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 mechanism by which alpha 2-adrenergic receptors regulate Na(+)-H+ exchange activity in opossum kidney (OK) cells was studied. Because receptors linked to inhibition of adenylate cyclase, like alpha 2-receptors, also can interact with additional signaling mechanisms, we examined specifically the role of adenosine 3',5'-cyclic monophosphate (cAMP) in the signaling pathway controlling Na(+)-H+ activity in OK cells. Parathyroid hormone (PTH), prostaglandin (PGE1), and forskolin, agents that stimulate cAMP production in these cells, inhibited the rate of amiloride-sensitive 22Na+ uptake by up to 40%. Epinephrine and UK 14304, acting through alpha 2-receptors, were able to reverse this inhibition of 22Na+ uptake to near-control levels and also attenuate PTH-, PGE1-, and forskolin-stimulated cAMP accumulation. Likewise, serotonin (5-HT) and SDZ21-009, acting through 5-HT1b receptors, could reverse inhibition of 22Na+ uptake and also attenuate stimulated cAMP accumulation. Neither epinephrine nor serotonin affected the rate of uninhibited 22Na+ uptake. Pertussis toxin pretreatment abolished the effects of alpha 2- and 5-HT1b receptors on both cAMP accumulation and 22Na+ uptake, suggesting that receptor-mediated inhibition of cAMP accumulation is involved in receptor modulation of Na(+)-H+ exchange activity. In contrast, epinephrine was not able to alter the inhibition of 22Na+ uptake mediated by the membrane-permeant cAMP analogues 8-bromo-cAMP and dibutyryl cAMP at any concentration of analogue that significantly inhibited 22Na+ uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alpha 2-adrenergic receptors regulate Na(+)-H+ exchange via a cAMP-dependent mechanism. 217 64

Effects of prostaglandin (PG) D2 analogues on the adenylate cyclase activity in membrane fractions of the iris-ciliary body complex were studied. PGD2 dose-dependently activated the adenylate cyclase with a maximal activity increase of about 60%. The concentration required to cause a half-maximal stimulation (EC50) was about 5 x 10(-7) M. The stimulatory effect of PGD2 was totally dependent on GTP with EC50 for GTP at about 10(-7) M. The rank order of potency of PGD2 analogues for stimulating the adenylate cyclase and BW245C (a selective PGD2 agonist) greater than PGD3 greater than PGD2 greater than 9 beta-PGD2. PGD2 metabolites and PGD2 analogues which have little hypotensive activity were essentially ineffective in stimulating the adenylate cyclase. This rank order was strikingly similar to that reported previously for their intraocular pressure-lowering effects. One exception was PGD2 methylester. This compound, though reportedly effective in reducing IOP, failed to activate the adenylate cyclase by itself, presumably because its hypotensive effect is due to its hydrolyzed product, PGD2. These results indicate that the abilities of PGD2 analogues to stimulate the adenylate cyclase of the iris-ciliary body complex in GTP-dependent manner are highly correlated with their ocular hypotensive activities, and suggest that a PGD2 receptor-stimulatory GTP-binding protein-adenylate cyclase complex is involved in the PGD2-induced ocular hypotension.
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PMID:Stimulatory effects of prostaglandin D2 analogues on adenylate cyclase in rabbit iris-ciliary body membrane fractions. 224 31

Epinephrine and norepinephrine exert many important actions by interacting with alpha 1- and alpha 2-adrenergic receptors in their target cells. Activation of alpha 2-adrenergic receptors causes platelet aggregation and other inhibitory cellular responses. Some of these responses are attributable to a decrease in cAMP due to inhibition of adenylate cyclase. Activation of alpha 2-adrenergic receptors promotes their coupling to an inhibitory guanine nucleotide binding protein (Ni). This coupling promotes the binding of GTP to Ni, causing it to dissociate into subunits. This results in inhibition of the catalytic component of adenylate cyclase. Activation of alpha 1-adrenergic receptors stimulates the contraction of most smooth muscles and alters secretion and metabolism in several tissues. The primary event is a breakdown of phosphatidylinositol-4,5-bisphosphate in the plasma membrane to produce two intracellular "messengers": myo-inositol-1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DAG). IP3 causes the release of Ca2+ from endoplasmic reticulum, producing a rapid rise in cytosolic Ca2+. Ca2+ binds to the regulatory protein calmodulin, and the resulting complex interacts with specific or multifunctional calmodulin-dependent protein kinases and other calmodulin-responsive proteins, altering their activities and thereby producing a variety of physiological responses. DAG also produces effects by activating a Ca2+-phospholipid-dependent protein kinase (protein kinase C) that phosphorylates and alters the activity of certain cellular proteins. Frequently there is synergism between the IP3 and DAG mechanisms.
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PMID:Mechanisms involved in alpha-adrenergic phenomena. 240 77

