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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we have used fluoride as a tool to investigate the involvement of G protein-coupled effector systems in the regulation of the depolarization-induced release of gamma-aminobutyric acid (GABA) from rat cerebral cortex. To distinguish among the activating effects of NaF on G proteins linked to different effectors, such as adenylate cyclase, polyphosphoinositide phospholipase C, and K+ channels, agents specific to these effectors have been used in parallel. NaF induced a marked dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, with an EC50 of 1.26 mM, increasing release by 103% at 5 mM NaF. No effect on basal release was seen up to 3 mM NaF, and no modulation of [3H]acetylcholine (ACh) release was seen up to 5 mM NaF. Phorbol 12,13-diacetate (PDA) produced a similar dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, potentiating the release of [14C]GABA by 50% at 10 microM PDA. The phosphodiesterase inhibitors, 3-isobutyl-1-methylxanthine (IBMX) and theophylline, inhibited the K(+)-evoked release of [14C]GABA, and IBMX reversed the NaF facilitation of GABA release in a dose-dependent manner (pA2 2.57). The K+ channel blocker (IA current) tetrahydroaminoacridine (THA), which markedly inhibits the K(+)-evoked release of [14C]GABA, also reversed the NaF facilitatory effect, but the release of [3H]ACh was less sensitive to the inhibitory effect of THA. On the other hand, the K+ channel blocker, tetraethylammonium, which has no effect on the release of [14C]GABA, caused a significant facilitation of K(+)-evoked release of [3H]ACh. From these studies, it is concluded that GABA release in cerebral cortex is subject to regulation by G protein-linked effector systems that are distinct from those affecting the release of [3H]ACh in cerebral cortex.
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PMID:Modulation of gamma-aminobutyric acid release in cerebral cortex by fluoride, phorbol ester, and phosphodiesterase inhibitors: differential sensitivity of acetylcholine release to fluoride and K+ channel blockers. 169 Feb 66

Scatter factor (SF) is a fibroblast-derived cytokine which stimulates motility of epithelial and vascular endothelial cells. We used a quantitative assay based on migration of cells from microcarrier beads to flat surfaces to study the regulation of motility in bovine brain endothelial cells (BBEC). Peptide growth factors (EGF, ECGF, basic FGF) did not stimulate migration. Tumor promoting phorbol esters (PMA, PDD) markedly stimulated migration, while inactive phorbol esters (4a-PDD, phorbol-13,20-diacetate) did not affect migration. Both SF- and PMA-stimulated migration were inhibited by 1) TGF-beta; 2) protein kinase inhibitors (e.g., staurosporine, K-252a); 3) activators of the adenylate cyclase signaling pathway (e.g., dibutyryl cyclic AMP, theophylline); 4) cycloheximide; and 5) anti-cytoskeleton agents (e.g., cytochalasin B, colcemid). However, PMA and SF pathways were distinguishable: 1) PMA induced additional migration at saturating SF concentrations; 2) the onset of migration-stimulation was immediate for PMA and delayed for SF; and 3) down-modulation of protein kinase C (PKC) ablated PMA but not SF responsiveness. Assessment of PKC by (3H)-phorbol ester (PDBu) binding and by immunoblot showed 1) scatter factor does not cause significant redistribution or down-modulation of PDBu binding or alpha-PKC; and 2) PDBu mediates redistribution and down-modulation of both binding and alpha-PKC. These findings suggest two pathways for BBEC motility: a PKC-dependent pathway and an SF-stimulated/PKC-independent pathway.
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PMID:Regulation of motility in bovine brain endothelial cells. 182 64

