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)

Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxidized. In rat skeletal muscle, the formation of malonyl-CoA is regulated acutely (in minutes) by changes in the activity of the beta-isoform of acetyl-CoA carboxylase (ACCbeta). This can occur by at least two mechanisms: one involving cytosolic citrate, an allosteric activator of ACCbeta and a precursor of its substrate cytosolic acetyl-CoA, and the other involving changes in ACCbeta phosphorylation. Increases in cytosolic citrate leading to an increase in the concentration of malonyl-CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation, in keeping with a diminished need for fatty acid oxidation in these situations. Conversely, during exercise, when the need of the muscle cell for fatty acid oxidation is increased, decreases in the ATP/AMP and/or creatine phosphate-to-creatine ratios activate an isoform of an AMP-activated protein kinase (AMPK), which phosphorylates ACCbeta and inhibits both its basal activity and activation by citrate. The central role of cytosolic citrate links this malonyl-CoA regulatory mechanism to the glucose-fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme. Lancet 1: 785-789, 1963) and to a mechanism by which glucose might autoregulate its own use. A similar citrate-mediated malonyl-CoA regulatory mechanism appears to exist in other tissues, including the pancreatic beta-cell, the heart, and probably the central nervous system. It is our hypothesis that by altering the cytosolic concentrations of LCFA-CoA and diacylglycerol, and secondarily the activity of one or more protein kinase C isoforms, changes in malonyl-CoA provide a link between fuel metabolism and signal transduction in these cells. It is also our hypothesis that dysregulation of the malonyl-CoA regulatory mechanism, if it leads to sustained increases in the concentrations of malonyl-CoA and cytosolic LCFA-CoA, could play a key role in the pathogenesis of insulin resistance in muscle. That it may contribute to abnormalities associated with the insulin resistance syndrome in other tissues and the development of obesity has also been suggested. Studies are clearly needed to test these hypotheses and to explore the notion that exercise and some pharmacological agents that increase insulin sensitivity act via effects on malonyl-CoA and/or cytosolic LCFA-CoA.
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PMID:Malonyl-CoA, fuel sensing, and insulin resistance. 988 45

Two potassium conductances have been isolated in rat Leydig cells by their sensitivity to cytosolic calcium and to K+ channel blockers. We used the whole-cell configuration of the patch-clamp technique to investigate their sensitivity to cyclic AMP, the main messenger of luteinizing hormone, which stimulates Leydig cell steroidogenesis. The voltage-dependent potassium conductance is not modified by exposing the cell to 1 mM chlorophenylthio-cyclic AMP (CPT-cAMP), a membrane-permeant analogue of cAMP. By contrast, the large, calcium-activated potassium conductance is upregulated by CPT-cAMP. Furthermore, the latter is potentiated by the chloride channel blocker 4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulfonic acid, sodium salt (SITS).
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PMID:Effect of cyclic AMP on the calcium-dependent potassium conductances of rat Leydig cells. 992 3

The effects of cannabinoids on ketogenesis in primary cultures of rat astrocytes were studied. Delta9-Tetrahydrocannabinol (THC), the major active component of marijuana, produced a malonyl-CoA-independent stimulation of carnitine palmitoyltransferase I (CPT-I) and ketogenesis from [14C]palmitate. The THC-induced stimulation of ketogenesis was mimicked by the synthetic cannabinoid HU-210 and was prevented by pertussis toxin and the CB1 cannabinoid receptor antagonist SR141716. Experiments performed with different cellular modulators indicated that the THC-induced stimulation of ketogenesis was independent of cyclic AMP, Ca2+, protein kinase C, and mitogen-activated protein kinase (MAPK). The possible involvement of ceramide in the activation of ketogenesis by cannabinoids was subsequently studied. THC produced a CB1 receptor-dependent stimulation of sphingomyelin breakdown that was concomitant to an elevation of intracellular ceramide levels. Addition of exogenous sphingomyelinase to the astrocyte culture medium led to a MAPK-independent activation of ketogenesis that was quantitatively similar and not additive to that exerted by THC. Furthermore, ceramide activated CPT-I in astrocyte mitochondria. Results thus indicate that cannabinoids stimulate ketogenesis in astrocytes by a mechanism that may rely on CB1 receptor activation, sphingomyelin hydrolysis, and ceramide-mediated activation of CPT-I.
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PMID:The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme. 1009 87