Desensitization of the responsiveness to hormones or drugs is often mediated by down-regulation of receptors. The stimulatory coupling protein (Ns) of adenylate cyclase has been shown to be involved in the down-regulation of stimulatory beta-adrenergic receptors. Whether the inhibitory coupling protein (Ni) is involved in the down-regulation of receptors that inhibit adenylate cyclase is not known. We wished to determine whether down-regulation of inhibitory muscarinic cholinergic and alpha 2-adrenergic receptors occurs in neuroblastoma X glioma hybrid cells after the ability of Ni to inhibit adenylate cyclase is inactivated by pertussis toxin. After treatment of cells with pertussis toxin, the ability of carbachol or epinephrine to inhibit prostaglandin E1-stimulated cAMP accumulation in intact cells was either completely prevented or markedly attenuated, respectively, indicating functional inactivation of Ni. Furthermore, pertussis toxin treatment of membrane fragments from these cells did not result in labeling of the 41,000-dalton alpha-subunit of Ni with ADP ribose from [32P] NAD, indicating maximal ADP ribosylation of Ni by prior treatment of cells with pertussis toxin. Carbachol treatment of cells resulted in down-regulation of muscarinic cholinergic receptors to 45.7 +/- 12.5% and 52.5 +/- 13.5% of control values for toxin-untreated and toxin-treated cells, respectively. Epinephrine treatment of cells caused homologous desensitization of alpha 2-receptor-mediated inhibition of cAMP accumulation and down-regulation of alpha 2-adrenergic receptors to 42.9 +/- 11.4% and 53.2 +/- 5.3% of control values for toxin-untreated and toxin-treated cells, respectively. Down-regulation of muscarinic cholinergic receptors by carbachol and of alpha 2-adrenergic receptors by epinephrine was not due to the effect of retained agonist and was agonist specific, since it could be prevented by the antagonists atropine and yohimbine, respectively. We conclude that agonist-mediated down-regulation of both the muscarinic cholinergic receptor and the alpha 2-adrenergic receptor does not require functional inhibitory coupling.
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PMID:Agonist-induced down-regulation of muscarinic cholinergic and alpha 2-adrenergic receptors after inactivation of Ni by pertussis toxin. 242 98

Jakobs, Bauer & Watanabe [(1985) Eur. J. Biochem. 151, 425-430] reported that treatment of platelets with phorbol 12-myristate 13-acetate (PMA) prevented GTP- and agonist-induced inhibition of adenylate cyclase in membranes from the platelets. This was attributed to the phosphorylation of the inhibitory guanine nucleotide-binding protein (Gi) by protein kinase C. In the present study, the effects of PMA on cyclic [3H]AMP formation and protein phosphorylation were studied in intact human platelets labelled with [3H]adenine and [32P]Pi. Incubation mixtures contained indomethacin to block prostaglandin synthesis, phosphocreatine and creatine kinase to remove ADP released from the platelets, and 3-isobutyl-1-methylxanthine to inhibit cyclic AMP phosphodiesterases. Under these conditions, PMA partially inhibited the initial formation of cyclic [3H]AMP induced by prostaglandin E1 (PGE1), but later enhanced cyclic [3H]AMP accumulation by blocking the slow decrease in activation of adenylate cyclase that follows addition of PGE1. PMA had more marked and exclusively inhibitory effects on cyclic [3H]AMP formation induced by prostaglandin D2 and also inhibited the action of forskolin. Adrenaline, high thrombin concentrations and, in the absence of phosphocreatine and creatine kinase, ADP inhibited cyclic [3H]AMP formation induced by PGE1. The actions of adrenaline and thrombin were attenuated by PMA, but that of ADP was little affected, suggesting differences in the mechanisms by which these agonists inhibit adenylate cyclase. sn-1,2-Dioctanoylglycerol (diC8) had effects similar to those of PMA. The actions of increasing concentrations of PMA or diC8 on the modulation of cyclic [3H]AMP formation by PGE1 or adrenaline correlated with intracellular protein kinase C activity, as determined by 32P incorporation into the 47 kDa substrate of the enzyme. Parallel increases in phosphorylation of 20 kDa and 39-41 kDa proteins were also observed. Platelet-activating factor, [Arg8]vasopressin and low thrombin concentrations, all of which inhibit adenylate cyclase in isolated platelet membranes, did not affect cyclic [3H]AMP formation in intact platelets. However, the activation of protein kinase C by these agonists was insufficient to account for their failure to inhibit cyclic [3H]AMP formation. Moreover, high thrombin concentrations simultaneously activated protein kinase C and inhibited cyclic [3H]AMP formation. The results show that, in the intact platelet, the predominant effects of activation of protein kinase C on adenylate cyclase activity are inhibitory, suggesting actions additional to inactivation of Gi.
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PMID:Effects of activation of protein kinase C on the agonist-induced stimulation and inhibition of cyclic AMP formation in intact human platelets. 244 6