1. Interactions between the effects of adenosine or 2-chloro-adenosine (CADO) and the effects of substances that interfere with the phosphoinositides/protein kinase C transducing system or with the adenylate cyclase transducing system, on endplate potentials (e.p.ps), were investigated. The preparation used was the innervated sartorius muscle of the frog in which twitches had been prevented with high magnesium concentrations. 2. The activator of protein kinase C, 4 beta-phorbol-12,13-diacetate (PDAc), reversibly increased the amplitude and the quantal content of e.p.ps and attenuated the inhibitory effects of adenosine and CADO on e.p.p. amplitude. The affinity of the adenosine receptor antagonist, 8-phenyltheophylline, was not modified by PDAc. 3. The phorbol ester 4 alpha-phorbol-12,13-didecanoate, which does not activate protein kinase C, did not modify either e.p.p amplitude or the inhibitory effect of adenosine on e.p.ps. 4. The inhibitor of protein kinase C, polymyxin B, reversibly decreased the amplitude and the quantal content of e.p.ps, prevented the enhancement caused by PDAc on e.p.p. amplitude, but did not modify the inhibitory effect of adenosine on e.p.ps. H-7, another inhibitor of protein kinases, also decreased e.p.p. amplitude but did not modify the effect of PDAc on the amplitude of e.p.ps. 5. Lithium chloride, which alters phosphoinositide signal transduction by inhibiting the breakdown of inositol phosphates, reversibly increased the amplitude and the quantal content of the e.p.ps. In the presence of adenosine or CADO the effect of lithium on e.p.p. amplitude was markedly attenuated. 6. The activator of adenylate cyclase, forskolin, reversibly increased the amplitude and the quantal content of the e.p.ps. 7. The results suggest that the phosphoinositides/protein kinase C transducing system, but not the adenylate cyclase transducing system, might be involved in the inhibitory effect of adenosine on neuromuscular transmission.
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PMID:Interactions between adenosine and phorbol esters or lithium at the frog neuromuscular junction. 216 62

Adenylate cyclase (ATP-pyrophosphate lyase (cyclizing); EC 4.6.1.1) in the human keratinocyte cell line SCC 12F was potentiated by 12-O-tetradecanoyl-phorbol-13-acetate (TPA), phorbol-12,13-diacetate, and 1,2-dioctanoylglycerol. Keratinocytes exposed to TPA showed a 2-fold enhancement of adenylate cyclase activity when assayed in the presence of isoproterenol or GTP. The half-maximal effective concentration (EC50) for both isoproterenol and GTP were unaltered by TPA treatment of the cells. Basal adenylate cyclase activity in membranes from TPA-treated cultures was also increased 2-fold relative to activity in control membranes. Potentiation of adenylate cyclase activity was dependent on the concentration of TPA to which the keratinocytes were exposed (EC50 for TPA = 3 nM). TPA actions on adenylate cyclase were maximal after 15 min of incubation of the cells with the compound, correlating well with the time course of translocation of protein kinase C (Ca2+/phospholipid-dependent enzyme) from cytosol to membrane. The action of cholera toxin on adenylate cyclase was additive with TPA. In contrast, pertussis toxin actions on adenylate cyclase were not additive with TPA. Treatment of control cells with pertussis toxin activated adenylate cyclase 1.5-fold, whereas cells exposed to pertussis toxin for 6 h followed by TPA for 15 min showed the same 2-fold increase in adenylate cyclase activity as observed in membranes from cells exposed to TPA without prior exposure to pertussis toxin. Pertussis toxin catalyzed ADP-ribosylation was increased 2-fold in membranes from SCC 12F cells exposed to TPA, indicating an increase in the alpha beta gamma form of Gi. These data suggest that exposure of human keratinocytes to phorbol esters increases adenylate cyclase activity by a protein kinase C-mediated increase in the heterotrimeric alpha beta gamma form of Gi resulting in decreased inhibition of basal adenylate cyclase activity.
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PMID:Modulation of adenylate cyclase in human keratinocytes by protein kinase C. 246 Apr 60

Neurohumoral agents modulate intestinal transport by interactions with cell membrane receptors. Intracellular second messenger systems implicated in mediation of membrane receptor regulation of cellular events include the phosphoinositide and adenylate cyclase systems. In this study we have investigated the effects of direct postreceptor activation of key components of these systems on intestinal water and electrolyte transport. Rabbit ileal segments (n = 35) were arterially perfused ex vivo with an oxygenated sanguineous solution. The lumen was perfused with an isotonic solution containing 14C-polyethylene glycol as a nonabsorbable marker. Net fluxes of H2O, Na+, and Cl- in six experimental groups were calculated for three 20-minute periods: basal, drug infusion, and recovery. The control group had no drug infusion. Two phorbol esters--phorbol 12, 13-diacetate (PDA; 10(-5) mol), and phorbol 12, 13-dibutyrate (PDB; 10(-5) mol)--were used to activate protein kinase C, an important component of the phosphoinositide system. The inactive 4 alpha-phorbol 12, 13-didecanoate (PDD; 10(-5) mol) served as a drug-infused control. Forskolin at two doses (FOR; 10(-5) mol and 10(-6) mol) was used to activate adenylate cyclase. The control and PDD groups had no changes in the flux of water and electrolytes. Both PDA and PDB had proabsorptive effects, with the more lipophilic and potent phorbol ester (PDB) having a more pronounced, significant effect (p less than 0.05). FOR caused significant secretion of H2O, Na+, and Cl- in a dose-dependent fashion (p less than 0.05). These results indicate that direct protein kinase C activation causes a proabsorptive effect and that direct activation of adenylate cyclase causes a secretory effect in the isolated small bowel. The activation status of these second messenger systems has a major influence on the transport state of the intestine.
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PMID:Postreceptor mechanisms of small-bowel water and electrolyte transport. 254 96

