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)

Serotonin 5-HT1A receptors have been reported to be negatively coupled to muscarinic receptor-stimulated phosphoinositide turnover in the rat hippocampus. In the present study, we have investigated further the pharmacological specificity of this negative control and attempted to elucidate the mechanism whereby 5-HT1A receptor activation inhibits the carbachol-stimulated phosphoinositide response in immature or adult rat hippocampal slices. Various 5-HT1A receptor agonists were found to inhibit carbachol (10 microM)-stimulated formation of total inositol phosphates in immature rat hippocampal slices with the following rank order of potency (IC50 values in nM): 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (11) greater than ipsapirone (20) greater than gepirone (120) greater than RU 24969 (140) greater than buspirone (560) greater than 1-(m-trifluoromethylphenyl)piperazine (1,500) greater than methysergide (5,644); selective 5-HT1B, 5-HT2, and 5-HT3 receptor agonists were inactive. The potency of the 5-HT1A receptor agonists investigated as inhibitors of the carbachol response was well correlated (r = 0.92) with their potency as inhibitors of the forskolin-stimulated adenylate cyclase in guinea pig hippocampal membranes. 8-OH-DPAT (10 microM) fully inhibited the carbachol-stimulated formation of inositol di-, tris-, and tetrakisphosphate but only partially antagonized (-40%) inositol monophosphate production. The effect of 8-OH-DPAT on carbachol-stimulated phosphoinositide turnover was not prevented by addition of tetrodotoxin (1 microM), by prior destruction of serotonergic afferents, by experimental manipulations causing an increase in cyclic AMP levels (addition of 10 microM forskolin), or by changes in membrane potential (increase in K+ concentration or addition of tetraethylammonium). Prior intrahippocampal injection of pertussis toxin also failed to alter the ability of 8-OH-DPAT to inhibit the carbachol response. Carbachol-stimulated phosphoinositide turnover in immature rat hippocampal slices was inhibited by the protein kinase C activators phorbol 12-myristate 13-acetate (10 microM) and arachidonic acid (100 microM). Moreover, the inhibitory effect of 8-OH-DPAT on the carbachol response was blocked by 10 microM quinacrine (a phospholipase A2 inhibitor) but not by BW 755C (100 microM), a cyclooxygenase and lipoxygenase inhibitor. These results collectively suggest that 5-HT1A receptor activation inhibits carbachol-stimulated phosphoinositide turnover by stimulating a phospholipase A2 coupled to 5-HT1A receptors, leading to arachidonic acid release. Arachidonic acid could in turn activate a gamma-protein kinase C with as a consequence an inhibition of carbachol-stimulated phosphoinositide turnover. This inhibition may be the consequence of a phospholipase C phosphorylation and/or a direct effect on the muscarinic receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Potential mechanisms involved in the negative coupling between serotonin 5-HT1A receptors and carbachol-stimulated phosphoinositide turnover in the rat hippocampus. 184 78

In cultured intact LLC-PK1 renal epithelial cells, a nonhydrolyzable ATP analogue, ATP gamma S, inhibits AVP-stimulated cAMP formation. In LLC-PK1 membranes, several ATP analogues inhibit basal, GTP-, forskolin-, and AVP-stimulated adenylate cyclase activity in a dose-dependent manner. The rank order potency of inhibition by ATP analogues suggests that a P2y type of ATP receptor is involved in this inhibition. The compound ATP gamma S inhibits agonist-stimulated adenylate cyclase activity in solubilized and in isobutylmethylxanthine (IBMX) and quinacrine pretreated membranes, suggesting that ATP gamma S inhibition occurs independent of AVP and A1 adenosine receptors and of phospholipase A2 activity. The ATP gamma S inhibition of AVP-stimulated adenylate cyclase activity is not affected by pertussis toxin but is attenuated by GDP beta S, suggesting a possible role for a pertussis toxin insensitive G protein in the inhibition. Exposure of intact LLC-PK cells to ATP gamma S results in a significant increase in protein kinase C activity. However, neither of two protein kinase C inhibitors (staurosporine and H-7) prevents ATP gamma S inhibition of AVP-stimulated adenylate cyclase activity, suggesting that this inhibition occurs by a protein kinase C independent mechanism. These findings suggest the presence of functional P2y purinoceptors coupled to two signal transduction pathways in cultured renal epithelial cells. The effect of P2y purinoceptors to inhibit AVP-stimulated adenylate cyclase activity may be mediated, at least in part, by a pertussis toxin insensitive G protein.
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PMID:ATP receptor regulation of adenylate cyclase and protein kinase C activity in cultured renal LLC-PK1 cells. 185 Jul 60

