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 stimulation of adenylate cyclase by dopamine and various beta-adrenergic agonists has been investigated in homogenates from 3 areas of cat brain: the cerebral cortex, cerebellum and hippocampus. The purpose of the study was to determine whether the beta-arenergic receptors coupled to adenylate cyclase could be classified as either beta 1 and beta 2 subtypes in the different regions studied. The stimulation of adenylate cyclase by the beta-adrenergic agonist, (-)isoproterenol (5 X 10(-6) M), was completely blocked by the specific beta-adrenergic antagonist, (p)alprenolol (1-(-5) M), but not by the dopaminergic antagonist, fluphenazine (10(-5) M), whereas the stimulation of adenylate cyclase by (-)epinephrine (10(-4) M) was blocked to varying extents by these two drugs in each of the 3 regions studied. The (-)epinephrine effect was always blocked in the combined presence of (p)alprenolol and fluphenazine. The adenylate cyclase stimulation by (p)epinephrine which is not blocked by (p)alprenolol was due to interaction of (p)epinephrine with a dopaminergic-sensitive adenylate cyclase which has been characterized in cerebral cortex, hippocampus and cerebellum. Regional differences in the affinity of beta-adrenergic-sensitive adenylate cyclase for various agonists were investigated in the presence of fluphenazine (10(-5) M). In the cerebellum the potency order was (+/-)protokylol greater than (+/-)hydroxybenzylisoproterenol greater than (+/-)isoproterenol greater than (-)epinephrine greater than (+/-)salbutamol greater than (-)norepinephrine, indicating the presence of a beta 2-adrenergic receptor. In the cerebral cortex the potency order was (-)isoproterenol greater than +/-)protokylol greater than (+/-)hydroxybenzylisoproterenol greater than (-)epinephrine = (-)norepinephrine ((+/-)salbutamol being inactive). A similar pattern was found in the hippocampus indicating the presence of a beta 1-adrenergic receptor in these two regions. (+/-)Salbutamol was a partial agonist in the cerebellum and a competitive antagonist in the cerebral cortex. The ratio of the antagonist potencies of (+/-)practolol and (+/-)butoxamine preferential beta 1- and beta 2-adrenergic antagonists respectively, to block the stimulation of adenylate cyclase was 25 in the cerebellum, compared to 0.5 in the cerebral cortex and 1.6 in the hippocampus. These results confirm the presence of a beta 2 subtype of receptor coupled to adenylate cyclase in the former and beta 1 subtypes in the latter two regions. The comparison between the affinities of a series of beta-adrenergic agonists and antagonists for the beta-adrenergic receptors coupled with an adenylate cyclase in cerebral cortex and cerebellum with their affinities for well characterized beta 2-adrenergic receptors in lung and beta 1-adrenergic receptor in heart substantiated this conclusion.
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PMID:The resolution of dopamine and beta 1- and beta 2-adrenergic-sensitive adenylate cyclase activities in homogenates of cat cerebellum, hippocampus and cerebral cortex. 4 16

Particulate fractions of myocardium taken from spontaneously hypertensive rats (SHR) contained an adenylate cyclase system that was less responsive than normotensive Wistar Kyoto rats to norepinephrine, isoproterenol (mixed beta-agonist), salbutamol (beta 2-agonist), dobutamine (beta 1-agonist), dopamine, histamine, and glucagon. Addition of 5'-guanylylimidodiphosphate to the SHR myocardial preparation again yielded a lessened sensitivity to all agents except norepinephrine, dopamine, and histamine. Chronic treatment of SHR with clonidine and a high dose of propranolol produced a cardiac enzyme that was insensitive to activation by norepinephrine. Similar treatment with a low dose of propranolol did not alter myocardial responses to norepinephrine.
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PMID:Alterations in myocardial adenylate cyclase in spontaneously hypertensive rats. 4 30

The adenylate cyclase system of a plasma membrane preparation from normal rat liver responds to various catecholamines in the following order: protokylol greater than isoproterenol greater than epinephrine greater than norepinephrine. In the Zadejela ascites hepatoma, the order of sensitivity is modified, indicating a transformation of the receptor from the beta2 to the beta1 type. These observations suggest that the catecholamine receptor might be a single entity, susceptible to secondary, and reversible, modification towards either a beta 1 or a beta 2 type.
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PMID:[Alteration of the catecholamine receptor during hepatic malignancy (author's transl)]. 18 80

