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 role of a pertussis toxin sensitive GTP-binding protein in mediating between cholecystokinin receptors and phosphatidylinositol 4,5-bisphosphate phosphodiesterase as well as in preventing cholecystokinin from increasing cellular cyclic AMP has been investigated using dispersed acini from rabbit pancreas. Pertussis toxin pretreatment (500 ng/ml, 2 h) did not affect cholecystokinin(octapeptide) (CCK-8)-induced increases in cytosolic free Ca2+ as judged from changes in fluorescence obtained from quin2-loaded acini. Although pretreatment with pertussis toxin was also without effect on resting acinar cell cyclic AMP levels, adenylate cyclase activity was increased, since inhibition of cyclic AMP phosphodiesterase activity by isobutylmethylxanthine (IBMX) resulted in an additional increase in cyclic AMP levels in toxin-treated acini, indicating that acinar cell adenylate cyclase activity is under some tonic inhibitory control by the pertussis toxin-sensitive inhibitory GTP-binding protein (Gi) of the adenylate cyclase system. CCK-8 gave an increase in cyclic AMP levels in both control (1.6-fold) and toxin-treated (2.3-fold) acini, leading to cyclic AMP levels in the toxin-treated acini 2-times as high as those in control acini. In the presence of IBMX, the cyclic AMP response to CCK-8 was again markedly enhanced in acini pretreated with the toxin (3.2- vs. 1.8-fold), resulting in cAMP levels in the toxin-treated acini 3.7-times those in the absence of IBMX, 2.5-times those in control acini in the presence of IBMX and 7.0-times those in control acini in the absence of IBMX. Neither the pretreatment with pertussis toxin, nor the presence of IBMX alone, nor the combination had an effect on basal amylase secretion. However, all three treatments potentiated the stimulatory effect of CCK-8 on amylase secretion and the amount of potentiation was proportional to the cyclic AMP levels reached. Our findings suggest that in the intact pancreatic acinar cell Gi inhibition of the catalytic subunit of the adenylate cyclase may largely be responsible for preventing cholecystokinin from increasing cellular cyclic AMP. They moreover show that cyclic AMP is a modulatory agent in rabbit pancreatic enzyme secretion, not able to stimulate secretion itself, but potentiating effects mediated by the phosphatidylinositol-calcium pathway.
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PMID:Pertussis toxin stimulates cholecystokinin-induced cyclic AMP formation but is without effect on secretagogue-induced calcium mobilization in exocrine pancreas. 243 69

Single rat lactotroph cells were studied after loading with the cytosolic free Ca2+ concentration ([Ca2+]i) indicator fura-2 either 1 or 3 days after cell dispersion. Under unstimulated conditions, two groups of lactotrophs were observed, the first (predominant at day 1) with large [Ca2+]i fluctuations (peaks up to 300 nM) probably due to spontaneous action potentials and the second (predominant at 3 days) with stable [Ca2+]i (values variable between 65 and 200 nM). The effect of dopamine on the resting [Ca2+]i was different in the two groups. Even at high dopamine concentrations, no change occurred in the second group; whereas in the first, disappearance of fluctuations and marked decrease of [Ca2+]i were observed. These effects of dopamine appear to be due to hyperpolarization that was demonstrated by the use of a specific fluorescent indicator, bis(oxonol). Two types of triggered [Ca2+]i transients were studied in detail: those due to redistribution of Ca2+ from the intracellular stores (induced by thyrotropin-releasing hormone) and those due to Ca2+ influx through voltage-gated Ca2+ channels (induced by high [K+]). Dopamine (1 microM) markedly inhibited both these transients by the action of D2 receptors (blocked by 1-sulpiride and domperidone). All effects of dopamine were prevented by treatment of the cells with pertussis toxin, indicating the involvement of one (or more) GTP-binding protein(s). Another consequence of D2 receptor activation is the inhibition of adenylate cyclase. Treatments (cholera toxin, forskolin), known to raise cAMP levels, were found to dissociate the effects of dopamine on [Ca2+]i inasmuch as they markedly relieved the inhibition of the redistributive transients by thyrotropin-releasing hormone but left hyperpolarization and inhibition of K+ transients unaffected. The spectrum of intracellular signals elicited by the activation of D2 receptors is therefore complex and includes at least two mechanisms that involve [Ca2+]i, one related and the other independent of the decrease of cAMP levels.
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PMID:Dopamine inhibits cytosolic Ca2+ increases in rat lactotroph cells. Evidence of a dual mechanism of action. 244 99

