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)

Metabolically stable GTP analogues were 10 to 40 times more potent activators of DL-isoproterenol-stimulated adenylate cyclase (EC 4.6.1.1) from pigeon erythrocyte membranes that GTP. The order of effectiveness was guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S) greater than guanylyl imidodiphosphate (Gpp(NH)p) greater than guanylyl methylenediphosphonate (Gpp(CH2)p greater than GTP. In contrast to activation with GTP, activation by analogues was independent of ATP concentration. The analogues seem to bind, however, to the same regulatory sites in membrane preparations to which GTP is bound but with higher affinity; Kdiss for (14C)Gpp-(nh)p and (3H)Gpp(CH2)p and membranes was 0.7 and 2.4 x 10-7 M, respectively. DL-Isoproterenol did not increase the amount of guanylnucleotide bound, it merely accelerated and potentiated activation. Bound radioactive GTP analogues were recovered unchanged from the membrane pellet. This and mutual displacement of analogues and GTP ruled out covalent attachment of the whole or of part of the nonphosphorylating GTP analogues. Treatment of the membrane preparation with Gpp(NH)p effectively (greater than 80%) protected DL-isoproterenol-activated adenylate cyclase against the action of Filipin or Lubrol PX. Activation of membrane-bound adenylate cyclase with GTP analogues resulted in a stable enzyme which could be nearly completely resolved from membranes with Lubrol PX and stripped of lipids and detergent without loss of activity. This effect was synergistically amplified by DL-isoproterenol. A protein fraction with an apparent molecular weight of 230,000, containing about 90% of (14C)Gpp(NH)p originally bound to membranes, could be solubilized and separated from adenylate cyclase activity by chromatography on Sepharose 4B. The binding protein was purified about 40- to 80-fold from activated membranes. Removal of the nucleotide binding protein was also achieved by affinity chromatography with GTP gamma S coupled to Sepharose via a spacer. When membranes which were not or only weakly and reversibly activated (with GMP) were used as source of the soluble preparation, removal of the binding protein resulted in 75% loss of Gpp(NH)p activation without change in basal and Mg2+/F-stimulated adenylate cyclase activity. It is assumed that the GTP analogues cause an unphysiological, irreversible activation of membrane-bound adenylate cyclase, because, in contrast to the natural guanylnucleotides whose action they mimic, they are metabolically inert and bound quasi-irreversibly to regulatory sites.
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PMID:Activation of pigeon erythrocyte membrane adenylate cyclase by guanylnucleotide analogues and separation of a nucleotide binding protein. 112 Jul 76

This study examine the regulation Na+, K(+)-ATPase activity in the medullary thick ascending limb of Henle Na+, K(+)-ATPase activity was determined in medullary thick ascending limb of Henle (mtal) segments dissected from rat kidneys. The sodium concentration in the medium (Nam) was 20 or 70 mM. Since the segments were permeabilized, intracellular Na+ (Nai) was assumed to be the same as Nam. Dibuturyl cyclic adenosine monophosphate (dbcAMP) and forskolin inhibited Na+, K(+)-ATPase activity independently of Nam. Arginine vasopressin (AVP) receptors coupled to adenylate cyclase have been identified in the medullary thick ascending limb of Henle. At Nam = 20 mMAVP caused a dose-dependent inhibition of Na+, K(+)-ATPase activity with a maximal effect (49%) at 10(-8) M. This inhibition was abolished in the presence of the adenylate cyclase inhibitor 2,5-dideoxyadenosine (2, 5-DDA). AVP had no effect on Na+, K(+)-ATPase activity in the mTAL at Nam = 70 mM. The guanosine-diphosphate analogue GDP beta S inhibited Na+, K(+)-ATPase activity at Nam = 70 mM but not at Nam = 20 mM. We conclude that increased cyclic adenosine monophosphate (cAMP) levels inhibit Na+, K(+)-ATPase activity in mTAL. AVP can, depending on Nai, produce this effect by adenylate cyclase activation. The guanonine nucleotide binding protein G-protein might be the site of Na(+)-dependence.
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PMID:Sodium-dependent regulation of sodium, potassium-adenosine-tri-phosphatase (Na+, K(+)-ATPase) activity in medullary thick ascending limb of Henle segments. Effect of cyclic-adenosine-monophosphate guanosine-nucleotide-binding-protein activity and arginine vasopressin. 131 76