The GTPase activity of a G protein alpha subunit functions as a timer to control the lifetime of the activated conformation of the protein. Expression of the GTPase-deficient Gi2 alpha subunit oncogene, gip2 (alpha i2Q205L), in Chinese hamster ovary cells inhibited the stimulation of adenylylcyclase and altered the calcium regulation of the Gi2-phospholipase A2 (PLA2) effector complex. The phenotypic consequence of the activated alpha i2 mutant on hormonal stimulation of PLA2 varied depending on the cytoplasmic calcium transient elicited by different Gi2-linked receptors. The stimulation of PLA2 by thrombin, which mobilized calcium only from internal stores, was markedly attenuated in gip2-expressing cells. In contrast, the attenuation of the PLA2 response to ATP, a purinergic agonist which mobilizes calcium from both extracellular space and internal stores, was significantly less than that observed for thrombin. Ionomycin, a calcium ionophore, stimulated PLA2 activity in clones which expressed gip2 to a level similar to that observed in wild-type Chinese hamster ovary cells. Thus, the dominant GTPase-deficient gip2 polypeptide will constitutively inhibit adenylylcyclase but differentially modulate enzymes regulated by calcium and coupled to Gi2.
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PMID:GTPase-deficient G alpha i2 oncogene gip2 inhibits adenylylcyclase and attenuates receptor-stimulated phospholipase A2 activity. 190 71

Levels of phospholipids (PL) and cholesterol (CS) were measured in erythrocytic membranes (EM) of 17 bronchial asthma (BA) patients. A relationship was established between BA aggravations and elevated CS but reduced PL concentrations in EM. These parameters responded positively on day 10 of glucocorticosteroids administration. There was a good clinical effect. The changes observed may be attributed to decreasing EM viscosity improving the function of adenylate cyclase and to the action of glucocorticosteroids on phospholipase A2 by rising PL values. Some patients, in the presence of abnormal PL and CS levels, showed qualitative shifts in PL: lower proportion of sphingomyelin-containing PL. Further study of specific membrane impairment in BA promises introduction of new approaches to BA treatment.
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PMID:[Changes in the lipid composition of cell membranes in patients with bronchial asthma after glucocorticosteroid therapy]. 202 8

The possibility that arachidonic acid (AA) plays a role in the regulation of steroidogenesis in goldfish was investigated using preovulatory ovarian follicles incubated in vitro. AA was shown to act in a time- and dose-dependent manner to stimulate testosterone production. AA in the range of 10(-5) to 10(-4) M increased testosterone production within 2 hr and had a maximal effect by 9 hr. The magnitude of the testosterone response to AA was similar to that observed when ovarian follicles were incubated with human chorionic gonadotropin (hCG). Ovarian follicles incubated with AA and either hCG or forskolin (adenylate cyclase activator) produced more testosterone than follicles incubated with either of these compounds alone. The actions of AA on testosterone production were completely blocked by cyclooxygenase inhibitors (indomethacin or ibuprofen) and were reduced by 50% by the lipoxygenase inhibitor nordihydroguaiaretic acid. Phospholipase C was far more effective than phospholipase A2 in the stimulation of testosterone production. Taken together, these results suggest that AA formed subsequent to the action of phospholipase C on membrane phospholipids has a role in the regulation of steroidogenesis in preovulatory goldfish ovarian follicles.
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PMID:Arachidonic acid stimulates steroidogenesis in goldfish preovulatory ovarian follicles. 210 68

In rat olfactory bulb homogenate, carbachol stimulated adenylate cyclase activity in a concentration-dependent manner (EC50 = 1.1 microM). The carbachol stimulation occurred fully in membranes that had been prepared in the presence of 1 mM EGTA and incubated in a Ca2(+)-free enzyme reaction medium. Under these conditions, exogenous calmodulin (1 microM) failed to stimulate adenylate cyclase activity. In miniprisms of olfactory bulb, carbachol (1 mM) increased accumulation of inositol phosphates, but this response was markedly reduced in a Ca2(+)-free medium. Moreover, the carbachol stimulation of adenylate cyclase activity was not affected by staurosporine at a concentration (1 microM) that completely blocked the stimulatory effect of phorbol 12-myristate 13-acetate, an activator of Ca2+/phospholipid-dependent protein kinase. Quinacrine, a nonselective phospholipase A2 inhibitor, reduced the carbachol stimulation of adenylate cyclase activity, but this inhibition appeared to be competitive with a Ki of 0.2 microM. Nordihydroguaiaretic acid and indomethacin, two inhibitors of arachidonic acid metabolism, failed to affect the carbachol response. These results indicate that in rat olfactory bulb, muscarinic receptors stimulate adenylate cyclase activity through a mechanism that is independent of Ca2+ and phospholipid hydrolysis.
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PMID:Ca2(+)-independent stimulation of adenylate cyclase activity by muscarinic receptors in rat olfactory bulb. 211 49

