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)

The effects of endogenous phospholipase A2 activation by melittin on components of the beta adrenoceptor linked adenylate cyclase system were examined in cultured cardiac cells. Exposure of cardiac cells for one hour to melittin concentrations ranging from 0.125 microgram/ml to 5.0 micrograms/ml induced a concentration dependent hydrolysis of radioactively labelled phospholipids and loss of lysophospholipids from the cell membrane. Melittin concentrations of 2.5 micrograms/ml or greater markedly attenuated the isoprenaline induced rise in cyclic AMP. In vitro studies using cell homogenates suggest that phospholipase A2 activation by the higher concentration of melittin (5 micrograms/ml) partially uncoupled the beta adrenoceptor from adenylate cyclase. Beta adrenoceptor number estimated by 125I-iodohydroxybenzylpindolol specific binding as well as the affinity of isoprenaline for these binding sites were unaffected by melittin pre-exposure. The percentage stimulation of adenylate cyclase by sodium fluoride or guanylylimidodi-phosphate was not significantly affected by activation of endogenous phospholipase A2. Phosphodiesterase activity in the soluble fraction of cell homogenates increased marginally (9%, P = 0.05) in cells exposed to melittin. These results suggest that activation of endogenous phospholipase A2 within the sarcolemma can modulate the activity of the beta adrenoceptor linked adenylate cyclase system of intact cardiac cells. The reduced beta adrenoceptor responsiveness of the cells appears to be primarily due to an alteration in coupling between the beta adrenoceptor and the guanine nucleotide binding protein components of the adenylate cyclase system and not between the latter and the catalytic subunit.
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PMID:The effects of endogenous phospholipase A2 activation on beta adrenoceptor function in cardiac cells. 631 71

The nonspecific lipid transfer protein from beef liver was used to modify the phospholipid composition of intact turkey erythrocytes in order to study the dependence of isoproterenol-stimulated adenylate cyclase activity on membrane phospholipid composition. Incorporation of phosphatidylinositol into turkey erythrocytes inhibited isoproterenol-stimulated cyclic AMP accumulation in a linear, concentration-dependent manner. Inhibition was relatively specific for phosphatidylinositol; phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and phosphatidic acid were from 3 to 7 times less effective as inhibitors of hormone-stimulated cyclase activity. Inhibition by phosphatidylinositol was not reversible when up to 90% of the incorporated phosphatidylinositol was removed, either by incubation with phosphatidylinositol-specific phospholipase C or a second incubation with transfer protein; possibly adenylate cyclase activity depends on a small pool of phosphatidylinositol that is inaccessible to either phospholipase C hydrolysis or removal by lipid transfer protein. Phosphatidylinositol incorporation inhibits adenylate cyclase activity by uncoupling beta-adrenergic receptors from the remainder of the cyclase complex. Phosphatidylinositol incorporation had no effect on stimulation of cAMP accumulation by either cholera toxin or forskolin, indicating that inhibition occurs only at the level of receptor. Phosphodiesterase activity was not altered in phosphatidylinositol-modified cells. Inhibition of cAMP accumulation was not the result of changes in either membrane fluidity or in cAMP transport out of modified turkey erythrocytes. Phosphatidylinositol inhibition of isoproterenol-stimulated cyclase activity may serve as a useful model system for hormone-induced desensitization.
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PMID:Inhibition of hormone-stimulated adenylate cyclase activity after altering turkey erythrocyte phospholipid composition with a nonspecific lipid transfer protein. Phosphatidylinositol uncouples catecholamine binding from adenylate cyclase activation. 663 Feb 18

The effects of lead, cadmium and mercury ions on adenylate cyclase activity of rat cerebrum, cerebellum and brain stem were studied in vitro and in vivo. Adenylate cyclase activity in homogenates of cerebellum as well as cerebrum and brain stem was found to be inhibited by micromolar concentrations of these heavy metal ions in vitro. Administration of lead acetate trihydrate (25 mg/kg body wt i.v.) produced an initial increase of adenylate cyclase activity in the cerebellum and brain stem 1 h after injection, followed by a significant decrease of enzyme activity in cerebrum and cerebellum 4 h after the injection. Chronic lead treatment achieved by feeding lead containing diets, which generated blood lead levels of 31.3 +/- 3.8, 68.8 +/- 1.5 and 121.5 +/- 8.6 microgram Pb/100 g blood resp., produced a significant increase of brain lead levels and a 10-30% reduction of adenylate cyclase activity in cerebrum, cerebellum and brain stem. Phosphodiesterase activity was reduced under these conditions in the range of 10-20% in cerebellum and brain stem, but not in cerebrum.
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PMID:Effects of lead, cadmium and mercury on brain adenylate cyclase. 742 32