Several drugs known to induce differentiation in tumor cells were analyzed for their effects on the beta-adrenergic receptor-coupled adenylate cyclase system in two human carcinoma cell lines, HeLa and A431. Each of the drugs was tested alone or in combination with sodium butyrate (NaBu), a known inducer of this signal transduction system. Puromycine amino nucleoside (PMAN) caused the largest increase in beta-adrenergic receptors in HeLa cells followed by hexamethylenebisacetamide (HMBA) whereas 5'-azacytidine (5AZC) was ineffective. In addition, PMAN but not the others acted together with NaBu to elevate receptor levels 12-fold over control values. In contrast, HMBA and 5AZC were much more effective on A431 cells, PMAN caused only a slight increase in beta receptors and none of the drugs acted in concert with NaBu. The increase in beta receptors was usually accompanied by a corresponding increase in isoproterenol-stimulated adenylate cyclase activity. These effects of the drugs appeared to require protein synthesis as they were blocked by cycloheximide. In addition, some of the drugs caused a substantial decrease in basal adenylate cyclase activity. This effect on basal activity was abolished in cells treated with pertussis toxin, which ADP-ribosylates the inhibitory GTP-binding protein, Gi. Both HeLa and A431 cells contained a 41 kDalton substrate for the toxin which corresponds to the alpha subunit of Gi. The Gi subunit was ADP-ribosylated by the toxin to a similar extent in membranes from control and drug-treated cells. Thus, the drugs appear to induce quantitative changes in beta-adrenergic receptors and qualitative changes in Gi which results in a highly responsive beta-adrenergic-stimulated adenylate cyclase.
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PMID:Modulation of the beta-adrenergic receptor-coupled adenylate cyclase by chemical inducers of differentiation: effects on beta receptors and the inhibitory regulatory protein Gi. 245 8

Arterial relaxant responses to beta adrenoceptor agonists are decreased in spontaneously hypertensive rats (SHR) when compared with normotensive Wistar-Kyoto rats (WKY). To determine which component of the beta adrenoceptor-adenylate cyclase (AC) system is involved in the decreased beta adrenoceptor responses, effects of two activators of AC-forskolin and cholera toxin and of dibutyryl cyclic AMP (DBcAMP) were compared between the strips of femoral arteries isolated from 13-week-old SHR and age-matched WKY. Arterial relaxant responses to either forskolin, an activator of AC or DBcAMP were not significantly different between the SHR and WKY, whereas the relaxant responses to norepinephrine (NE) via beta adrenoceptors were significantly weaker in the SHR than in the WKY. In the absence of timolol, a beta adrenoceptor antagonist, contractile responses to NE were significantly greater in the SHR than in the WKY. Timolol augmented the contractile responses to NE to a greater extent in the WKY than in the SHR. After the blockade by timolol of beta adrenoceptors, contractile responses to alpha adrenoceptor stimulation with NE were not significantly different between the two strains. The pretreatment of the strips with cholera toxin, an activator of stimulatory GTP-binding protein (Gs), antagonized the alpha adrenoceptor-mediated contractions much greater in the WKY than in the SHR. The alpha adrenoceptor-mediated contractions after the pretreatment with cholera toxin were comparable to the contractile responses to NE determined in the absence of timolol in either the SHR or the WKY. Forskolin and DBcAMP also antagonized the alpha adrenoceptor-mediated contractions. However, these antagonisms were not significantly different between the two strains. The cellular cAMP content in arterial strips after the stimulation with NE was significantly less in the SHR than in the WKY, whereas the cAMP contents were similar in arterial strips from both strains which were stimulated with forskolin. These results suggest that the reduced function of Gs is involved in the abnormality of beta adrenoceptor-AC system in the SHR femoral artery.
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PMID:Reduced function of the stimulatory GTP-binding protein in beta adrenoceptor-adenylate cyclase system of femoral arteries isolated from spontaneously hypertensive rats. 245 80

