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 present study was designed to describe the relationships among thyroid status, myocardial growth and myocardial beta-adrenergic receptors in the developing rat ventricle. In normal rat myocardium the beta-adrenergic binding capacity (Bmax) for (-)-[3H] DHA decreased with increasing age and heart size. In order to determine the effect of thyroid status on ventricular growth characteristics and beta-adrenergic receptors, animals were rendered: (1) hypothyroid with propylthiouracil (PTU), (2) euthyroid with PTU and daily thyroxine (T4) replacement, (3) hyperthyroid for several days with daily thyroxine injections or (4) normal controls with sham saline injections. Growth characteristics were similar in euthyroid and normal rat myocardium; ventricular weight, protein and DNA content were similar at postnatal days 5, 15 and 28. Growth in hypothyroid pups was normal until postnatal day 14 at which time the heart weight and protein content were significantly lower than in normal or euthyroid pups, whereas the number of beta-adrenergic receptors was decreased in hypothyroid myocardium at all ages studied. On postnatal day 5 the (-)-[3H]DHA binding (Bmax) was 37 +/- 9 in hypothyroid myocardium compared to 63 +/- 8 fmole per mg protein mean +/- S.D. in euthyroid myocardium. The function of the beta-adrenergic receptors was also decreased in hypothyroid as compared to euthyroid or normal myocardium as demonstrated by a decrease in maximal catecholamine sensitive adenylate cyclase activity in myocardial membranes at 28 days of age. Treatment of hypothyroid or normal pups with T4 resulted in an increase in heart size, protein content and beta-adrenergic receptors. Ventricular DNA content, which describes hyperplastic growth, was not decreased in hypothyroid rats demonstrating that postnatal hypertrophic but not hyperplastic ventricular growth is dependent on thyroid hormone.
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PMID:beta-Adrenergic receptors and catecholamine sensitive adenylate cyclase in developing rat ventricular myocardium: effect of thyroid status. 628 64

We have studied the properties of beta-adrenergic receptors and of their interaction with adenylate cyclase in the chick myocardium during embryogenesis. Between 4.5 and 7.5 days in ovo the number of receptors determined by (-)-[3H]dihydroalprenolol ([3H]DHA) binding is constant at approx. 0.36 pmol of receptor/mg of protein. By day 9 the density decreases significantly to 0.22 pmol of receptor/mg of protein. At day 12.5--13.5 the number was 0.14--0.18 pmol of receptor/mg of protein. This number did not change further up to day 16. The same results were obtained with guanosine 5'-[beta, gamma-imido]triphosphate (p[NH]ppG) added to the assay mixtures. There was no significant change in receptor affinity for the antagonist [3H]DHA between days 5.5 and 13. Despite the decrease in numbers of beta-adrenergic receptors, there was no change in basal, p[NH]ppG-, isoprenaline- or isoprenaline-plus-p[NH]ppG-stimulated adenylate cyclase activity between days 3 and 12 of development. We conclude that beta-adrenergic receptors and adenylate cyclase are not co-ordinately regulated during early embryonic development of the chick heart. Some of the beta-adrenergic receptors present very early in the ontogeny of cardiac tissue appear not to be coupled to adenylate cyclase since their loss is not reflected in decreased activation of the enzyme.
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PMID:Non-co-ordinate development of beta-adrenergic receptors and adenylate cyclase in chick heart. 628 5

The receptor alterations involved in catecholamine-induced desensitization of adenylate cyclase in human neutrophils have been investigated as has the ability of hydrocortisone to modify such alterations. Incubation of human neutrophils with isoproterenol for 3 h in vitro resulted in an 86% reduction in the ability of isoproterenol to stimulate cyclic AMP accumulation in the cells. Two types of receptor alterations were documented. There was a 40% reduction in the number of beta adrenergic receptors (42 vs. 25 fmol/mg protein, P < 0.005) present after desensitization as assessed by [(3)H]dihydroalprenolol ([(3)H]DHA) binding. In addition the receptors appeared to be relatively uncoupled from adenylate cyclase. This uncoupling was assessed by examining the ability of the agonist isoproterenol to stabilize a high-affinity form of the receptor, detected by computer modelling of competition curves for [(3)H]DHA binding. Desensitized receptors were characterized by rightward-shifted agonist competition curves. When hydrocortisone was added to the desensitizing incubations (combined treatment) there was a statistically significant attenuation in the desensitization process as assessed by the ability of isoproterenol to increase cyclic AMP levels in the cells. Although combined treatment did not prevent the decline in receptor number, it did attenuate the uncoupling of the receptors. Combined treatment resulted in competition curves intermediate between the control and the rightward-shifted desensitization curves. Prednisolone was similar to hydrocortisone in attenuating isoproterenol-induced uncoupling. Thus, steroids appeared to attenuate agonist-induced desensitization of the beta adrenergic receptor-adenylate cyclase system by dampening the ability of agonists to uncouple receptors without modifying their ability to promote down-regulation of beta adrenergic receptors.
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PMID:In vitro desensitization of beta adrenergic receptors in human neutrophils. Attenuation by corticosteroids. 629 79

