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 effects of pertussis toxin, forskolin, and cAMP analogues on the antinociceptive action of nicotine were examined to investigate the possible involvement of adenylate cyclase and G-proteins in nicotine's antinociceptive effect. Intrathecal injection of pertussis toxin (0.25 and 0.50 micrograms) in mice inhibited nicotine-induced antinociception in the tail-flick test. The effect of the toxin was dose and time dependent. Forskolin, a potent adenylate cyclase activator, and 8-(-4-chlorophenylthio) adenosine-3':5' monophosphate, cyclic (8-CPT-cAMP), a cAMP analogue, inhibited the antinociceptive effects of nicotine in a dose-dependent manner. EGTA reversal of 8-CPT-cAMP's inhibitory effects suggests that calcium may to be involved. These data implicate the possible involvement of a G-protein and a second messenger system (activation of a cAMP-dependent protein kinase and increase in cyclic AMP levels) in nicotine-induced analgesia in mice.
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PMID:Nicotine-induced antinociception in mice: role of G-proteins and adenylate cyclase. 802 3

The neuromodulator adenosine is known to decrease neurotransmitter release at the neuromuscular junction by activation of an A1 adenosine receptor coupled to a pertussis toxin-sensitive G protein. Among the mechanisms that could contribute to the depression of neurotransmitter release is reduced entry of calcium through channels located in the presynaptic terminal. In the present study, we have examined the effects of adenosine on high-voltage-activated (HVA) calcium currents in motoneurons, the presynaptic cells of the neuromuscular junction. The motoneurons were isolated from embryonic mice, placed in primary tissue culture for 16 hr, and analyzed by means of the whole-cell patch-clamp technique. Adenosine (40 microM) reduced both transient and sustained components of HVA calcium current. This effect was blocked by the A1 antagonist 8-cyclopentyltheophylline (CPT; 100 nM) and was mimicked by the A1 agonist N6-cyclohexyladenosine (CHA; 50 nM to 10 microM) but not by the A2a agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine (CGS-21680; 1 micron). Pretreatment with pertussis toxin (200 ng/ml, > 16 hr) abolished the depression of HVA calcium current by adenosine receptor activation. Brief (3 min) exposure of the cells to 10 microM omega-conotoxin GVIA irreversibly blocked a part of the HVA current, which can therefore be attributed to N-type channels; the remaining current was unaffected by adenosine receptor activation. Hence, it appears that adenosine decreases only the N-current portion of HVA current and that this inhibition occurs via an A1 receptor linked to a pertussis toxin-sensitive G protein. Other investigators have shown that N-type channels do not play a primary role in eliciting transmitter release at the mammalian neuromuscular junction. Thus, it is uncertain what motoneuronal functions are influenced by adenosine modulation of N-type channels.
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PMID:Adenosine acting at an A1 receptor decreases N-type calcium current in mouse motoneurons. 820 77

Liddle's disease is an autosomal dominant genetic disorder characterized by severe low renin hypertension ("pseudoaldosteronism") that has been genetically linked to a locus on chromosome 16 encoding the beta-subunit of an amiloride-sensitive Na+ channel (ASSC) (15). Peripheral blood lymphocytes (PBL) express ASSC that are functionally indistinguishable from those expressed by Na(+)-reabsorbing renal epithelial cells (3, 5). The amiloride-sensitive Na+ conductance in PBL from affected and unaffected individuals from the original Liddle's pedigree was examined using whole cell patch clamp. Typically, the basal Na+ currents in cells from affected individuals were maximally activated. Basal Na+ currents in cells from unaffected individuals were minimal and could be maximally activated by superfusion with 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (CPT-cAMP). Affected cells could not be further stimulated with CPT-cAMP. Superfusion with a supermaximal concentration of amiloride (2 microM) inhibited both the cAMP-activated Na+ conductance in unaffected cells and the constitutively activated inward conductance in affected cells. Cytosolic addition of a peptide identical to the terminal 10 amino acids of the truncated beta-subunit normalized the cAMP-mediated but not the pertussis toxin-induced regulation of the mutant ASSC. The findings show that lymphocyte ASSC are constitutively activated in affected individuals, that a mutation of the beta-subunit alters ASSC responsiveness to specific regulatory effectors, and that the cellular mechanism responsible for the pathophysiology of Liddle's disease is abnormal regulation of Na+ channel activity. These findings have important diagnostic and therapeutic implications and provide a cellular phenotype for the diagnosis of pseudoaldosteronism.
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PMID:Liddle's disease: abnormal regulation of amiloride-sensitive Na+ channels by beta-subunit mutation. 877 46