The two-microelectrode voltage-clamp technique was used to monitor K+ channel activity in Xenopus oocyte follicular cells, which are electrically coupled to the oocyte itself by gap junctions. Endogenous vasodilators such as calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), prostaglandin E2 (PGE2) and adenosine activate glibenclamide-ATP-sensitive K+ (KATP) channels in Xenopus oocyte follicular cells. The mechanism of action of CGRP was studied in detail. CGRP effects undergo a rapid desensitization. CGRP acts via CGRPI receptors. Its effects are antagonised by the amino-truncated CGRP analog hCGRP(8-37). The second messenger for CGRP activation of KATP channels is cAMP. Phosphodiesterase inhibition by 3-isobutyl-1-methylxanthine enhances the CGRP response while adenyl cyclase inhibition by either 2',5'-dideoxyadenosine or progesterone nearly completely depresses the CGRP response. Vasoconstrictors such as ACh and angiotensin II also have receptors in follicular cells. ACh strongly inhibits the CGRP activation of K+ channels as it inhibits the activation of KATP channels by P1060, but angiotensin II does not. It is concluded that as in vascular smooth muscle cells, CGRP and probably other hyperpolarizing vasodilators open KATP channels in follicular cells by protein kinase A activation.
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PMID:CGRP-induced activation of KATP channels in follicular Xenopus oocytes. 753 Aug 40

The action of the A2a-adenosine analogue, CGS 21680C, on electrically evoked [3H]acetylcholine ([3H]-ACh) release, and its interaction with forskolin (an activator of adenylate cyclase), MDL 12,330A (an irreversible inhibitor of adenylate cyclase), rolipram (an inhibitor of cyclic AMP specific phosphodiesterase), dibutyryl- (db-cAMP) and 8-bromo- (8-Br-cAMP) cyclic AMP analogues (substances that mimic intracellular actions of cyclic AMP), were investigated using rat phrenic nerve-hemidiaphragm preparations. CGS 21680C facilitated [3H]-ACh release. Forskolin (but not 1,9-dideoxy forskolin), rolipram, db-cAMP and 8-Br-cAMP also increased evoked neurotransmitter release in a concentration-dependent manner. When the evoked [3H]-ACh release that is dependent on stimulation of the adenylate cyclase/cyclic AMP transduction system was supramaximally stimulated by these compounds, CGS 21680C (3 nmol/l) could not further increase [3H]-ACh release. Phosphodiesterase inhibition with low concentrations (< or = 30 mumol/l) of rolipram significantly potentiated the augmenting effect of CGS 21680C (1 nmol/l) on evoked [3H]-ACh release. MDL 12,330A (an irreversible inhibitor of adenylate cyclase) decreased evoked [3H]-ACh release. The irreversible blocking action of MDL 12,330A on [3H]-ACh release was overcome by by-passing cyclase activation with db-cAMP and 8-Br-cAMP, but could not be overcome with FSK or CGS 21680C. The inhibitory effect of MDL 12,330A on evoked [3H]-ACh release was not mimicked by nifedipine. It is concluded that the increase in [3H]-ACh release caused by CGS 21680C results from activation of an A2a-adenosine receptor positively linked to the adenylate cyclase/cyclic AMP system.
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PMID:Evidence that the presynaptic A2a-adenosine receptor of the rat motor nerve endings is positively coupled to adenylate cyclase. 787 Jan 91