D1 dopamine receptors on NS20Y neuroblastoma cells stimulate adenylate cyclase activity, whereas muscarinic receptors on the same cells negatively regulate adenylate cyclase. To determine the mechanisms which underlie these processes, cyclic AMP accumulation was measured in intact cells following either cholera or pertussis toxin treatment. Pretreatment with pertussis toxin (100 ng/ml), which ribosylated greater than 95% of inhibitory quinine nucleotide binding protein (Gi), caused the complete loss of muscarinic induced inhibition. Conversely, pertussis toxin did not affect the ability of dihydrexidine (1 microM, a full efficacy D1 agonist), PGE1 (100 nM), or forskolin (1 microM, a direct activator) to stimulate cAMP accumulation. Both the dihydrexidine-induced stimulation and the carbachol-induced inhibition of cyclic AMP accumulation were unaffected by either removal of extracellular calcium, or increased intracellular calcium caused by the addition of the calcium ionophore A23187. Cholera toxin dose- and time-dependently induced large accumulations of cAMP. At low cholera toxin concentrations, the effects of dihydrexidine (300 nM) were additive with those of cholera toxin. At cholera toxin concentrations greater than 100 ng/ml, dihydrexidine became ineffective in stimulating further cAMP synthesis. Conversely, forskolin (1 microM) still caused marked increases in cAMP accumulation after all cholera toxin treatments. Dihydrexidine-stimulated cAMP accumulation was additive with forskolin-stimulated cAMP accumulation at low forskolin concentrations (10 nM-3 microM), but synergistic at high concentrations (3-100 microM). Additionally, forskolin was much more potent after cholera toxin treatment, suggesting that an activated stimulatory guanine nucleotide binding protein (Gs) may be required for full activation of adenylate cyclase by forskolin in this cell type.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Guanine nucleotide binding proteins and the regulation of cyclic AMP synthesis in NS20Y neuroblastoma cells: role of D1 dopamine and muscarinic receptors. 168 5

The purpose of the present study was to characterize the effects of xamoterol in the human myocardium. In the presence of forskolin or milrinone, xamoterol increased isometric force of contraction, contraction velocity, and relaxation velocity in isolated, electrically driven preparations from human myocardium, but had no effect alone. There was no difference in the effect of xamoterol between right atrial myocardium and left ventricular myocardium from nonfailing (NF), moderately failing (NYHA II-III), and severely failing (NYHA IV) human hearts. The positive inotropic and lusitropic effects of isoprenaline were reduced depending on the severity of heart failure in left ventricular myocardium (i.e., NF greater than NYHA II-III greater than NYHA IV). In the presence of norepinephrine, xamoterol produced negative inotropic effects similar to those of the beta-adrenoceptor antagonists pindolol and propranolol. Xamoterol alone had no effects on force of contraction, whereas pindolol and propranolol markedly reduced contractile force. In NYHA class IV, isoprenaline stimulated adenylate cyclase about twofold but xamoterol, like pindolol or propranolol, had no effect. Experiments with the beta 1- and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, showed that the positive inotropic and lusitropic effects of xamoterol were mediated by beta 1-adrenoceptors. Consistently, xamoterol had a selectivity of 13.8 at beta 1-adrenoceptors as measured in radioligand binding experiments. It is concluded that xamoterol acts as a beta 1-adrenoceptor antagonist with a selectivity of 13.8 in human ventricular myocardium. The compound has an intrinsic sympathomimetic activity, as it produces beta 1-adrenoceptor-mediated positive inotropic and lusitropic effects in the presence of forskolin. The beneficial effects of xamoterol in patients with heart failure could be due to prevention of the detrimental effects of norepinephrine such as beta 1-adrenoceptor downregulation of an increase of Gi (inhibitory guanine-nucleotide binding protein).
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PMID:Effects of xamoterol on inotropic and lusitropic properties of the human myocardium and on adenylate cyclase activity. 197 79

The density of beta-adrenergic receptors in both the outer and inner layers of the human myometrium decreases during the last weeks of pregnancy. Although in preterm myometrium (32-35 weeks of pregnancy) beta-adrenergic receptors are positively coupled to adenylate cyclase, we found that isoproterenol, epinephrine, and norepinephrine did not stimulate the enzyme in the inner or outer myometrial layer at term (39-40 weeks of pregnancy). At this stage, the addition of 10(-4) mol/L guanyl-5'-imidodiphosphate increased (from 10(-8) to 10(-4) mol/L) basal adenylate cyclase activity in a dose-dependent manner, indicating that the catalytic component of the enzyme remains linked to the stimulatory guanyl nucleotide binding protein (Gs). Compared to the preterm response, at term the myometrial adenylate cyclase response to 10(-4) mol/L guanyl-5'-imidodiphosphate was decreased, which may reflect a decrease in the amount of functional Gs. Altogether these changes are consistent with reduced Gs coupling to the catalytic component. However, the similarity of the responses of preterm and term myometrium to forskolin excluded the possibility of an alteration of the catalytic component of adenylate cyclase during the last weeks of pregnancy. The fact that a stimulatory effect of isoproterenol on adenylate cyclase was found after islet-activating protein pretreatment indicates that human term myometrium contains a functional inhibitory guanyl nucleotide binding protein which is involved in the modulation of the beta-adrenergic adenylate cyclase response. Our data suggest that modifications in the coupling mechanisms between receptors and the catalytic component are implicated in the loss of beta-adrenergic adenylate cyclase stimulation in the myometrium at the end of pregnancy.
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PMID:Disappearance of beta-adrenergic response of human myometrial adenylate cyclase at the end of pregnancy. 254 86