Cyclic AMP regulates melatonin synthesis in vertebrate photoreceptor cells. In the present study, we investigated whether the circadian rhythm of melatonin synthesis in Xenopus retinal photoreceptor layers is driven by rhythmic changes in cyclic AMP. When the photoreceptor layers were continuously treated with 8-(4-chlorophenylthio)-cyclic AMP (8-CPT-cAMP) at a saturating concentration (1 mM), melatonin release was increased at all times of the day, but robust melatonin rhythms were maintained for 2 days in constant darkness (DD). We also measured cyclic AMP efflux and melatonin release simultaneously from photoreceptor layers that were continuously treated with forskolin and/or 3-isobutyl-1-methylxanthine (IBMX) in light-dark (LD) and DD. Circadian rhythmicity was observed in melatonin release, but not in cyclic AMP efflux, suggesting that changes of melatonin levels are not always caused by the changes of the cyclic AMP levels. In addition, the simultaneous treatment of forskolin and IBMX appeared to saturate sensitivity of melatonin synthesis to cyclic AMP, but this treatment did not abolish melatonin rhythms. These results suggest that circadian rhythms of melatonin can be driven without rhythmic changes of cyclic AMP, and that cyclic AMP regulates melatonin in parallel with the output pathways from the circadian oscillator.
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PMID:Modulation of rhythmic melatonin synthesis in Xenopus retinal photoreceptors by cyclic AMP. 1019 46

The circadian oscillator in Xenopus retinal photoreceptor layers can be reset in similar ways by light and agonists of D2-like dopamine receptors. Treatments that increase cyclic AMP levels act on this oscillator in an opposite fashion, mimicking darkness in the induction of phase shifts. Light and dopamine have each been reported to inhibit adenylate cyclase in photoreceptors. Together, these data suggest that the transduction pathways for entrainment by dopamine and/or light include suppression of cyclic AMP or a cyclic AMP-sensitive step. In these studies, we examined this hypothesis by measuring the effects of treatment with a cyclic AMP analogue on the phase shifts induced in photoreceptor melatonin rhythms by light or a D2 receptor agonist (quinpirole). When photoreceptor layers were treated simultaneously with 8-(4-chlorophenylthio)cyclic AMP (8-CPT-cAMP) and quinpirole at any of three different phases of the circadian cycle, the resulting phase shifts of the melatonin rhythm were always the same as those caused by 8-CPT-cAMP alone. This indicates that there is a cyclic AMP-sensitive step in the dopamine entrainment pathway. In contrast, light pulses did reset the oscillator in the presence of elevated cyclic AMP. This suggests a separate cyclic AMP-insensitive transduction pathway for entrainment by light. Quinpirole reduced basal levels of cyclic AMP in photoreceptors, but light did not. These data suggest that cyclic AMP plays a role in the entrainment pathway activated by dopamine but not in the entrainment pathway activated by light.
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PMID:A role for cyclic AMP in entrainment of the circadian oscillator in Xenopus retinal photoreceptors by dopamine but not by light. 1021 57