Two adenylate cyclase inhibitors: 9-(tetrahydro-2-furyl)adenine and 2'5'-dideoxyadenosine decreased cAMP levels in LH-stimulated immature rat Leydig cells by 20-40%, independent of the concentration of LH. Steroid production was not correlated with this decrease in cAMP, but was increased (146%). The phorbol ester 4 beta-phorbol-12-myristate-13-acetate stimulated steroidogenesis and the phosphorylation of a 17 kD and a 33 kD protein, which was also stimulated by LH, whereas the inactive phorbol ester 4 beta-phorbol-12,13-diacetate did not have any effects. Moreover, the Ca2+-channel blocker diltiazem inhibited LH effects, but had no direct effects on the cholesterol side chain cleavage enzyme. It is concluded that cAMP may not be the only second messenger in LH action, and that other second messenger systems are probably also involved.
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PMID:Is cAMP the obligatory second messenger in the action of lutropin on Leydig cell steroidogenesis. 298 30

In primary cultures of rat hepatocytes the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was studied in the presence of putative local hormone and substrate modulators which form clear concentration gradients during liver passage such as adenosine, ketone bodies and ammonia. 1) Adenosine inhibited the induction of phosphoenolpyruvate carboxykinase in a concentration-dependent manner between 50 and 200 microM up to 4 h after glucagon application; AMP had similar, adenine, inosine and guanosine had no effect. Adenosine was almost totally metabolized by the liver cells during the first 4 h of the induction period. The inhibitory action of adenosine was also observed using dibutyryl-cAMP or 8-bromo-cAMP as inducer; it could not be prevented by the adenosine receptor antagonist caffeine nor could it be mimicked by the selective adenosine receptor agonist N6-(phenylisopropyl)adenosine. 2) Acetoacetate suppressed the induction of phosphoenolpyruvate carboxykinase in a concentration-dependent manner between 5 and 20mM during the first 4 h after glucagon addition. beta-Hydroxybutyrate showed no effect. Neither starting with acetoacetate nor with beta-hydroxybutyrate did the cell cultures establish the thermodynamic equilibrium between the two compounds. 3) Ammonia did not affect induction of phosphoenolpyruvate carboxykinase at concentrations up to 2mM. Ammonia was converted to urea within the first 4 h; yet it remained at clearly hyperphysiological concentrations in the medium during that period. It is concluded that the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was modulated by the local hormone adenosine via a mechanism not involving adenylate cyclase and by acetoacetate via an unknown mechanism. The inhibitory action of adenosine may, that of acetoacetate can hardly be physiologically relevant.
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PMID:Modulation of the glucagon-dependent induction of phosphoenolpyruvate carboxykinase by adenosine, but not ketone bodies or ammonia in rat hepatocyte cultures. Possible significance for the zonal heterogeneity of liver parenchyma. 344 1