Rat islets were used to compare the mechanisms whereby adenosine and adrenaline inhibit insulin release. Adenosine (1 microM-2.5 mM) and its analogue N6(-)-phenylisopropyladenosine (L-PIA) (1 nM-10 microM) caused a concentration-dependent but incomplete (45-60%) inhibition of glucose-stimulated release. L-PIA was more potent than D-PIA [the N6(+) analogue], but much less than adrenaline, which caused nearly complete inhibition (85% at 0.1 microM). 8-Phenyltheophylline prevented the inhibitory effect of L-PIA and 50 microM-adenosine, but not that of 500 microM-adenosine or of adrenaline. In contrast, yohimbine selectively prevented the inhibition by adrenaline. Adenosine and L-PIA thus appear to exert their effects by activating membrane A1 receptors, whereas adrenaline acts on alpha 2-adrenergic receptors. Adenosine, L-PIA and adrenaline slightly inhibited 45Ca2+ efflux, 86Rb+ efflux and 45Ca2+ influx in glucose-stimulated islets. The inhibition of insulin release by adenosine or L-PIA was totally prevented by dibutyryl cyclic AMP, but was only attenuated when adenylate cyclase was activated by forskolin or when protein kinase C was stimulated by a phorbol ester. Adrenaline, on the other hand, inhibited release under these conditions. It is concluded that inhibition of adenylate cyclase, rather than direct changes in membrane K+ and Ca2+ permeabilities, underlies the inhibition of insulin release induced by activation of A1-receptors. The more complete inhibition mediated by alpha 2-adrenergic receptors appears to result from a second mechanism not triggered by adenosine.
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PMID:Comparison of the inhibition of insulin release by activation of adenosine and alpha 2-adrenergic receptors in rat beta-cells. 247 Mar 46

A study with ten identical twin pairs discordant for cigarette smoking for over 20 years was undertaken to evaluate the effect of smoking on platelet alpha 2-adrenoceptor binding ([3H]-yohimbine) and prostacyclin (IloprostR) sensitivity. Since plasma catecholamines, adrenaline and noradrenaline were increased in smokers (3.95 +/- 0.7 vs 2.26 +/- 0.1 pmol/ml, p less than 0.05) at rest, the objective of an acute additional adrenergic discharge by physical exercise was to uncover possible tachyphylaxis. Aggregation of adrenaline-stimulated platelets was significantly reduced in smokers after exercise and the refractoriness appeared to be maintained for 15 and 30 min afterwards. However, the densities of binding sites for the radioligand were not markedly different between the study groups at rest or after exercise. The binding affinity decreased after exercise in both groups. Adrenaline-stimulated platelets responded to prostacyclin by inhibiting aggregation and activating cAMP production equally in smokers and nonsmokers implying a preserved sensitivity to prostacyclin. Although smoking introduces long-term sympathoadrenergic effects, it does not alter alpha 2-adrenoceptor binding in platelets. Thus, the present data support a theory that smoking mediates its effects by platelet to vessel wall interaction and vasoactivity, rather than directly changing the properties of adrenoceptor in platelet or the coupling to adenylate cyclase.
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PMID:The platelet alpha 2-adrenoceptor and prostacyclin sensitivity are not altered by cigarette smoking--a study of monozygotic twin pairs discordant for smoking. 247 69