We examined beta-adrenergic receptor density, basal, maximal isoproterenol and fluoride-stimulated adenylate cyclase activities, and morphologic characteristics of rabbit and rat native and heterotopic isograft cardiac tissue. Four weeks after graft placement there were only subtle histologic differences between native and graft tissue. Membrane preparations from isografts of rabbits demonstrated increases in beta-receptor density (maximum [3H]DHA binding = 111 +/- 19.3 fmol/mg versus 52.4 +/- 4.9 in native hearts, p less than 0.05). In a small number of experiments, rat isografts also demonstrated a suggestive increase in beta-receptor density (69.8 +/- 7.1 fmol/mg versus 40.2 +/- 7.3 in native hearts). Isoproterenol-stimulated adenylate cyclase activity was greater in rabbit graft hearts (3.98 +/- 0.20 X basal activity) than in native tissue 2.67 +/- 0.16 X basal activity, p less than 0.05). We conclude that cardiac denervation may lead to a postsynaptic form of beta-adrenergic supersensitivity that is due to an increase in beta-receptor density.
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PMID:Increased beta-adrenergic receptor density in an experimental model of cardiac transplantation. 630 58

beta-Adrenergic receptors were demonstrated in membrane preparations from 6 human Ewing's sarcomas and compared to those from 46 other pediatric cancers with the use of the beta-adrenergic antagonist (-)-(3H)dihydroalprenolol [(-)[3H]DHA]. In contrast to the high numbers of receptor sites found in Ewing's sarcomas (55-640 fmol x mg-1 protein; dissociation constant Kd, 1-2 nM), other childhood cancers (neuroblastoma, rhabdomyosarcoma, brain tumors, lymphoma, osteosarcoma, hepatoblastoma, yolk sac, and Wilms' tumor) contained in general fewer beta-adrenergic receptor sites. Characteristics of (-)-[3H]DHA binding were therefore more fully characterized in the Ewing's tumors. Competition of (-)-[3H]DHA binding by classical catecholamine agonists, as well as by subtype selective agents metoprolol and zinterol, demonstrated the presence of a homogeneous population of beta 1-adrenergic sites in several Ewing's tumors. Adenylate cyclase activity in all Ewing's sarcomas was enhanced by GTP and NaF. However, in spite of high numbers of beta-adrenergic receptors, (-)-isoproterenol was not very effective in the activation of adenylate cyclase activity in several of the Ewing's tumors tested. Neither guanyl-5'-yl-imidophosphate nor GTP altered agonist potency for the receptor site in these catecholamine-insensitive tumors. Hill coefficients obtained from the competition experiments with (-)-isoproterenol (in the presence or absence of guanine nucleotide) were approximately 1.0. These uncoupled receptors were resistant to N-ethylmaleimide denaturation and were densensitized only 50% during culture in the presence of (-)-isoproterenol. Thus Ewing's sarcomas are relatively rich in beta-adrenergic sites, and several tumors appear to have a coupling lesion involving guanine nucleotide-dependent regulatory protein interaction with beta-adrenergic receptors and adenylate cyclase, similar in phenotype to that described in the (unc) variant of S49 mouse lymphoma.
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PMID:beta-Adrenergic receptors in pediatric tumors: uncoupled beta 1-adrenergic receptor in Ewing's sarcoma. 631 52

Patients with insulin-dependent diabetes mellitus (IDDM) have been found to have a heightened hyperglycemic response to epinephrine. To determine if patients with IDDM have increased sensitivity of cellular beta 2-adrenergic receptor-effector systems, we assessed beta 2-adrenergic receptors and adenylate cyclase sensitivities to isoproterenol in partially purified mononuclear leukocyte (MNL) plasma membranes from 10 patients with IDDM (without adrenergic neuropathy) and 10 matched nondiabetic controls. MNL beta 2-adrenergic receptor densities (Bmax = 48 +/- 8 fmol [3H] DHA/mg protein in IDDM, 44 +/- 3 fmol [3H] DHA/mg protein in controls) and binding affinities (apparent KD = 0.3 +/- 0.07 nM in IDDM, 0.3 +/- 0.04 nM in controls) did not differ. Further, MNL adenylate cyclase activities were not significantly different either at baseline (325 +/- 86 pmol/mg protein/15 min in IDDM, 275 +/- 49 pmol/mg protein/15 min in controls) or in response to isoproterenol (842 +/- 229 pmol/mg protein/15 min in IDDM, 608 +/- 86 pmol/mg protein/15 min in controls). Thus, the data do not support the presence of a generalized alteration of beta-adrenergic receptors or adenylate cyclase sensitivity in IDDM. To the extent that MNL beta 2-adrenergic receptors and adenylate cyclase activities reflect those of extravascular catecholamine target cells, these findings suggest that the heightened hyperglycemic response to epinephrine exhibited by patients with IDDM is not due to increased sensitivity of cellular beta 2-adrenergic receptor-effector systems and is best attributed to the altered hormonal milieu of the insulin-deficient state.
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PMID:Mononuclear leukocyte beta 2-adrenergic receptors and adenylate cyclase sensitivity in insulin-dependent diabetes mellitus. 631 56