We investigated the mechanism for lithium-induced inhibition of vasopressin-stimulated adensoine 3',5'-cyclic monophosphate (cAMP) production in the renal epithelial cell line LLC-PK1. In LLC-PK1 membranes lithium caused direct inhibition of hormone-stimulated adenylate cyclase activity by competing with magnesium. Fifty percent inhibition occurred at 20 mM lithium. The maximum transport activity (Vmax) but not the activation constant (Ka) for activation by vasopressin was altered. Activation by GTP and its nonhydrolyzable analogues was also inhibited by lithium. Furthermore, kinetic studies revealed that the lag phase in the activation of adenylate cyclase by 5'-guanylimi-dotriphosphate [Gpp(NH)p] was prolonged from 1 to 3 min, suggesting an effect of lithium on magnesium-dependent activation of the stimulatory GTP binding protein Gs. The function of the corresponding inhibitory GTP-binding protein Gi, as assessed by GTP inhibition of vasopressin-stimulated adenylate cyclase activity in the presence and absence of pertussis toxin pretreatment, was unaffected. Intact LLC-PK1 cells incubated in 10 mM lithium (approximate urinary concentration in lithium-treated patients) attained an intracellular lithium concentration of 17 mM, which led to a 40% reduction in cAMP formation. Magnesium loading of intact cells with the ionophore A23187 reversed the inhibitory effect of lithium. It is concluded that lithium directly inhibits the activation of vasopressin-sensitive adenylate cyclase in renal epithelia by competing with magnesium for activation of Gs. This direct effect on Gs activation accounts for the inhibitory effect of lithium on cAMP production in the intact cell.
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PMID:Mechanism of Li inhibition of vasopressin-sensitive adenylate cyclase in cultured renal epithelial cells. 246 Oct 98

1. Arterial relaxant responses to beta-adrenoceptor agonists are decreased in spontaneously hypertensive rats (SHR) when compared with normotensive Wistar-Kyoto rats (WKY). To establish which component of the beta-adrenoceptor.adenylate cyclase (AC) system is impaired in the SHR arteries, effects of two activators of AC--cholera toxin (CTX) and forskolin--and of dibutyryl cyclic AMP (db cyclic AMP) were compared between strips of femoral arteries isolated from 13 week-old SHR and age-matched WKY. 2. In the absence of timolol, a beta-adrenoceptor antagonist, contractile responses of the strips to noradrenaline (NA) were significantly greater in the SHR than in the WKY. Timolol augmented the contractile responses to NA to a smaller extent in the SHR than in the WKY. 3. After blockade by timolol of beta-adrenoceptors, contractile responses of the strips to NA through the activation of alpha-adrenoceptors were not significantly different between the two strains. 4. Pre-treatment of the strips with CTX, an activator of the stimulatory GTP-binding protein (Gs), produced a slow-onset and long-lived antagonism of the alpha-adrenoceptor-mediated contractions. The antagonism was much smaller in the SHR than in the WKY. 5. The dose-response curves of the strips from both strains for alpha-adrenoceptor stimulation with NA determined after pretreatment with CTX were comparable to those determined in the absence of timolol. 6. Forskolin, an activator of the catalytic subunit of AC, and DB cyclic AMP also antagonized the alpha-adrenoceptor-mediated contractions. However, these antagonisms were not significantly different between the two strains. 7. Isobutyl methylxanthine (IBMX), an inhibitor of cyclic AMP phosphodiesterase, produced a similar antagonism of the alpha-adrenoceptor-mediated contractions between the two strains. 8. These results suggest that a reduced function of Gs is the main factor responsible for the decreased responsiveness to beta-adrenoceptor stimulation in the SHR femoral artery.
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PMID:Role of stimulatory GTP-binding protein (Gs) in reduced beta-adrenoceptor coupling in the femoral artery of spontaneously hypertensive rats. 246 85

The inotropic effects of sympathetic stimulation on the heart are mainly ascribed to the activation of beta-adrenoceptors. However, several findings suggest that alpha-adrenoceptors also may help mediate the inotropic response to catecholamines under certain conditions. The onset of the positive inotropic effect mediated by beta-adrenoceptors occurs within seconds and is associated with a faster rate of relaxation. Both beta 1- and beta 2-adrenoceptors are stimulatorily coupled to the enzyme adenylate cyclase, thereby leading to the generation of cyclic AMP. Cyclic AMP increases the slow inward calcium current and enhances the uptake of calcium into the sarcoplasmic reticulum. GTP-binding protein Gs is important for the transmembrane signal transduction. Muscarine and adenosine receptors are inhibitorily coupled to adenylate cyclase, thereby decreasing the inotropic response to catecholamines. Another GTP-binding protein, Gi, is involved in this pathway. The stimulation of the myocardium through the activation of alpha-adrenoceptors seems to differ both qualitatively and quantitatively. Myocardial alpha-adrenoceptors of most species are, if existent, predominantly of the alpha 1-subtype; the functional role of these receptors obviously considerably varies among species.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adrenoceptor-mediated changes of excitation and contraction in isolated heart muscle preparations. 247 96