Hyperosmotic stimuli produce profound changes in cellular morphology and biosynthetic activities within the hypothalamic paraventricular and supraoptic nuclei (SON) of the rat. The mechanisms by which osmoreceptive signals are transduced within these nuclei are poorly understood. We examined several components of the cAMP-associated second messenger system after giving rats 2% saline to drink for one week, a strong hyperosmotic stimulus. We found that mRNA levels for both the stimulatory and inhibitory guanine-nucleotide binding protein alpha-subunits were increased in the paraventricular nucleus and SON. In the SON, these changes were accompanied by increased basal cAMP levels, cholera toxin-stimulated adenylate cyclase, and Gs alpha. Our results suggest that Gs alpha levels are not saturated with respect to adenylate cyclase coupling and that osmoreception activates the cAMP second messenger system.
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PMID:Plasma hyperosmolality increases G protein and 3',5'-cyclic adenosine monophosphate synthesis in the paraventricular and supraoptic nuclei. 285 4

Beta-adrenergic agonists, but not antagonists, were found to reduce the disulfide bond of 5,5'-dithiobis-2-nitrobenzoic acid (DTNB). The extent of DTNB reduction was proportional to the intrinsic activity for these agonists. The results suggest a novel mechanism for transmission of the signal when a beta-adrenergic agonist occupies its receptor. We proposed that beta-adrenergic agonists exert their effects to activate the adenylate cyclase by reducing a disulfide bond in the receptor (R) or guanyl nucleotide binding protein (G) component of the adenylate cyclase complex leading to tight binding of GTP to G and activation of G.
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PMID:Reduction of a disulfide bond by beta-adrenergic agonists: evidence in support of a general "reductive activation" hypothesis for the mechanism of action of adrenergic agents. 288 7

The activation of adenylate cyclase by forskolin was investigated in terms of the dissociation model of guanyl nucleotide binding protein (Ns). It was demonstrated that the biphasic forskolin concentration-response of adenylate cyclase could be explained by the dissociation of the beta subunit. The equations developed from such a theoretical approach gave an accurate description of concentration response data from S49 cultured mouse lymphoma cells.
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PMID:Adenylate cyclase activity as a function of forskolin concentration. 298 62

Adenylate cyclase in human platelets is under dual control of prostaglandins (PGI2 and PGE1) and catecholamines. The adenylate cyclase complex in membranes of platelets from ten patients with uraemia was investigated. The activation of the platelet cyclase by PGE1 is increased in the uraemic state, Vmax 4436 +/- 607 pmol cAMP mg-1 15 min-1. In the normal state Vmax is 2098 +/- 309 pmol cAMP mg-1 15 min-1. The alpha 2-adrenergic receptor was assayed with 3H-yohimbine binding. The density of receptors was equal in the uraemic (175 fmol mg-1 membrane protein) and the normal (170 fmol mg-1 membrane protein) states. Norepinephrine/3H-yohimbine competition binding revealed that catecholamines were bound with normal affinity in platelets in uraemia. Yet the inhibition of adenylate cyclase through the alpha 2-adrenergic receptor was diminished since Vmax values of adenylate cyclase with PGE1 and PGE2 + norepinephrine did not significantly differ. In the normal state, norepinephrine significantly (P less than 0.05) inhibited the PGE1 stimulated cyclase. It is concluded that platelet adenylate cyclase in the uraemia has an increased capacity for activation which is the result of both a sensitized stimulatory mechanism (prostaglandin mediated) and a deficient inhibitory mechanism (catecholamine mediated). It is suggested that a defect exists in the inhibitory nucleotide binding protein (NI) which is the coupling unit between the adenylate cyclase catalytic subunit (C).
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PMID:Abnormality of adenylate cyclase regulation in human platelet membranes in renal insufficiency. 298 84

Prostaglandin E (PGE) potently inhibits acid secretion stimulated by histamine, but not by acetylcholine or gastrin, and is accompanied by decreased intracellular cAMP. Adenylate cyclase receptor systems are composed of three complex proteins: cell receptor, nucleotide binding protein, and the catalytic subunit. The exact mechanism of PGE interaction with this complex remains unclear and elucidation of this site of action is the purpose of this study. We utilized molecular probes directed at the various components of adenylate cyclase. Cholera toxin alters the stimulatory subunit of the nucleotide binding proteins (Ns), rendering it resistant to normal deactivation, whereas N-ethylmaleimide (NEM) blocks the inhibitory subunit (Ni). Forskolin acts as a direct activator of the catalytic subunit of adenylate cyclase and 8-bromo-cAMP acts as a cyclic AMP mimetic. We measured in vitro acid secretion in isolated parietal cells by the assessment of [14C]aminopyrine (AP) accumulation. The PGE1 analog (miso) and the PGE2 analog (DMPG) were incubated in graded doses (10(-11) to 10(-6) M) with histamine (10(-6) M). Miso (10(-7) M) reduced AP accumulation to 21 +/- 8% of histamine alone (100%) and DMPG (10(-6) M) reduced AP to 61 +/- 9% (P less than 0.005 for both). AP accumulation stimulated by 8-Br-cAMP (10(-6) M) and forskolin (10(-6) M) was not significantly affected by either PGE analog (P greater than 0.05) suggesting that the site of PGE interaction is proximal to the activation of the catalytic subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin inhibition of acid is cAMP dependent. 303 81


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