1. Intracellular recordings were used to study the role of metabotropic glutamate receptors (mGluRs) in modulating GABA-mediated giant depolarizing potentials (GDPs) in immature rat hippocampal CA3 neurones. 2. The mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM) reduced the frequency of GDPs. The broad-spectrum ionotropic glutamate receptor antagonist kynurenic acid (1 mM) blocked GDPs. 3. In the presence of kynurenic acid, both tetanic stimulation of the hilus or bath application of quisqualic acid (1 microM) and trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 20 microM) induced the appearance of GDPs. These effects were antagonized by MCPG (1 mM) or L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and blocked by bicuculline (10 microM). 4. 8-Bromo-cAMP (8-Br-cAMP, 0.3 mM), 3-isobutyl-1-methylxanthine (IBMX, 200 microM) or forskolin (30 microM) mimicked the effects of mGluR agonists on GDPs. The forskolin analogue 1,9-dideoxyforskolin (30 microM), which does not activate adenylate cyclase, was ineffective. 5. Incubation of slices in the presence of the protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) (500 microM) or superfusion of Rp-cAMPS (20 microM) prevented the effects of forskolin or t-ACPD on GDPs. In the presence of kynurenic acid, the protein kinase C activator, phorbol 12,13-diacetate (2 microM) induced the appearance of GDPs. This effect was prevented by staurosporine (1 microM). However, staurosporine (1-3 microM) did not modify the effects of t-ACPD on GDPs. 6. It is suggested that, during development, mGluRs enhance the synchronous release of GABA, responsible for GDPs, through cAMP-dependent protein kinase.
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PMID:Cyclic AMP-dependent modulation of giant depolarizing potentials by metabotropic glutamate receptors in the rat hippocampus. 858 96

We studied the effect of the adenylate cyclase activator forskolin, of protein kinase C-activating phorbol esters and of prolonged preganglionic input activation on the inhibitory response of the perfused superior cervical ganglion of the cat to exogenous met-enkephalin (Met-ENK). Met-ENK inhibited, in a concentration-dependent manner, the postganglionic compound action potential evoked by cervical sympathetic trunk stimulation. The inhibition was reversible, was blocked by naloxone as well as by pertussis toxin and showed no homologous desensitization in the concentration range 0.01-10 microM. Pretreatment of the ganglion with 4 beta-phorbol 12,13-dibutyrate or 4 beta-phorbol 12,13-diacetate depressed the Met-ENK response for several hours, while pretreatment with forskolin had no effect. This action of phorbol esters was prevented by the protein kinase inhibitor H-7 but not by the calmodulin antagonist W-7 or the protein kinase A inhibitor HA 1004 and was calcium-dependent. Recovery of the response from the depression produced by phorbol esters was not affected by a protein synthesis inhibitor. A 40 Hz 20 min stimulus train to the cervical sympathetic trunk mimicked the effect of phorbol esters, depressing for several hours the inhibition produced by Met-ENK. Stimulus trains of duration shorter than 5 min or frequency lower than 5 Hz were ineffective. This effect of prolonged preganglionic stimulation occurred even when the stimulus train was delivered during complete block of nicotinic and muscarinic ganglionic transmission but was lost when the stimulus train was delivered during perfusion with calcium-free Krebs. The protein kinase inhibitor H-7 prevented the depression of the Met-ENK response by the train, while W-7 and HA 1004 had no effect. These findings suggest that, in the superior cervical ganglion of the cat, a kinase, activated by phorbol esters and inhibited by H-7, exerts a long-term control of the ganglion cell responsiveness to opiate receptor activation. A similar mechanism can be synaptically activated by a non-cholinergic transmitter, released by the preganglionic axons during prolonged, high frequency, activity.
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PMID:Long-term depression of a sympathetic ganglionic response to opioids by prolonged synaptic activity and by phorbol esters. 896 46

Selective activation of second messenger pathways were tested on presynaptic metabotropic glutamate receptor action at mossy fibre-CA3 synapses, using a rat hippocampal slice preparation. Application of the protein kinase C activator, phorbol 12,13-diacetate, or the adenylate cyclase activator, forskolin, markedly enhanced the mossy fibre field excitatory postsynaptic potentials, and suppressed the relative magnitude of the synaptic depression induced by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine, an agonist at group-II metabotropic glutamate receptors. These effects were also observed in a low Ca2+ solution, suggesting that they were not due to saturation of transmitter release process. Inactive analogues of the respective activators (4alpha-phorbol 12,13-didecanoate and 1,9-dideoxyforskolin) neither enhanced the mossy fibre responses nor suppressed (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine-induced synaptic depression. These results suggest that the presynaptic inhibitory action of group-II metabotropic glutamate receptors at mossy fibre-CA3 synapses could be negatively regulated by protein kinase C- and cyclic AMP-dependent mechanisms.
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PMID:Phorbol ester and forskolin suppress the presynaptic inhibitory action of group-II metabotropic glutamate receptor at rat hippocampal mossy fibre synapse. 925 23


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