The beta 1-adrenergic receptors of turkey erythrocyte membranes have been identified by binding of the radioactively labeled antagonist (--)-[3H]dihydroalprenolol, solubilized by treatment of the membranes with the detergent digitonin, and purified by affinity chromatography. Binding of (--)-[3H]dihydroalprenolol to the membranes occurred to a single class of non-cooperative binding sites (0.2--0.3 pmol/mg protein) with a equilibrium dissociation constant (Kd) of 8 (+/- 2) nM. These sites were identified as the functional, adenylate-cyclase-linked beta 1-adrenergic receptors on the basis of: firstly, the fast association and dissociation binding kinetics at 30 degrees C; secondly, the stereospecific displacement of bound (--)-[3H]dihydroalprenolol by beta-adrenergic agonists and antagonists; and thirdly, the order of potencies for agonists to displace bound tracer (isoproterenol congruent to protokylol greater than norepinephrine congruent to epinephrine) similar to the one found for adenylate cyclase activation, and typical for beta 1-adrenergic receptors. Treatment of the membranes with the detergent digitonin solubilized 30% of the receptors in an active form. Digitonin solubilized also adenylate cyclase activity with a yield of 20 to 30%, provided the membranes were first treated with an effector known to produce a persistent active state of the enzyme: e.g. sodium fluoride. Binding sites for guanine nucleotides ([3H]p[NH]ppG) were solubilized as well. Their concentration (24 pmol/mg protein) was in large excess over the concentration of solubilized receptors (0.30--0.45 pmol/mg protein). Solubilized receptors were purified 500--2000-fold by affinity chromatography with a 25 to 35% yield, using an alprenolol-agarose affinity matrix. Affinity purified receptors were devoid of measurable adenylate cyclase activity and guanine nucleotide binding sites, thus showing that receptors and adenylate cyclase are distinct membrane constituents, and that guanine nucleotides apparently do not bind directly to the receptor molecules. Membrane-bound, solubilized and purified receptors were sensitive to inactivation by dithiothreitol, but not by N-ethylmaleimide, suggesting that receptors are at least partly constituted of protein molecules, with essential disulfide bonds.
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PMID:Affinity chromatography of the beta-adrenergic receptor from turkey erythrocytes. 22 63

The present study investigated the effects of celiprolol a novel beta 1-antagonist with partial beta 2-agonist activity on the human failing heart. Experiments were performed on isolated electrically driven atrial and ventricular cardiac preparations and in membrane preparations from the left ventricles of nine patients (four with dilated cardiomyopathy; five with ischemic cardiomyopathy) undergoing cardiac transplantation for terminal heart failure. Celiprolol produced a negative inotropic effect in atrial and ventricular heart muscle. However, in the presence of forskolin--which activates the catalyst of the adenylate cyclase-or the cAMP phosphodiesterase inhibitor milrinone, celiprolol produced concentration-dependent positive inotropic effects and positive lusitropic effects. Experiments with the beta 1-and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, suggest that the positive inotropic response is mediated by beta 2-adrenoceptors. In radioligand binding experiments, a selectivity of 15.7 [-Gpp(NH)p] or 23.9 [+Gpp(NH)p] as judged from the Ki values--of binding to beta 2-adrenoceptors was measured in the failing human ventricular myocardium. Competition curves with celiprolol alone and in the presence of the guanine nucleotide Gpp(NH)p revealed no evidence for agonist activity at beta 1- or beta 2-adrenoceptors. It is concluded that amplification of the cAMP response is able to unmask partial agonist activity of celiprolol in the failing human heart at beta 2-adrenoceptors. The inotropic measurements are a more sensitive approach than radioligand binding studies. Whether the pharmacological profile of celiprolol will be useful in conditions like heart failure is questionable with respect to the potential downregulation of beta 2-adrenoceptors by its partial agonist activity.
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PMID:Positive inotropic effects due to partial agonistic activity of the beta-adrenoceptor antagonist celiprolol following amplification of cAMP formation in failing human myocardium. 127 96

