Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is known that the composition of phospholipids in lung changes with age. The final step in the de novo synthesis of phosphatidylcholine, a major component of lung surfactant, by the CDP-choline pathway, requires the enzyme cholinephosphotransferase (CPT). Even though CPT has earlier been proposed to be located exclusively in the endoplasmic reticulum, we have recently demonstrated its presence also in the mitochondria. We have earlier reported a gestational variation of CPT activity in fetal mitochondria and microsomes. In the present study we examined the subcellular distribution of CPT activity in lung as a function of age. After birth, the microsomal CPT activity continued to increase until adulthood (24 wks of age), thereafter it gradually decreased. On the otherhand, the CPT activity of mitochondria continued to increase with the advancement of age and beyond 72 wks of age, it was approximately 2-fold higher than that of the microsomal fraction.
Mol Cell Biochem 1993 Apr 07
PMID:Effects of aging on cholinephosphotransferase activity on guinea pig lung mitochondria and microsomes. 838 81

The effect of incubation with the protein kinase C activator, 4 beta-phorbol 12,13-dibutyrate (beta-PDBu) on the electrophysiological responses to hypoxia and combined hypoxia and hypoglycemia was investigated in the rat hippocampal slice. Preincubation with beta-PDBu prevents adenosine-mediated inhibition of synaptic transmission under normoxic, normoglycemic conditions. beta-PDBu preincubation also reduces the adenosine-mediated hypoxia-induced depression of synaptic transmission revealing a substantial adenosine-independent hypoxia-induced depression of synaptic transmission. During combined hypoxia and hypoglycemia, slices preincubated in beta-PDBu display a significant shortening of the time of anoxic depolarization, an effect of beta-PDBu that is not mimicked by application of the adenosine antagonist cyclopentyltheophylline (8-CPT). It is concluded that the state of PKC activation may influence the electrophysiological responses to hypoxia and ischemia.
Mol Chem Neuropathol 1995 Sep
PMID:Phorbol ester alters the electrophysiological responses to hypoxia and ischemic-like conditions in the rat hippocampal slice. 858 22

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.
Comp Biochem Physiol B Biochem Mol Biol 1996 Jan
PMID:Comparison of the effects of cyclic AMP analogues on cholesterol metabolism in cultured rat and hamster hepatocytes. 893 53

This study was designed to determine if acute (in vitro) or chronic (in vivo) adriamycin inhibits cardiac fatty acid oxidation and if so at what sites in the fatty acid oxidation pathway. In addition, the role of L-carnitine in reversing or preventing this effect was examined. We determined the effects of adriamycin in the presence or absence of L-carnitine on the oxidation of the metabolic substrates [1-14C]palmitate. [1(-14)C] octanoate. [1(-14)C]butyrate, [U-14C]glucose, and [2(-14)C]pyruvate in isolated cardiac myocytes. Acute exposure to adriamycin caused a concentration- and time-dependent inhibition of carnitine palmitoyl transferase 1 (CPT 1) dependent long-chain fatty acid, palmitate, oxidation. Chronic exposure to (18 mg/kg) adriamycin inhibited palmitate oxidation 40% to a similar extent seen in vitro with 0.5 mM adriamycin. Acute or chronic administration of L-carnitine completely abolished the adriamycin-induced inhibition of palmitate oxidation. Interestingly, medium- and short-chain fatty acid oxidation, which are independent of CPT 1, were also inhibited acutely by adriamycin and could be reversed by L-carnitine. In isolated rat heart mitochondria, adriamycin significantly decreased oxidation of the CPT 1 dependent substrate palmitoyl-CoA by 50%. However, the oxidation of a non-CPT 1 dependent substrate palmitoylcarnitine was unaffected by adriamycin except at concentrations greater than 1 mM. These data suggest that after in vitro or in vivo administration, adriamycin, inhibits fatty acid oxidation in part secondary to inhibition of CPT 1 and/or depletion of its substrate, L-carnitine, in cardiac tissue. However, these findings also suggest that L-carnitine plays an additional role in fatty acid oxidation independent of CPT 1 or fatty acid chain length.
J Mol Cell Cardiol 1997 Feb
PMID:Acute and chronic effects of adriamycin on fatty acid oxidation in isolated cardiac myocytes. 914 Aug 35