Alpha1-adrenoceptor agonists may potentiate relaxation to beta-adrenoceptor agonists, although the mechanisms are unclear. We compared relaxations induced by beta-adrenoceptor agonists and cyclic AMP-dependent vasodilators in rat pulmonary arteries constricted with prostaglandin F2alpha (PGF2alpha) or the alpha1-adrenoceptor agonist phenylephrine (PE). In addition, we examined whether differences were related to cyclic AMP- or nitric oxide (NO) and cyclic GMP-dependent pathways. Isoprenaline-induced relaxation was substantially potentiated in arteries constricted with PE compared with PGF2alpha. Methoxamine was similar to PE, whereas there was no difference between PGF2alpha and 30 mM KCl. The potentiation was primarily due to a marked increase in the NO-independent component of relaxation, from 9.1+/-1.7% for PGF2alpha to 55.1+/-4.4% for PE. NO-dependent relaxation was also enhanced, but to a lesser extent (50%). Relaxation to salbutamol was almost entirely NO-dependent in both groups, and was potentiated approximately 50% by PE. Relaxation to forskolin (activator of adenylate cyclase) was also enhanced in PE constricted arteries. Part of this relaxation was NO-dependent, but the major effect of PE was to increase the NO-independent component. Propranolol diminished but did not abolish the potentiation. There was no difference in response to CPT cyclic AMP (membrane permeant analogue) between PE and PGF2alpha, suggesting that mechanisms distal to the production of cyclic AMP were unchanged. Relaxation to sodium nitroprusside (SNP) was the same for PE and PGF2alpha, although relaxation to acetylcholine (ACh) was slightly depressed. This implies that potentiation by PE does not involve the cyclic GMP pathway directly. Mesenteric arteries constricted with PE did not show potentiation of isoprenaline-induced relaxation compared to those constricted with PGF2alpha, suggesting that this effect may be specific to the pulmonary circulation. These results clearly show that PE potentiates both the NO-independent and -dependent components of cyclic AMP-mediated relaxation in pulmonary arteries of the rat, although the effect on the former is more profound. We suggest that potentiation of both components is largely due to direct activation of adenylate cyclase via alpha1-adrenoceptors, within the smooth muscle and endothelial cells respectively.
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PMID:Potentiation of cyclic AMP-mediated vasorelaxation by phenylephrine in pulmonary arteries of the rat. 1036 85

The possible role of the AMP-activated protein kinase (AMPK), a highly conserved stress-activated kinase, in the regulation of ketone body production by astrocytes was studied. AMPK activity in rat cortical astrocytes was three times higher than in rat cortical neurons. AMPK in astrocytes was shown to be functionally active. Thus, incubation of astrocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a cell-permeable activator of AMPK, stimulated both ketogenesis from palmitate and carnitine palmitoyltransferase I. This was concomitant to a decrease of intracellular malonyl-CoA levels and an inhibition of acetyl-CoA carboxylase/fatty acid synthesis and 3-hydroxy-3-methylglutaryl-CoA reductase/cholesterol synthesis. Moreover, in microdialysis experiments AICAR was shown to stimulate brain ketogenesis markedly. The effect of chemical hypoxia on AMPK and the ketogenic pathway was studied subsequently. Incubation of astrocytes with azide led to a remarkable drop of fatty acid beta-oxidation. However, activation of AMPK during hypoxia compensated the depression of beta-oxidation, thereby sustaining ketone body production. This effect seemed to rely on the cascade hypoxia --> increase of the AMP/ATP ratio --> AMPK stimulation --> acetyl-CoA carboxylase inhibition --> decrease of malonyl-CoA concentration --> carnitine palmitoyltransferase I deinhibition --> enhanced ketogenesis. Furthermore, incubation of neurons with azide blunted lactate oxidation, but not 3-hydroxybutyrate oxidation. Results show that (a) AMPK plays an active role in the regulation of ketone body production by astrocytes, and (b) ketone bodies produced by astrocytes during hypoxia might be a substrate for neuronal oxidative metabolism.
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PMID:The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. 1050 Dec 15

The effects of muscarinic and beta-adrenergic agonists on Cl(-) currents in acinar cells were investigated to clarify their role in the regulation of fluid secretion in rat perfused submandibular glands. Additions of isoproterenol (IPR) at 10(-8) to 10(-6) M and 8-(4-chlorophenylthio)-cyclic AMP (CPT-cAMP) at 10(-3) M to the perfusate suppressed carbachol (CCh; 10(-6) M)-induced fluid secretion. IPR and CPT-cAMP also diminished CCh-induced oscillatory Cl(-) current and increased CCh-stimulated non-oscillatory Cl(-) current. Propranolol blocked the effect of IPR on fluid secretion. IPR did not modulate the CCh-induced increase in intracellular concentration of calcium ions and intracellular pH in isolated cells. Propranolol blocked IPR-induced changes in Cl(- )currents, while propranolol itself increased CCh-induced K(+) current and reduced CCh-induced oscillatory Cl(-) current. Increasing external osmolarity with 50 mM sucrose abolished IPR-enhanced non-oscillatory Cl(-) current. Neither CCh-induced oscillatory Cl(-) current nor IPR-induced suppression of the oscillatory Cl(-) current was influenced by the hypertonicity. Perfusion of the gland with the hypertonic solution did not affect the IPR-induced suppression of fluid secretion. These results suggest that IPR induces the suppression of CCh-induced oscillatory Cl(-) current and potentiation of the non-oscillatory Cl(-) current via an increase in cyclic AMP level, and that suppression of the oscillatory Cl(-) current by IPR may contribute to the inhibition of fluid secretion from submandibular glands.
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PMID:Modulation of carbachol-induced Cl(-) currents and fluid secretion by isoproterenol in rat submandibular acinar cells. 1052 93