Prenalterol, an allegedly beta 1-selective adrenergic agonist with high intrinsic sympathomimetic activity (ISA), was shown to be weakly lipolytic in rat adipocytes. However, in pertussis-toxin-treated adipocytes, the ISA of prenalterol was markedly increased (from 10-20% to approx. 100% of that of isoprenaline). The cellular sensitivity was also increased (EC50 approx. 60 nM and approx. 3 microM in pertussis-toxin-treated and control cells respectively). A similar effect was seen for other partial agonists such as the beta 2-selective agonist terbutaline and for beta-adrenergic antagonists with some intrinsic activity (metoprolol, pindolol). There was no clear change in sensitivity to isoprenaline's ability to stimulate adenylate cyclase in adipocyte membranes from pertussis-toxin-treated animals but the cyclase activity was increased approx. 4-fold in the presence of 1 microM-GTP. Prenalterol stimulated lipolysis by only small increases in intracellular cyclic AMP (cAMP) levels (less than 10% of that seen with isoprenaline). Basal lipolysis was increased in cells from pertussis-toxin-treated rats and the cellular sensitivity to the non-degradable cAMP analogue, N6-monobutyryl-cAMP, was increased. In control cells, a submaximal concentration of prenalterol (0.1 microM) increased the sensitivity to the cAMP analogues, N6-monobutyryl-cAMP and 8-bromo-cAMP. A low concentration (1 mM) of 8-bromo-cAMP also increased the effect of prenalterol. Similar effects were seen when the phosphodiesterase was inhibited. Thus (1) lipolysis is extremely sensitive to small increases in intracellular cAMP; (2) the degree of activation of adenylate cyclase and thus cAMP formation is the rate-limiting step for the biological response of partial agonists; (3) the inhibitory GTP-binding protein, Gi, is an important modulator ('tissue factor') of the beta-adrenergic agonistic property; (4) low levels of cAMP exert a priming effect on protein kinase A.
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PMID:The inhibitory GTP-binding protein (Gi) regulates the agonistic property of beta-adrenergic ligands in isolated rat adipocytes. Evidence for a priming effect of cyclic AMP. 128 Jan 15

Previous studies have shown a strong reduction of catecholamine-induced lipolysis in perirenal white fat cells in aging rabbits. The molecular basis of this observation was explored on scapular and perirenal adipocytes from 45 and 300- to 500-day-old rabbits. ACTH and forskolin were used to define the maximal lipolytic potencies of the adipocytes. beta-Adrenergic responsiveness was explored with isoproterenol and specific agonists of the "atypical" beta-adrenoceptor (beta-AR) (BRL37344 and (+/-)CGP12177); beta 1/beta 2-ARs were identified with [125I]cyanopindolol. alpha 2-adrenergic responses were evaluated with the full alpha 2-agonist, UK14304. The alpha 2 AR number was determined with the alpha 2-antagonist radioligand [3H]RX821002. Whatever the fat deposit, the relative order of lipolytic potency of the beta-agonists was: isoproterenol greater than BRL37344 greater than (+/-)CGP12177. As previously reported for catecholamines, the maximal lipolytic response initiated by isoproternol decreased with aging; the stronger reduction was observed in perirenal adipocytes compared to subscapular adipocytes. The most striking observation concerns the parallel and complete disappearance of the lipolytic responses induced by the atypical beta-agonists (BRL37344 and (+/-)CGP12177) and the preservation of a residual action of isoproterenol (30% of that described in young animals) which was attributed to the stimulation of beta 1/beta 2-ARs. The number of beta 1/beta 2-AR binding sites was practically equivalent whatever the fat deposite and the age of the animals. alpha 2-Adrenergic responsiveness and alpha 2-adrenergic receptor number were increased with aging in the various deposits but the stronger changes were observed in the perirenal adipocytes where epineprine initiated a biphasic effect on lipolysis (antilipolytic and then lipolytic). To conclude, the reduction of catecholamine-induced lipolysis observed in the rabbit fat cells with aging can be explained by changes in the atypical beta-AR/alpha 2-AR balance. First, a loss of responsiveness to the atypical beta-adrenergic agents was observed (it is impossible for the moment to distinguish between the loss of atypical beta-AR binding sites and their putative uncoupling from the adenylate cyclase system) whereas beta 1/beta 2-AR-mediated responses were maintained. Second, an increment of alpha 2-adrenergic responsiveness and of the alpha 2-AR binding sites accompanied aging and fattening. In the absence of, or after a strong reduction of the atypical beta-AR component of the lipolytic response in fat cells of aged rabbits, epinephrine exerts a biphasic effect on lipolysis, demonstrating the changes occurring in the atypical beta-AR/alpha 2-AR balance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Drop in the "atypical" beta-adrenergic response and modification of the beta/alpha 2-adrenoceptor balance in fat cells from aging rabbits. 130 35

In order to investigate the general cause of beta-adrenergic receptor neuroeffector abnormalities in the failing human heart, we measured ventricular myocardial adrenergic receptors, adrenergic neurotransmitters, and beta-adrenergic receptor-effector responses in nonfailing and failing hearts taken from nonfailing organ donors, subjects with endstage biventricular failure due to idiopathic dilated cardiomyopathy (IDC), and subjects with primary pulmonary hypertension (PPH) who exhibited isolated right ventricular failure. Relative to nonfailing PPH left ventricles, failing PPH right ventricles exhibited (a) markedly decreased beta 1-adrenergic receptor density, (b) marked depletion of tissue norepinephrine and neuropeptide Y, (c) decreased adenylate cyclase stimulation in response to the beta agonists isoproterenol and zinterol, and (d) decreased adenylate cyclase stimulation in response to Gpp(NH)p and forskolin. These abnormalities were directionally similar to, but generally more pronounced than, corresponding findings in failing IDC right ventricles, whereas values for these parameters in nonfailing left ventricles of PPH subjects were similar to values in the nonfailing left ventricles of organ donors. Additionally, relative to paired nonfailing PPH left ventricles and nonfailing right ventricles from organ donors, failing right ventricles from PPH subjects exhibited decreased adenylate cyclase stimulation by MnCl2. These data indicate that: (a) Adrenergic neuroeffector abnormalities present in the failing human heart are due to local mechanisms; systemic processes do not produce beta-adrenergic neuroeffector abnormalities. (b) Pressure-overloaded failing right ventricles of PPH subjects exhibit decreased activity of the catalytic subunit of adenylate cyclase, an abnormality not previously described in the failing human heart.
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PMID:Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. 131 17