Phosphodiesterase inhibitors were used as a tool to manipulate cellular nucleotide levels in vitro and in vivo. The lipopolysaccharide (LPS)-induced release of tumor necrosis factor alpha (TNF-alpha) from mouse peritoneal macrophages was inhibited by prostaglandin E2 with an IC50 of 0.05 microM and by dibutyryl-cAMP with an IC50 of 180 microM. In the presence of the phosphodiesterase inhibitors zardaverine or rolipram the intracellular cAMP concentration of LPS-stimulated macrophages was significantly increased. In these cells, LPS-inducible TNF release was inhibited by zardaverine (IC50 = 1.5 microM) or by rolipram (IC50 = 0.35 microM). In a model of septic shock, i.e. LPS challenge of galactosamine-sensitized mice, a dose-dependent protection against liver injury was observed following oral application of rolipram (ED50 = 0.55 mg/kg) or of zardaverine (ED50 approximately 30 mg/kg). The adenylate cyclase activator forskolin was also protective. Rolipram also protected against TNF-induced liver injury in mice while zardaverine failed to do so. It is concluded that the intracellular cAMP level of macrophages is a critical determinant of LPS-inducible TNF release and therefore modulates the susceptibility to septic shock.
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PMID:Protection by phosphodiesterase inhibitors against endotoxin-induced liver injury in galactosamine-sensitized mice. 839 40

Using CHO cells stably transfected with rat mu-opioid receptor cDNA, we show that the mu-agonists morphine and [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin are negatively coupled to adenylylcyclase and inhibit forskolin-stimulated cAMP accumulation. Chronic exposure of cells to morphine leads to the rapid development of tolerance. Withdrawal of morphine or [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin following chronic treatment (by wash or addition of the antagonist naloxone) leads to an immediate increase in cyclase activity (supersensitization or overshoot), which is gradually reversed upon further incubation with naloxone. Phosphodiesterase inhibitors do not affect the overshoot, indicating that it results from cyclase stimulation rather than phosphodiesterase regulation. Morphine's potency to inhibit cAMP accumulation is the same before and after chronic treatment, suggesting that the apparent tolerance results from cyclase activation, rather than from receptor desensitization. The similar kinetics of induction of tolerance and overshoot support this idea. Both the overshoot and acute opioid-induced cyclase inhibition are blocked by naloxone and are pertussis toxin-sensitive, indicating that both phenomena are mediated by the mu-receptor and Gi/G(o) proteins. The supersensitization is cycloheximide-insensitive, indicating that it does not require newly synthesized proteins. This is supported by the rapid development of supersensitization. Taken together, these results show that mu-transfected cells can serve as a model for investigating molecular and cellular mechanisms underlying opiate drug addiction.
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PMID:Adenylylcyclase supersensitization in mu-opioid receptor-transfected Chinese hamster ovary cells following chronic opioid treatment. 853 Mar 63

In vascular smooth muscle cells (VSMCs) of rat tail artery, prostaglandin E2 (PGE2) inhibited a voltage-dependent, delayed rectifier K channel current (Ik). The inhibition was concentration-dependent, via a receptor-mediated mechanism involving the activation of G protein(s) (Ren et al., 1995). In this study, we show that the PGE2-induced inhibition of Ik was mediated by activation of protein kinase A (PKA) and possibly protein kinase C (PKC). Pretreatment of the cells with cyclic adenosine 3',5'-monophosphothioate Rp-isomer (Rp-cAMPs), an inhibitor of adenosine 3', 5'-cAMP-dependent protein kinase (PKA), almost completely abolished the PGE2-induced inhibition. Forskolin, dibutyryl cAMP (Db-cAMP) and cyclic adenosine 3',5'cyclic monophosphothioate Sp-isomer (Sp-cAMPs), activators of adenylate cyclase and PKA, mimicked the effect of PGE2 on Ik. Phosphodiesterase inhibition by 3-isobutyl-1-methylxanthine did not alter the PGE2-induced inhibition of Ik. Moreover, we also found that phorbol myristate acetate (PMA), a PKC activator, significantly suppressed Ik. Both the kinase inhibitor staurosporine and down-regulation of PKC by prolonged exposure of the cells to PMA blocked the PGE2-induced inhibition of Ik, but had no effects on the forskolin, Db-cAMP or SpcAMP-induced effect on Ik. Pretreatment of the cells with Rp-cAMPs only partially diminished the degree of Ik inhibition evoked by PMA. Assay of cAMP content indicated that both PGE2 and PMA induced cAMP accumulation. These results strongly suggest that the modulation of Ik by PGE2 in rat tail artery VSMCs involves signal transduction through both PKA and PKC activation. The activation of PKC may potentiate the cAMP-PKA stimulation, whereas the cAMP-PKA cascade did not seem to affect the PKC pathway. These observations suggest that "cross talk" between the two second-messenger systems is involved in the mechanisms that mediate the effect of PGE2.
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PMID:The actions of prostaglandin E2 on potassium currents in rat tail artery vascular smooth muscle cells: regulation by protein kinase A and protein kinase C. 861 46