Low concentrations of angiotensin II (Ang II) increase, whereas high concentrations inhibit the apical Na/H antiporter activity in the proximal tubule, but the respective roles of the different signaling pathways in mediating these effects remains unsettled. We studied the effects of both low and high doses of Ang II in the presence of selective signaling pathway inhibitors, on the apical Na/H antiport activity of rat proximal tubule. Experiments were carried out in intact cells of freshly prepared tubule fragments obtained from the outer third of cortex, that is, devoid of basolateral Na/H antiport activity in the absence of bicarbonate transport and H(+)-ATPase activity. In tubules acid-loaded by an NH4Cl prepulse, Na/H antiport activity was assessed by the initial rate of intracellular pH recovery (dpHi/dt), measured with BCECF. When tubules were preincubated with low dose Ang II (10(-11) M for 3 min), dpHi/dt increased by 25 +/- 8%, whereas incubation with high dose Ang II (10(-7) M for 3 min) decreased dpHi/dt by 30 +/- 4%, compared to control (P < 0.01 in both cases). Both effects were abolished in the presence of 2.10(-3) M amiloride. Low dose Ang II-induced increase in dpHi/dt was not affected by preincubation with a specific PKA inhibitor, Rp-CPT-cAMP 10(-4) M, and was completely abolished by preincubation with PKC inhibitors, staurosporine 10(-7) M, sphingosine 5.10(-6) M, or calphostin 10(-6) M. In addition, pretreatment of rats with pertussis toxin led to a partial inhibition of the effect of low dose Ang II. The high dose-Ang II-induced decrease in dpHi/dt was not affected by pretreatment with a calcium-calmodulin kinase inhibitor W-7 10(-4) M. Conversely, pretreatment with the cytochrome P-450 inhibitor econazole 10(-5) M reversed the inhibitory effect of high dose Ang II to a stimulatory effect (24 +/- 8%, P < 0.01), quantitatively similar to the effect of low dose Ang II. In addition, arachidonate was found to exert an econazole-sensitive dose-dependent inhibitory effect on dpHi/dt, and 5,6-EET 10(-6) M, a cytochrome P-450 derived-arachidonic acid metabolite, induced a 38 +/- 9% inhibition, similar to that observed with high dose Ang II alone. There was no additive effect of 5,6-EET and high dose Ang II. Finally, pretreatment with two PLA2 inhibitors (BromoPhenacylBromide, 6.10(-6) M, and oleyloxyethyl phosphorylcholine, 5.10(-6) M) reversed the inhibitory effect of high dose Ang II to a stimulatory effect (32 +/- 11% and 25 +/- 11%, respectively, P < 0.05 for both inhibitors). We conclude that, in intact rat proximal cells, low dose Ang II stimulates the apical Na/H antiport through a pertussis toxin-sensitive G protein-dependent PKC pathway, whereas high dose Ang II inhibits the Na/H antiport activity through the PLA2- and cytochrome P-450-dependent metabolites of arachidonate.
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PMID:Signaling pathways in the biphasic effect of angiotensin II on apical Na/H antiport activity in proximal tubule. 891 15

The effect of anisoosmolarity on the abundance of various mRNA species was examined in perfused rat liver and H4IIE rat hepatoma cells. Hyperosmotic exposure (385 mosmol/l) of isolated rat livers increased mRNA levels for tyrosine aminotransferase (TAT) by 246% and those for phosphoenolpyruvate carboxykinase (PEPCK) by 186%, whereas hypoosmotic exposure (225 mosmol/l) decreased their levels to 43% and 42%, respectively. mRNA levels for fructose-1,6-bisphosphatase (FBP), argininosuccinate lyase (ASL), argininosuccinate synthetase (ASS), glutamine synthetase (GS), glutaminase (GA) and glucokinase (GK) were largely unaffected. In H4IIE cells the modulation of TAT and PEPCK mRNA levels by anisoosmotic exposure was similar to that found in perfused rat liver. ASL and glutaminase mRNA levels were influenced in an opposite manner. The effects of anisoosmolarity on PEPCK mRNA levels in H4IIE cells were largely abolished in the presence of the protein kinase inhibitors H-7, H-89 and HA-1004. Other protein kinase inhibitors such as Go-6850, KN-62, Rp-8-CPT-cAMPS, rapamycin, wortmannin, genistein or herbimycin did not prevent the osmosensitivity of PEPCK mRNA levels. Also pertussis and cholera toxin, vanadate and colchicine did not affect the osmosensitivity of PEPCK mRNA levels. The data suggest that anisoosmotic exposure acts on the levels of some but not all mRNA species and that this action may involve changes in protein phosphorylation. They further indicate that the recently identified osmosensitive signal transduction pathway which involves a G-protein and tyrosine kinase dependent activation of mitogen-activated protein kinases is apparently not involved in the osmoregulation of PEPCK mRNA levels.
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PMID:Anisoosmotic regulation of hepatic gene expression. 892 14