The syndrome of cancer cachexia is accompanied by several alterations of lipid metabolism, especially that in the liver. In this study we have investigated a possible mechanism whereby the presence of the Walker 256 carcinosarcoma affects hepatic fatty acid oxidative capacity in tumour-bearing rats. Hepatic mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I), generally accepted as the main site of regulation of fatty acid oxidation, was unaffected by the presence of the extra-hepatic tumour. However, mitochondrial inner-membrane carnitine palmitoyltransferase II (CPT II) activity was markedly decreased in mitochondria isolated from the liver of tumour-bearing rats. Immuno-detection by Western blotting using a CPT II-specific antibody identified two bands (corresponding to M(r) 69,000 and 54,000) in tumour-bearing rats whereas only the normal-sized CPT II was present (at the expected M(r) 69,000) in mitochondria from control rats. It is suggested that the emergence of the second, smaller protein may represent a catalytically less active protein that arises in vivo, since its appearance was not affected by the inclusion of proteolysis inhibitors in the mitochondrial preparation buffers. Treatment of the tumour-bearing rats with indomethacin, a prostaglandin (including PGE2) synthesis inhibitor, increased CPT II activity to levels even higher than those found in the control animals. It is suggested that PGE2 may play a role in the control of CPT II expression in the liver of tumour-bearing rats. Indomethacin treatment did not affect either of the two CPT activities of the mitochondria isolated from tumour tissue.
Biochem Mol Biol Int 1998 Jan
PMID:Carnitine palmitoyltransferase II activity is decreased in liver mitochondria of cachectic rats bearing the Walker 256 carcinosarcoma: effect of indomethacin treatment. 950 62

Carnitine palmitoyltransferase-I (CPT-I) plays a crucial role in regulating cardiac fatty acid oxidation which provides the primary source of energy for cardiac muscle contraction. CPT-I catalyzes the transfer of long chain fatty acids into mitochondria and is recognized as the primary rate controlling step in fatty acid oxidation. Molecular cloning techniques have demonstrated that two CPT-I isoforms exist as genes encoding the 'muscle' and 'liver' enzymes. Regulation of fatty acid oxidation rates depends on both short-term regulation of enzyme activity and long-term regulation of enzyme synthesis. Most early investigations into metabolic control of fatty acid oxidation at the CPT-I step concentrated on the hepatic enzyme which can be inhibited by malonyl-CoA and can undergo dramatic amplification or reduction of its sensitivity to inhibition by malonyl-CoA. The muscle CPT-I is inherently more sensitive to malonyl-CoA inhibition but has not been found to undergo any alteration of its sensitivity. Short-term control of activity of muscle CPT-I is apparently regulated by malonyl-CoA concentration in response to fuel supply (glucose, lactate, pyruvate and ketone bodies). The liver isoform is the only CPT-I enzyme present in the mitochondria of liver, kidney, brain and most other tissues while muscle CPT-I is the sole isoform expressed in skeletal muscle as well as white and brown adipocytes. The heart is unique in that it contains both muscle and liver isoforms. Liver CPT-I is highly expressed in the fetal heart, but at birth its activity begins to decline whereas the muscle isoform, which is very low at birth, becomes the predominant enzyme during postnatal development. In this paper, the differential regulation of the two CPT-I isoforms at the protein and the gene level will be discussed.
Mol Cell Biochem 1998 Mar
PMID:Differential regulation in the heart of mitochondrial carnitine palmitoyltransferase-I muscle and liver isoforms. 954 27