Sera from patients with dilated cardiomyopathy contain autoantibodies modifying cardiac beta-adrenergic pathways. The influence of the methodology used to determine the prevalence of these antibodies was examined by comparing in 51 patients with idiopathic dilated cardiomyopathy the results of three assays: (1) isoproterenol-sensitive adenylate cyclase; (2) ligand binding inhibition; (3) enzyme-linked immunoassay (ELISA) of beta-receptor peptides. In 20% of the patients, all three tests gave positive results, while the concordance of the adenylate cyclase assay with either of the other two tests was 65%. ELISA was positive for a beta 1-receptor peptide corresponding to the second extracellular loop, but negative for a beta 2-receptor peptide. The results suggest that autoantibodies in dilated cardiomyopathy sera interact with several components of the beta-receptor-adenylate cyclase, and therefore a combination of methodologic approaches is needed to evaluate the prevalence and consequences of beta-receptor autoimmunity.
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PMID:Assessment of immune modulation of beta-adrenergic pathways in human dilated cardiomyopathy: influence of methodologic factors. 131 61

1. The long-term effects of sinoaortic denervation on the development of left ventricular hypertrophy (assessed by the measurement of the ratio (R): heart weight/total body weight and LVT: left ventricular thickness), myocardial beta-adrenergic receptivity (measured by [125I]-cyanopindolol binding and adenylate cyclase activity) and plasma catecholamine levels (measured by h.p.l.c.) were investigated in three groups of dogs: normotensive controls (group 1), dogs made hypertensive by sinoaortic denervation and evaluated 1 (group 2) and 18 months (group 3) later. 2. Noradrenaline (NA) and adrenaline (A) plasma levels were 461 +/- 54 and 85 +/- 45 pg ml-1 in controls, 861 +/- 185 and 191 +/- 23 pg ml-1 in group 2 (P less than 0.05). They were normal in group 3 (426 +/- 132 and 110 +/- 16 pg ml-1). 3. R and LVT values were significantly (P less than 0.05) higher in sinoaortic denervated dogs (R = 7.7 +/- 0.1 and 7.8 +/- 0.2; LVT = 13.6 +/- 1.3 and 14.2 +/- 0.9 mm in groups 2 and 3 respectively) than in normotensive dogs (group 1: R = 6.7 +/- 0.1, LVT = 9.3 +/- 0.8 mm). 4. In group 1, the total number of beta-adrenoceptors (Bmax) was 37 +/- 11 and 29 +/- 6 fmol mg-1 protein in the left ventricle (LV) and right auricle (RA) respectively. In group 2, Bmax was significantly lower (10 +/- 3 in LV and 13 +/- 2 fmol mg-1 protein in RA, P less than 0.05) than in group 1. There was no difference between group 1 and group 3 (37 +/- 3 fmol mg-1 prot in LV and 31 +/- 3 fmol mg-1 protein in RA). 5. The percentage of beta 1-adrenoceptors was 82 +/- 4 in LV and 75 +/- 5 in RA in group 1. It was significantly lower (P less than 0.05) in groups 2 (LV: 33 +/- 6 and RA: 33 +/- 5) and 3 (LV: 59 +/- 3 and RA: 55 +/- 4). 6. Basal values of adenylate cyclase activity in LV significantly decreased after sinoaortic denervation.7. These data show that sinoaortic denervation is associated with left ventricular hypertrophy which appears early (1 month) and persists until 18 months despite the normalization of plasma catecholamine levels. The total number of myocardial beta-adrenoceptors is closely related to catecholamine levels but a selective decrease in beta 1-adrenoceptors is observed during cardiac hypertrophy. The fall in basal adenylate cyclase activity suggests that cardiac hypertrophy is associated with an impairment of transmembrane signalling.
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PMID:Myocardial hypertrophy, cardiac beta-adrenoceptors and adenylate cyclase activity during sinoaortic denervation in dogs. 131 24


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