The influence of aniso-osmolarity on the activity of the MAP kinases Erk-1 and Erk-2 was studied in C6 glioma cells. Hypo-osmotic treatment (205 mosmol/l) led to an increased activity of Erk-1 and Erk-2 within 3 min, which became maximal at 10 min and returned to basal level within 120 min. In contrast, Erk activity was reduced under hyper-osmotic conditions (405 mosmol/l), compared to the normo-osmotic control (305 mosmol/l). Erk activation was accompanied by a mobility shift of Raf-1. Hypo-osmotic exposure increased the cytosolic Ca2+ concentration ([Ca2+]i). Absence of extracellular Ca2+ largely abolished the [Ca2+]i response to hypo-osmolarity, whereas Erk activation following hypo-osmotic stimulation remained unaffected, suggesting a Ca2+ independence of the osmosignalling pathway to the MAP kinases. Both the Ca2+ response as well as the Erk activation following hypo-osmotic exposure were maintained in the presence of the phospholipase C inhibitor U73122. Application of 8-CPT cAMP, forskolin/isobutylmethylxanthine or isoproterenol blocked Erk activation following hypo-osmotic treatment of the cells, suggesting a role of the Ras/Raf pathway upstream from Erk-1 and Erk-2. Protein kinase C (PKC) is unlikely to play a role in the hypo-osmolarity- induced signalling towards MAP kinases, as revealed by inhibition of PKC with Go6850. Inhibition of pertussis- or cholera toxin-sensitive G-proteins as well as inhibition of tyrosine kinases with genistein and of PI3 kinase by wortmannin had no effect on the Erk response to hypo-osmolarity. It is concluded that osmosignalling in C6 glioma cells differs upstream of the MAP kinases from that observed in primary rat astrocytes, H4IIE rat hepatoma cells and isolated rat hepatocytes.
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PMID:Osmosignalling in C6 glioma cells. 900 90

Recent studies have shown that beta 2-adrenergic receptor (beta 2-AR)-stimulated increases in the intracellular Ca2+ (Cai) transient and contraction in cardiac myocytes are dissociated from the increase in adenosine 3',5'-cyclic monophosphate (cAMP) level and are not accompanied by an increase in phospholamban phosphorylation, an acceleration in relaxation, or a reduction in myofilament Ca2+ response. Thus we hypothesized that the beta 2-AR modulation of cardiac excitation-contraction (EC) coupling may be mediated by either a cAMP-independent mechanism or a compartmentalized cAMP pathway. To directly distinguish between these two possibilities, the responses of the L-type Ca2+ current (ICa), Cai transient, and contraction to beta 2-AR as well as to beta 1-AR stimulation were examined in rat ventricular myocytes in the presence or absence of specific inhibitory cAMP analogs, Rp diastereomers of adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS) and 8-(4-chlorophenylthio)-cAMP (Rp-CPT-cAMPS). As expected, the positive inotropic effect induced by an adenylyl cyclase activator, forskolin (2 x 10(-7) M), or a beta 1-AR agonist, norepinephrine (5 x 10(-8) M) plus prazosin (10(-6) M), was completely blocked by Rp-CPT-cAMPS. More importantly, the responses of ICa, Cai transient, and contraction to beta 2-AR stimulation by zinterol (10(-5) M) or isoproterenol plus a selective beta 1-AR antagonist, CGP-20712A, were also entirely abolished by Rp-cAMPS (in the patch-pipette solution) or Rp-CPT-cAMPS (in the bath solution). In pertussis toxin-treated cells, although the response of cAMP was not altered, the beta 2-AR-stimulated increase in contraction amplitude was markedly enhanced and accompanied by a hastened relaxation, resulting in a tight association between cAMP and contraction. These results indicate that beta 2-AR modulation of cardiac excitation-contraction coupling requires cAMP. The dissociation of beta 2-AR-stimulated cAMP production and regulation of myofilament and sarcoplasmic reticulum functions is attributable to a functional compartmentation of the cAMP-dependent signaling due to an activation of beta 2-AR-coupled Gi and/or G(o).
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PMID:Localized cAMP-dependent signaling mediates beta 2-adrenergic modulation of cardiac excitation-contraction coupling. 932 56