Phosphodiesterases (PDEs) regulate intracellular cyclic nucleotide metabolism and, thus, contraction and relaxation of smooth musculature. The aim of the present study was to evaluate the functional effects of isoenzyme-selective inhibitors and their effects on cyclic nucleotide levels in the human detrusor smooth muscle. In addition, the functional relevance of the cAMP versus the cGMP pathways in the regulation of the detrusor smooth muscle tone was assessed. Relaxant responses to various PDE inhibitors, forskolin and sodium nitroprusside (SNP) were investigated in vitro using a standard organ bath setup. Cyclic nucleotide levels were measured after incubation with the same substances using cAMP and cGMP radioimmunoassays (RIAs). Significant relaxant responses were only induced by non-selective PDE inhibition, the PDE I inhibitor vinpocetine and the adenylate cyclase activator forskolin. Relaxant responses to these substances were paralleled by increases in cyclic nucleotide levels. Our data suggest that the cAMP pathway and calcium/calmodulin-stimulated PDE (PDE I) may be of functional importance in the regulation of the human detrusor smooth muscle tone in vitro.
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PMID:Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. II. Effect of various PDE inhibitors on smooth muscle tone and cyclic nucleotide levels in vitro. 883 79

1. The role of non-calcineurin protein phosphatases in the cyclic AMP signal transduction pathway was examined in mouse pituitary corticotroph tumour (AtT20) cells. 2. Blockers of protein phosphatases, calyculin A and okadaic acid, were applied in AtT20 cells depleted of rapidly mobilizable pools of intracellular calcium and activated by various cyclic AMP generating agonists. Inhibitors of cyclic nucleotide phosphodiesterases were present throughout. The accumulation of cyclic AMP was monitored by radioimmunoassay, phosphodiesterase activity in cell homogenates was measured by radiometric assay. 3. Neither calyculin A nor okadaic acid altered basal cyclic AMP levels but cyclic AMP formation induced by 41 amino acid residue corticotrophin releasing-factor (CRF) was strongly inhibited (up to 80%), 1-Norokadaone was inactive. Similar data were also obtained when isoprenaline or pituitary adenylate cyclase activating peptide1-38 were used as agonists. 4. Pertussis toxin did not modify the inhibition of CRF-induced cyclic AMP production by calyculin A. 5. Pretreatment with calyculin A completely prevented the stimulation of cyclic AMP formation by cholera toxin even in the presence of 0.5 mM isobutylmethylxanthine (IBMX) and 0.1 mM rolipram. Cholera toxin mediated ADP-ribosylation of the 45 K and 52 K molecular weight Gs alpha isoforms in membranes from calyculin A-pretreated cells was enhanced to 150-200% when compared with controls. 6. Cholera toxin-induced cyclic AMP was reduced by calyculin A within 10 min when calyculin A was applied after a 90 min pretreatment with cholera toxin. Under these conditions the effect of calyculin A could be blocked by the combination of 0.5 mM IBMX and 0.1 mM rolipram, but not by 0.5 mM IBMX alone. 7. Phosphodiesterase activity in AtT20 cell homogenates showed a significant, 2.7 fold increase after treatment with calyculin A. In control cells phosphodiesterase activity was blocked by 80% in the presence of IBMX (0.5 mM), or IBMX plus rolipram (0.1 mM). In calyculin A-treated cells phosphodiesterase activity was also strongly inhibited by IBMX, but because of the stimulating effect of calyculin A, the activity remaining was still 55% of that found in control homogenates. This activity was reduced to 5% of control by using IBMX and rolipram in combination. Assay of phosphodiesterase in Ca2+ free conditions showed that calyculin A markedly increases the activity of rolipram sensitive (type 4) phosphodiesterase. 8. Taken together, blockers of protein phosphatases (PPases) impaired signal transduction through Gs-mediated pathways and activated cyclic AMP degrading phosphodiesterase(s), indicating that PPases 1 and/or 2A are essential for agonist-mediated regulation of cyclic AMP levels in AtT20 cells, and are thus important in maintaining the secretory phenotype of the cells.
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PMID:Involvement of calyculin A inhibitable protein phosphatases in the cyclic AMP signal transduction pathway of mouse corticotroph tumour (AtT20) cells. 922 58


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