Fatty acids are the preferred substrate of ischemic, reperfused myocardium and may account for the decreased cardiac efficiency during aerobic recovery. Neonatal cardiac myocytes in culture respond to hypoxia/serum- and glucose-free medium by a slow decline in ATP which reverses upon oxygenation. This model was employed to examine whether carnitine palmitoyltransferase I (CPT-I) modulates high rates of beta-oxidation following oxygen deprivation. After 5 h of hypoxia, ATP levels decline to 30% control values and CPT-I activity is significantly stimulated in hypoxic myocytes with no alteration in cellular carnitine content or in the release of the mitochondrial matrix marker, citrate synthase. This stimulation was attributed to an increase in the affinity of hypoxic CPT-I for carnitine, suggesting that the liver CPT-I isoform is more dominant following hypoxia. However, there was no alteration in hypoxic CPT-I inhibition by malonyl-CoA. DNP-etomoxiryl-CoA, a specific inhibitor of the liver CPT-I isoform, uncovered identical Michaelis kinetics of the muscle isoform in control and hypoxic myocytes with activation of the liver isoform. Northern blotting did not reveal any change in the relative abundance of mRNA for the liver vs. the muscle CPT-I isoforms. The tyrosine phosphatase inhibitor, pervanadate, reversed the hypoxia-induced activation of CPT-I and returned the affinity of cardiac CPT-I for carnitine to control. Reoxygenation was also associated with a return of CPT-I activity to control levels. The data demonstrate that CPT-I is activated upon ATP depletion. Lower enzyme activities are present in control and reoxygenated cells where ATP is abundant or when phosphatases are inhibited. This is the first suggestion that phosphorylation may modulate the activity of the liver CPT-I isoform in heart.
Mol Cell Biochem 1998 Mar
PMID:The liver isoform of carnitine palmitoyltransferase I is activated in neonatal rat cardiac myocytes by hypoxia. 954 43

A receptor can be activated either by specific ligand-directed changes in conformation or by intrinsic, spontaneous conformational change. In the beta(2)-adrenergic receptor (AR) overexpression transgenic (TG4) murine heart, spontaneously activated beta(2)AR (beta(2)-R*) in the absence of ligands has been evidenced by elevated basal adenylyl cyclase activity and cardiac function. In the present study, we determined whether the signaling mediated by beta(2)-R* differs from that of a ligand-elicited beta(2)AR activation (beta(2)-LR*). In ventricular myocytes from TG4 mice, the properties of L-type Ca(2+) current (I(Ca)), a major effector of beta(2)-LR* signaling, was unaltered, despite a 2.5-fold increase in the basal cAMP level and a 1.9-fold increase in baseline contraction amplitude as compared with that of wild-type (WT) cells. Although the contractile response to beta(2)-R* in TG4 cells was abolished by a beta(2)AR inverse agonist, ICI118,551 (5 x 10(-7) M), or an inhibitory cAMP analog, Rp-CPT-cAMPS (10(-4) M), no change was detected in the simultaneously recorded I(Ca). These results suggest that the increase in basal cAMP due to beta(2)-R*, while increasing contraction amplitude, does not affect I(Ca) characteristics. In contrast, the beta(2)AR agonist, zinterol elicited a substantial augmentation of I(Ca) in both TG4 and WT cells (pertussis toxin-treated), indicating that L-type Ca(2+) channel in these cells can respond to ligand-directed signaling. Furthermore, forskolin, an adenylyl cyclase activator, elicited similar dose-dependent increase in I(Ca) amplitude in WT and TG4 cells, suggesting that the sensitivity of L-type Ca(2+) channel to cAMP-dependent modulation remains intact in TG4 cells. Thus, we conclude that beta(2)-R* bypasses I(Ca) to modulate contraction, and that beta(2)-LR* and beta(2)-R* exhibit different intracellular signaling and target protein specificity.
Mol Pharmacol 1999 Sep
PMID:Spontaneous beta(2)-adrenergic signaling fails to modulate L-type Ca(2+) current in mouse ventricular myocytes. 1046 36