Many newly developed positive inotropic agents are phosphodiesterase inhibitors. In the heart at least four phosphodiesterases (PDE I-IV) have been isolated. Depending on the species investigated, the positive inotropic effects of the PDE inhibitors appear to be correlated to the inhibition of a soluble or particulate PDE III or to a particulate PDE bound to the sarcoplasmic reticulum. In human ventricular tissue isolated from hearts with end-stage heart failure due to idiopathic dilated cardiomyopathy the positive inotropic effect of phosphodiesterase inhibitors is greatly reduced compared to healthy controls. This cannot be explained by an impaired sensitivity of the PDEs because the PDEs were similarly inhibited by PDE inhibitors in both healthy and diseased hearts. However, because the reduced positive inotropic effect is accompanied by a reduced increase in cellular cAMP concentration, an impaired formation of cAMP by the adenylate cyclase is probably involved. The impaired adenylate cyclase activity can result from an increased inhibitory GTP-binding protein (Gi-protein) recently observed in failing hearts.
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PMID:Phosphodiesterase inhibition and positive inotropic effects. 247 97

The stimulation of osteocalcin synthesis by human osteoblast-like cells in response to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is antagonised by several bone regulatory agents. We have shown that agents which activate adenylate cyclase inhibit this action of 1,25(OH)2D3 on human osteoblast-like cells. Activation of adenylate cyclase, either via the stimulatory GTP-binding protein using cholera toxin, or directly at the catalytic via the stimulatory GTP-binding protein using cholera toxin, or directly at the catalytic subunit using forskolin, results in a suppression of osteocalcin synthesis. Whilst the activation of adenylate cyclase induces this inhibitory response, neither exogenous dibutyryl cyclic AMP nor the phosphodiesterase inhibitor, IBMX, exerted any apparent effect on the production of osteocalcin. The tumour promoting phorbol ester, 4 beta-phorbol 12,13-dibutyrate, also inhibited 1,25(OH)2D3-stimulated osteocalcin production. This was not apparent in response to the non-tumour promoting phorbol ester 4 beta-phorbol suggesting the involvement of protein kinase C.
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PMID:Agents affecting adenylate cyclase activity modulate the stimulatory action of 1,25-dihydroxyvitamin D3 on the production of osteocalcin by human bone cells. 248 Jan 11

The kinetics of prostaglandin-regulated cyclic AMP formation by intact human platelets were studied in the presence and absence of phosphodiesterase inhibitors. In the case of iloprost, a chemically stable analogue of prostaglandin I2, the shape of the time course varied with prostaglandin concentration. In the presence of phosphodiesterase inhibitors, low concentrations of iloprost gave a linear rate of cyclic AMP formation. At higher concentrations of iloprost, the initial rate increased as a saturable function of prostaglandin concentration but the curves decayed with time to give new linear rates of cyclic AMP formation with a different prostaglandin concentration dependence from the initial rates. Time courses were simulated using KINSIM [Anal. Biochem. 130: 134-145 (1983)], a kinetic simulation program that employs numerical integration, over a wide range of iloprost concentration (3 nM to 30 microM) by use of a simple model involving rapid activation of adenylate cyclase, followed by slow reversible transition of adenylate cyclase to an inactive form (desensitization) through a distinct inhibitory receptor. The model requires that the affinity for prostaglandins of both the stimulatory and inhibitory receptors declines with prostaglandin concentration, which may be related to the existence of high and low affinity receptor forms depending on the activation state of the appropriate GTP-binding protein. The same two-receptor model can be used to describe cyclic AMP metabolism in the absence of phosphodiesterase inhibitors, giving rise to characteristic peak and plateau effects in the time courses. The putative inhibitory receptor has an apparent affinity for prostaglandin lower than the stimulatory receptor in the case of iloprost and a higher affinity than the stimulatory receptor in the case of prostaglandin E1. The contribution of phosphodiesterase activation to the time course of cyclic AMP formation through phosphorylation by cyclic AMP-dependent protein kinase was assessed. It was shown that phosphodiesterase activation must be rapid. A plausible and perhaps complete description of prostaglandin-regulated cyclic AMP metabolism in platelets is presented.
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PMID:Model of prostaglandin-regulated cyclic AMP metabolism in intact platelets: examination of time-dependent effects on adenylate cyclase and phosphodiesterase activities. 248 Dec 25


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