The antisecretory effects of flufenamate in the rat distal colon were investigated with the Ussing-chamber and the patch-clamp method as well as by measurements of the intracellular Ca(2+) concentration using fura-2-loaded isolated crypts. Flufenamate (5.10(-4) mol l(-1)) suppressed the short-circuit current (Isc) induced by carbachol (5.10(-5) mol l(-1)), forskolin (5.10(-6) mol l(-1)) and the Isc induced by the membrane-permeable analogue of cyclic AMP, CPT - cyclic AMP (10(-4) mol l(-1)). Indomethacin (10(-6) - 10(-4) mol l(-1)) did not mimic the effect of flufenamate, indicating that the antisecretory effect of flufenamate is not related to the inhibition of the cyclo-oxygenase. When the basolateral membrane was depolarized by a high K(+) concentration and a Cl(-) current was induced by a mucosally directed Cl(-) gradient, the forskolin-stimulated Cl(-) current was blocked by flufenamate, indicating an inhibition of the cyclic AMP-stimulated apical Cl(-) conductance. When the apical membrane was permeabilized by the ionophore, nystatin, flufenamate decreased the basolateral K(+) conductance and inhibited the Na(+) - K(+)-ATPase. Patch-clamp experiments revealed a variable effect of flufenamate on membrane currents. In seven out of 11 crypt cells the drug induced an increase of the K(+) current, whereas in the remaining four cells an inhibition was observed. Experiments with fura-2-loaded isolated crypts indicated that flufenamate increased the basal as well as the carbachol-stimulated intracellular Ca(2+) concentration. These results demonstrate that flufenamate possesses multiple action sites in the rat colon: The apical Cl(-) conductance, basolateral K(+) conductances and the Na(+) - K(+)-ATPase.
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PMID:Multiple action sites of flufenamate on ion transport across the rat distal colon. 1086 95

A component of isoprenaline-mediated vasorelaxation in pulmonary arteries is mediated by nitric oxide (NO). We examined the effects of physiological concentrations (</=400 microM) of L-arginine on isoprenaline-induced relaxation in rat pulmonary arteries, and following inhibition of L-arginine uptake with L-lysine. In addition, we examined the role of the endothelium, and whether L-arginine affected acetylcholine (ACh)-induced relaxation. Isoprenaline-induced relaxation was potentiated by 400 microM L-arginine in pulmonary arteries; maximum relaxation was increased from 83+/-4% of initial tone to 94+/-4% (P<0.05). L-lysine (10 mM) not only abolished the potentiation by L-arginine, but suppressed relaxation compared to control (70+/-4%, P<0.05), even in the absence of L-arginine added to the bath. Blockade of NO synthase with 100 microM L-NMMA or removal of the endothelium inhibited isoprenaline-induced relaxation to the same extent as L-lysine, and under these conditions the presence or absence of 400 microM L-arginine made no difference. L-lysine had no additional effect when applied in combination with L-NMMA. The effect of extracellular L-arginine was concentration dependent, with an apparent EC(50) of approximately 1-7 microM. Relaxation to the membrane permeant cyclic AMP analogue CPT cyclic AMP was also potentiated by L-arginine and inhibited by L-lysine. There was however no difference in relaxation induced by acetylcholine (ACh) in the presence of L-arginine or L-lysine, and isoprenaline-induced relaxation of mesenteric arteries was unaffected by L-arginine or L-lysine. These results strongly suggest that extracellular L-arginine is critically important for development of the NO- and endothelium-dependent component of cyclic AMP-induced vasorelaxation in rat pulmonary arteries, but is not required for ACh-induced relaxation. As the apparent EC(50) for this effect is in the low micromolar range it is likely to be fully activated in vivo, as plasma L-arginine is >150 microM.
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PMID:Critical dependence of the NO-mediated component of cyclic AMP-induced vasorelaxation on extracellular L-arginine in pulmonary arteries of the rat. 1088 83


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