The effect of supplementation with n-3 polyunsaturated fatty acids on beta-adrenoceptor function in lymphocytes has been studied in ten healthy male volunteers. Ten Max-Epa capsules containing 320 mg n-3 polyunsaturated fatty acids per capsule were given for 3 weeks, and the cyclic AMP accumulation response in lymphocytes to adrenaline and the prostacyclin analogue iloprost (ZK 36374) were assessed before and after supplementation. After supplementation about 30% less cAMP was accumulation by the lymphocytes in response to either adrenaline or iloprost. Propranolol inhibited the adrenaline-induced increase in cAMP both before and after supplementation, but the difference in the basal cAMP concentration between the groups still persisted. Adrenaline stimulation after pre-incubation of the lymphocytes with the alpha-adrenoceptor antagonist phentolamine resulted in an even more pronounced difference between pre- and post-supplementation cAMP concentrations. The results suggest that fish oil supplementation may lead to decreased responsiveness of adenylate cyclase to catecholamine and prostaglandin stimulation.
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PMID:Decreased cyclic AMP accumulation in lymphocytes in response to adrenaline and prostacyclin after n-3 polyunsaturated fatty acid supplementation in man. 247 49

It has been shown that adipose tissue lipolytic activity is increased in endurance-trained subjects. In women, adipose tissue is extensive and it was thought interesting to confirm that endurance training increases the capacity of female adipose tissue to mobilize lipids, and moreover to more fully understand the mechanisms involved. So, biopsies of fat were obtained from the periumbilical region of 13 trained female runners (T) and 17 sedentary women (S) and the in vitro response to catecholamines of the collagenase-isolated fat cells was studied. Glycerol release, chosen as adipocyte lipolysis indicator, was measured by bioluminescence for various epinephrine and norepinephrine concentrations. In both groups, these substances provoked an increase in lipolysis, but the response was significantly higher in T. In both groups, isoproterenol increased the lipolytic activity above basal concentrations at 10(-8) M and above. Lipolytic activity in T was significantly higher (P less than 0.01) than the S control at 10(-7) M and above. Epinephrine plus propranolol decreased lipolysis in both groups, but at 10(-5) M, lipolytic activity was significantly lower in S than in T (P less than 0.05). It is concluded that in female subjects, endurance training increases the sensitivity of subcutaneous abdominal adipose tissue to the lipolytic action of catecholamines; this effect seems to be related both to a decreased efficiency of the alpha 2-adrenergic pathway and to an increased efficiency of the beta-adrenergic pathway. This latter effect seems to take place at a step beyond the receptor-adenylate cyclase system in the lipolytic cascade.
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PMID:Lipolytic response of fat cells to catecholamines in sedentary and exercise-trained women. 253 83

The function of beta-adrenoceptors was investigated in ventricular myocardium obtained from patients undergoing open heart surgery. 1. Dopamine increased contractile force up to 1/2 and 1/4 of the maximum increase caused by (-)-noradrenaline or (-)-adrenaline in right and left ventricular preparations, respectively. 2. beta-Adrenoceptors were labelled with 3H-(-)-bupranolol. For 3/4 of the receptors (beta 1) the affinity of (-)-noradrenaline was 20 times higher than for the remaining 1/4 (beta 2). (-)-Adrenaline and dopamine appeared to be non-selective for beta 1 and beta 2. 3. Dopamine was able to stimulate the adenylate cyclase only up to 1/3 of the maximum stimulation caused by (-)-noradrenaline and (-)-adrenaline. 4. Increases in contractile force by (-)-noradrenaline were closely associated with small increases of cyclase activity through beta 1-adrenoceptors, consistent with a common link. 5. The experiments on human myocardium were compared with similar experiments on feline myocardium. Feline ventricle exhibited a 20- to 30-fold higher sensitivity to catecholamines as activators of contractile force than did human ventricle. However, the binding affinities for catecholamines were similar in cat and man. 6. A 3 h exposure of human and feline ventricular myocardium to (-)-isoprenaline caused desensitization by uncoupling beta-adrenoceptors from the adenylate cyclase. Desensitization reduced the maximum contractile response to (-)-isoprenaline in human but not in feline ventricle. 7. The more efficient activation of contractile force by (-)-noradrenaline in cat, compared to man, appears to be related to a 2-fold higher density of beta 1-adrenoceptors, a 6-fold higher production of cyclic AMP per beta 1-adrenoceptor and possibly to a more effective use of cyclic AMP for contraction.
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PMID:Relations between beta-adrenoceptor occupancy and increases of contractile force and adenylate cyclase activity induced by catecholamines in human ventricular myocardium. Acute desensitization and comparison with feline ventricle. 254 8


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