The effects of cAMP on the oxytocin-stimulated increase in phosphatidylinositide turnover and the possible pathways involved were investigated in a human myometrial cell line (PHM1-41) and in COS-M6 cells overexpressing the oxytocin receptor. Preincubation with chlorophenylthio-cAMP (CPT-cAMP), forskolin, or relaxin inhibited oxytocin-stimulated phosphatidylinositide turnover in PHM1-41 cells, and the inhibition was reversed by H-89, a relatively specific protein kinase A inhibitor. Both CPT-cAMP and transiently expressed protein kinase A catalytic subunit inhibited stimulation by oxytocin and carbachol of [3H]inositol 1,3,4-trisphosphate formation in COS-M6 cells expressing oxytocin or muscarinic M1 receptors, respectively. CPT-cAMP also inhibited phosphatidylinositide turnover stimulation by endothelin-1 in PHM1-41 cells, further demonstrating the generality of the cAMP-inhibitory mechanism. Since G betagamma activation of phospholipase Cbeta2 (PLCbeta2) is a suggested target of protein kinase A, the possibility that the oxytocin receptor couples to PLCbeta2 via G alpha(i)G betagamma activation was explored. Western blot analysis of PHM1-41 cells and COS-M6 cells detected PLCbeta1 and PLCbeta3, but not PLCbeta2. In PHM1-41 cells, pertussis toxin reduced the oxytocin-stimulated increase in [3H]inositol 1,3,4-trisphosphate by 53%, and this was reversed completely by H-89. Thus, the inhibitory effect of pertussis toxin may result from an indirect effect of cAMP elevation. These data suggest that receptor/G alpha(q)-coupled stimulation of PLCbeta1 or PLCbeta3 can be inhibited by cAMP through a phosphorylation mechanism involving protein kinase A that does not involve PLCbeta2. In smooth muscle, this mechanism could constitute potentially important cross-talk between pathways regulating contraction and relaxation.
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PMID:Evidence for inhibition by protein kinase A of receptor/G alpha(q)/phospholipase C (PLC) coupling by a mechanism not involving PLCbeta2. 956 32

Two independent signal transduction pathways regulate lymphocyte amiloride-sensitive sodium channels (ASSCs), one utilizing cAMP as a second messenger and the other utilizing a GTP-binding protein. This implies that two plasma membrane receptors play a role in the regulation of lymphocyte ASSCs. In this study, we tested the hypothesis that alpha1- and alpha2-adrenergic receptors independently regulate lymphocyte ASSCs via the two previously identified second messengers. Direct measurements indicated that norepinephrine increased lymphocyte cAMP and activated ASSCs. The alpha2-specific inhibitor, yohimbine, blocked this activation, thereby linking alpha2-adrenergic receptors to ASSC regulation via cAMP. The alpha1-specific ligand, terazosin, acted as an agonist and activated lymphocyte ASSCs but inhibited ASSC current that had been preactivated by norepinephrine or 8-(4-chlorophenylthio) (CPT)-cAMP. Terazosin had no effect on the lymphocyte whole cell ASSC currents preactivated by treatment with pertussis toxin. This finding indirectly links alpha1-adrenergic receptors to lymphocyte ASSC regulation via GTP-binding proteins. Terazosin had no direct inhibitory or stimulatory effects on alpha,beta,gamma-endothelial sodium channels reconstituted into planar lipid bilayers and expressed in Xenopus oocytes, ruling out a direct interaction between terazosin and the channels. These findings support the hypothesis that both alpha1- and alpha2-adrenergic receptors independently regulate lymphocyte ASSCs via GTP-binding proteins and cAMP, respectively.
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PMID:Alpha-adrenergic receptors regulate human lymphocyte amiloride-sensitive sodium channels. 973 Sep 54

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


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