmitate to ketone bodies. CPT-I from astrocytes was sensitive to malonyl-CoA (IC50 = 3.4 +/- 0.8 microM) and cross-reacted on western blots with an antibody raised against liver CPT-I. On the other hand, astrocytes expressed significant acetyl-CoA carboxylase (ACC) activity, and consequently they contained considerable amounts of malonyl-CoA. Western blot analysis of ACC isoforms showed that ACC in astrocytes--like in neurons, liver, and white adipose tissue--mostly comprised the 265-kDa isoform, whereas the 280-kDa isoform--which was highly expressed in skeletal muscle--showed much lower abundance. Forskolin was used as a tool to study the modulation of the ketogenic pathway in astrocytes. Thus, forskolin decreased in parallel ACC activity and intracellular malonyl-CoA levels, whereas it stimulated CPT-I activity and [14C]palmitate oxidation to both ketone bodies and CO2. Results show that in cultured astrocytes (a) CPT-I exerts a very high degree of control over ketogenesis from palmitate, (b) the ACC/malonyl-CoA/CPT-I system is similar to that of liver, and (c) the ACC/malonyl-CoA/CPT-I system is subject to regulation by cyclic AMP.
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PMID:Role of carnitine palmitoyltransferase I in the control of ketogenesis in primary cultures of rat astrocytes. 975 Nov 93

In AtT20 mouse corticotroph tumour cells large conductance Ca2+-activated K+-channels (BK-channels) have an essential role in the early glucocorticoid inhibition of adrenocorticotrophin (ACTH) secretion evoked by corticotrophin-releasing factor. The present study examined whether or not BK-channels are also pivotal to glucocorticoid inhibition of normal rat anterior pituitary cells. A membrane-permeant, non-metabolizable cyclic AMP analogue, 8-(4-Chlorophenylthio)adenosine-3',5'-cyclic-monophosphate (CPT-cAMP) was used as the primary secretagogue stimulus, as this mimics the increase of intracellular cyclic AMP caused by corticotrophin-releasing factor, but is not subject to the complex Ca2+-dependent regulation of cyclic AMP metabolism that is evident in corticotroph cells. Experiments in AtT20 cells showed that ACTH secretion stimulated by 1 mM CPT-cAMP was suppressed to 34+/-1.5% (n = 12) of the control stimulus by a maximal dose of 100 nM dexamethasone. The ACTH secretion evoked by the combination of 1 mM CPT-cAMP with either 5 microm (-)BayK8644 (L-type Ca2+-channel activator) or 5 mM TEA (K+-channel blocker) was respectively 69.1+/-7.6% and 69.3+/-11.8% of control after 2 h preincubation with 100 nM dexamethasone (P<0.05 vs CPT-cAMP). The ACTH response elicited by 5 microM (-)BayK8644 and 5 mM TEA given together was completely resistant to inhibition by 100 nM dexamethasone. Furthermore, TEA and (-)BayK8644 given together synergistically stimulated ACTH release in combination with 0.1 mM or 1 mM CPT-cAMP, and these ACTH responses were not inhibited by 100 nM dexamethasone. In primary cultures of rat anterior pituitary cells, TEA (up to 20 mM), charybdotoxin (30 nM) or apamin (100 nM) failed to modify the glucocorticoid inhibition of 0.1 mM CPT-cAMP-induced ACTH release. The combination of 5 mM TEA and 5 microM (-)BayK8644 elicited a small but significant increase in ACTH secretion but did not modify the inhibition of 0.3 mM CPT-cAMP-induced ACTH secretion by 100 nM dexamethasone. In primary cultures of rat anterior pituitary cells, depolarization of the membrane potential with 40 mM KCl enhanced the ACTH response to CPT-cAMP and markedly reduced the maximal inhibitory effect of dexamethasone to 55+/-1.2% as well as that of corticosterone to 33+/-2.1% vs 100+/-2.5% and 100+/-1.9% inhibition respectively, when 0.1 mM CPT-cAMP was used alone. Introduction of 5 microM (-)BayK8644 with 40 mM KCl in this system had no additional effect on glucocorticoid inhibition. No glucocorticoid inhibition of ACTH release to any of the stimuli applied was observed in cells pretreated with the mRNA synthesis inhibitor, 5,6-dichloro-furanosyl-benzimidazole riboside (DRB) (0.1 mM) or the protein synthesis blocker, puromycin (0.1 mM). In summary, early glucocorticoid inhibition of stimulated ACTH release by cultured rat anterior pituitary cells was dependent on the synthesis of new mRNA and protein. Depolarization of the membrane potential potentiated CPT-cAMP-induced ACTH secretion in AtT20 cells as well as cultured rat corticotrophs and this was associated with a resistance to the early inhibitory effect of glucocorticoids. Glucocorticoid inhibition in rat anterior pituitary corticotrophs was unaltered by TEA, charybdotoxin as well as apamin, and hence it is unlikely to involve predominantly BK-or SK-type Ca2+-activated K+-channels. These results support the thesis that a prime target of glucocorticoid feedback inhibition in anterior pituitary corticotrophs is the membrane potential and indicate that glucocorticoid-induced proteins regulate the activities of several distinct plasma membrane ion channels.
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PMID:Depolarization counteracts glucocorticoid inhibition of adenohypophysical corticotroph cells. 975 91

While a differential sensitivity to cyclic AMP (cAMP)-mediated signaling between Th1 and Th2 cells has been hypothesized, differential activity of downstream signaling through cAMP-dependent protein kinase (cAK) isoforms remains unexplored. We herein report the effects of type 1- and type 2-specific cAK agonists and antagonists on proliferative responses and cytokine generation from ragweed-driven peripheral blood mononuclear cells (PBMCs) and Amb a 1-specific Th1 and Th2 clones. Rp-8-Cl- and Rp-8-CPT-cAMP were utilized as single agent antagonists of cAKI and cAKII, respectively; 8-AHA-cAMP, with and without 8-PIP-cAMP, and 8-CPT-cAMP, with and without 6-Bnz-cAMP, were used as synergistic agonist pairs specific for the cAKI and cAKII, respectively. Activation of either cAKI or cAKII individually was ineffective in down-regulating proliferative responses of PBMCs or T cell clones; concentration-response curves for the Th1 and Th2 clones were identical. Moreover, inhibition of either cAKI or cAKII individually was ineffective in overcoming the down-regulatory effects of phosphodiesterase inhibition. Activation of either cAKI or cAKII individually was ineffective in down-regulating proinflammatory cytokine generation from T cell clones (interleukin-4 from Th2; interferon-gamma from Th1). However, concurrent activation of both cAKI and cAKII produced down-regulatory effects equivalent to those of the phosphodiesterase inhibitor on both proliferation and cytokine generation. These data suggest a critical role for concurrent activation of cAKI and cAKII in the functional efficacy of antigen-driven downstream signaling due to elevations of intracellular cAMP and argue against differential regulation of Th1 and Th2 responses by cAK subtypes.
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PMID:Co-regulation of antigen-specific T lymphocyte responses by type I and type II cyclic AMP-dependent protein kinases (cAK). 977 49


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