Mechanisms of stimulus-response coupling in platelets are as complex and varied as the compounds that elicit the responses. The complexities are compounded by feedback mechanisms from substances released or synthesized by platelets as well as by "cross-talk" between signal transduction pathways. Examples of cross-talk include the ability of epinephrine to inhibit platelet adenylate cyclase through a G protein-mediated mechanism while causing platelet aggregation by some other mechanism and the ability of cAMP to inhibit thrombin-stimulated diacylglycerol formation. Despite the complexities, certain common threads are beginning to emerge, such as the involvement of G proteins in transducing many receptor-mediated processes, the involvement of relatively few second messenger pathways and the role of calcium in many of events leading to platelet responses, and the common involvement of protein kinases in carrying out second messenger function. The latter offers a useful assay for the effect of many agonists because they lead to the phosphorylation of specific proteins that can readily be detected by radioautography. Indeed, the emphasis has shifted in the past 10 years from relatively crude measurements of platelet function such as aggregation to precise, quantifiable measurement of processes such as protein phosphorylation and calcium release, which are indicators of the fundamental mechanisms involved in platelet function and thus serve as assays of these processes. On the other hand, there are other pathways and regulators yet to be discovered, notably regarding the action of epinephrine and the regulation of phospholipase A2. In addition, certain receptors remain elusive, including those for ADP and eicosanoids. The mechanisms of action of thrombin and cathepsin G, which involve their proteolytic activities, also remain an enigma. The combination of new insights into second messenger function and the techniques of molecular biology will allow many of these problems to be resolved, providing new approaches to therapy of thromboembolic disorders.
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PMID:Mechanisms of platelet activation and inhibition. 215 2

Cholera toxin (CT) stimulated adenylate cyclase and a phospholipase which elevated cellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) and arachidonic acid (AA). The AA was quickly converted to prostaglandins (PGs) via the cyclo-oxygenase pathway. Chloroquine exerted minimal inhibition of cAMP levels in CT-treated cells, although CT-induced release of [3H]AA and PGs was blocked completely when the drug was added in concentrations as low as 0.1 mM (50 micrograms/ml). Inhibition of [3H]AA release was complete when chloroquine was added before or within 30 min after CT. The capacity of chloroquine to inhibit either phospholipase C (PLC) or phospholipase A2 (PLA2) could explain the antisecretory activity of this drug.
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PMID:Chloroquine inhibition of cholera toxin. 217 11

Manoalide is a marine natural product that has anti-inflammatory and anti-proliferative activities and is an irreversible inhibitor of phospholipase A2 and phospholipase C. It is now shown that the compound is a potent inhibitor of Ca2+ mobilization in several cell types. In A431 cells the increase in epidermal growth factor receptor-mediated Ca2+ entry and release from intracellular Ca2+ stores were blocked by manoalide in a time-dependent manner with an IC50 of 0.4 microM. The effect of manoalide on phosphoinositide metabolism, namely the production of inositol monophosphate, did not coincide with its effect on the epidermal growth factor response. In GH# cells, manoalide blocked the thyrotropin-releasing hormone-dependent release of Ca2+ from intracellular stores without inhibition of the formation of inositol phosphates from phosphatidylinositol 4,5-bisphosphate. Manoalide also blocked the K+ depolarization-activated Ca2+ channel in these cells as well as the activation of the channel by Bay K8644 with an IC50 of 1 microM. In addition, manoalide also inhibited the Ca2+ influx induced by concanavalin A in mouse spleen cells in a time- and temperature-sensitive manner with an IC50 of 0.07 microM. However, neither forskolin-activated adenylate cyclase in A431 cells nor the distribution of the potential sensitive dye, 3,3'-dipropylthiodicarbocyanide iodide in GH3 cells was affected by manoalide. Thus, manoalide acts as a Ca2+ channel inhibitor in all cells examined. This action may account for its effects on inflammation and proliferation and may be independent of its effect on phospholipases.
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PMID:Manoalide, a natural sesterterpenoid that inhibits calcium channels. 243 21

Using an in vitro pig skin-slice incubation system, we investigated the effect of melittin, a phospholipase A2 (PLA2) stimulator, on the adenylate cyclase-cyclic AMP (cAMP) system. Significant decreases of various epidermal (beta-adrenergic, adenosine, and histamine) adenylate cyclase responses were observed as early as 1 h following the melittin treatment (50 micrograms/ml). The effect of melittin was concentration-dependent and the minimal concentration of melittin was 10 micrograms/ml for the inhibition of the beta-adrenergic adenylate cyclase response, whereas more than 50 micrograms/ml concentration was required for the inhibition of the adenosine and histamine adenylate cyclase responses. There was no significant difference in either low or high Km cAMP phosphodiesterase activity between control and melittin-treated skin. The beta-adrenergic augmentation effect by various chemicals (colchicine and Ro10-1670, an active form of Ro10-9359) were suppressed by the simultaneous addition of melittin in the incubation medium. Our data indicate that melittin affects not only on the beta-adrenergic adenylate cyclase system but also on the adenosine and histamine adenylate cyclase systems. However, the beta-adrenergic system was shown to be more sensitive to melittin than the other receptor adenylate cyclase systems.
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PMID:Melittin-induced alteration of epidermal adenylate cyclase responses. 244 46


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