Nitric oxide (NO) relaxes vascular smooth muscle in part through an accumulation of cGMP in the target cells. We hypothesized that a similar effect may also exist on collagen gel contraction mediated by human fetal lung (HFL1) fibroblasts, a model of wound contraction. To evaluate this, HFL1 cells were cultured in three-dimensional type I collagen gels and floated in serum-free DMEM with and without various NO donors. Gel size was measured with an image analyzer. Sodium nitroprusside (SNP, 100 microM) significantly augmented collagen gel contraction by HFL1 cells (78.5 +/- 0.8 vs. 58.3 +/- 2. 1, P < 0.01), whereas S-nitroso-N-acetylpenicillamine, 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride, NONOate, and N(G)-monomethyl-L-arginine did not affect the contraction. Sodium ferricyanide, sodium nitrate, or sodium nitrite was not active. The augmentory effect of SNP could not be blocked by 1H-[1,2, 4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, whereas it was partially reversed by 8-(4-chlorophenylthio) (CPT)-cGMP. To further explore the mechanisms by which SNP acted, fibronectin and PGE(2) production were measured by immunoassay after 2 days of gel contraction. SNP inhibited PGE(2) production and increased fibronectin production by HFL1 cells in a concentration-dependent manner. CPT-cGMP had opposite effects on fibronectin and PGE(2) production. Addition of exogenous PGE(2) blocked SNP-augmented contraction and fibronectin production by HFL1 cells. Therefore, SNP was able to augment human lung fibroblast-mediated collagen gel contraction, an effect that appears to be independent of NO production and not mediated through cGMP. Decreased PGE(2) production and augmented fibronectin production may have a role in this effect. These data suggest that human lung fibroblasts in three-dimensional type I collagen gels respond distinctly to SNP by mechanisms unrelated to the NO-cGMP pathway.
Am J Physiol Lung Cell Mol Physiol 2000 May
PMID:Sodium nitroprusside augments human lung fibroblast collagen gel contraction independently of NO-cGMP pathway. 1078 35

We hypothesized that nitric oxide (NO) plays an important role in mediating the anti-adrenergic effect of adenosine on atrioventricular (AV) nodal conduction. In guinea-pig hearts instrumented for measurement of AV nodal conduction time (atrium-to-His bundle, A-H, interval), the NO synthase (NOS) inhibitor, l-NMMA (100 microm), reversibly inhibited 80% (P=0.009, n=6) of adenosine's anti-adrenergic action on the positive dromotropic effect of isoproterenol (0.01 microm). In parallel studies carried out in rabbit AV nodal myocytes, intracellular mechanisms whereby NO mediates the inhibitory effect of adenosine on isoproterenol-induced A-H interval shortening were studied. Adenosine (3 microm) inhibited isoproterenol-stimulated (0.1 microm) I(Ca,L)(beta -I(Ca,L)) by 46+/-6% (P<0.001, n=17). Consistent with isolated heart data, the NOS inhibitors, l -NMMA (100 microm) and L-NNA (500 microm) attenuated the effect of adenosine on beta -I(Ca,L)by 69+/-8% (P<0.001, n=16) and 69+/-7% (P<0.001, n=10), respectively. An inhibitor of NO-stimulated guanylyl cyclase LY83538 (40 microm) reduced the inhibitory effect of adenosine on beta -I(Ca,L)by 97+/-6% (P=0.004, n=15). Similarly, the non-specific inhibitor of cAMP-phosphodiesterases IBMX (50 microm) decreased the anti-adrenergic effect of adenosine by 60% (P=0.02, n=6), whereas the extracellular application of the non-hydrolyzeable cAMP analog 8-Br-cAMP (500 microm) prevented this action of adenosine. Activation of cGMP-dependent protein kinase (PKG) by CPT-cGMP (300 microm) diminished beta -I(Ca,L), but to a significantly smaller degree (16+/-4%, P=0.025, n=12) than that caused by adenosine. NO mediates the anti-adrenergic effect of adenosine on AV nodal conduction by a mechanism predominately involving activation of cGMP-dependent cAMP-phosphodiesterase and to a lesser extent activation of PKG.
J Mol Cell Cardiol 2000 Sep
PMID:Antagonism of the positive dromotropic effect of isoproterenol by adenosine: role of nitric oxide, cGMP-dependent cAMP-phosphodiesterase and protein kinase G. 1096 24


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