The cardiac beta-adrenergic coupled adenylate cyclase system was examined in young and old male Wistar rats. The concentration of binding sites for (-)3H-DHA in membranes prepared from cardiac ventricles was 21.1 +/- 2.78 (SD) fmoles/mg protein in 3-4 month old rats (young rats) and 31.2 +/- 2.20 fmoles/mg protein in 24 month old rats (old rats). The dissociation constant, KD was 4.3 +/- 1.8 nM and 6.7 +/- 1.7 nM for young and old rats, respectively. Various compounds were used to study the characteristics of activation of adenylate cyclase in homogenates from cardiac ventricles. Basal adenylate cyclase was reduced 30% in old animals compared to young (6.1 pmoles/min/mg protein in 24 month vs. 8.6 pmoles/min/mg protein in 3-4 month). (-)Isoproterenol (10(-5) M) alone stimulated adenylate cyclase greater than two-fold in young rats (10.6 pmoles/min/mg protein above basal) and this stimulation was 34% lower in old animals. GppNHp (100 microM), fluoride (10 mM), and forskolin (100 microM) activation of adenylate cyclase above basal was reduced 38, 37, and 34%, respectively, in the old animals. No significant changes between the two groups were noted in the apparent affinity of GppNHp either alone or in the presence of (-)isoproterenol nor in the affinities of catecholamine agonists for activation of cyclase. These results suggest a reduction in the amount of functional regulatory protein or possibly cyclase in 24 month old rat ventricular tissue compared to 3-4 month old tissue. However, this data does not rule out the possibility of altered molecular interactions of a full complement of regulatory protein(s) with beta-adrenergic receptor and/or catalytic adenylate cyclase.
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PMID:Decreased response with age of the cardiac catecholamine sensitive adenylate cyclase system. 631 79

We have shown that binding of 3H-dihydroalprenolol ( [3H] DHA) to DDT1 MF-2 cells and cell membranes was of high affinity, saturable, stereoselective and reversible. The [3H]DHA dissociation constants were 0.63 +/- 0.15 nM (n = 6) and 0.83 +/- 0.04 nM (n = 5) for intact cells and cell membranes, respectively, with a binding site concentration for cells of 27,300 +/- 5,200 sites/cell (n = 6) and for membranes 468 +/- 24 fmoles/mg protein (n = 5). The order of agonist competition for the [3H]-DHA binding site of DDT1 cell membranes was isoproterenol (Ki = 0.20 +/- 0.07 microM) greater than epinephrine (Ki = 0.4 +/- 0.2 microM) greater than norepinephrine (Ki = 66.5 +/- 5.15 microM) consistent with a beta 2-adrenergic receptor interaction. Zinterol, a beta 2-selective antagonist, (Ki = 0.05 +/- 0.01 microM) was 18X more effective than metoprolol, a beta 1-selective antagonist (Ki = 0.9 +/- 0.1 microM), in competing for the DHA binding site. A nonlinear iterative curve fitting analysis of zinterol and metoprolol binding isotherms indicated that (p greater than 0.05) DDT1 cells possess a pure population of beta 2-adrenergic receptors. Finally, we have shown that DDT1 MF-2 cell beta 2-adrenergic receptor is functionally coupled to adenylate cyclase via a G/F protein complex as demonstrated in part by a guanine nucleotide requirement for isoproterenol stimulation of adenylate cyclase activity. In addition, guanine nucleotide mediated a reduction in the affinities of isoproterenol and epinephrine for the [3H]DHA binding site.
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PMID:Characteristics of an adenylate cyclase coupled beta 2-adrenergic receptor in a smooth muscle tumor cell line. 632 9

The beta-adrenergic receptor, transduction processes and catalytic activity of the adenylate cyclase enzyme complex have been investigated in rabbit heart at different stages of biological maturation. The binding of [3H]-dihydroalprenolol to a washed membrane preparation isolated from rabbit ventricular muscle was used to characterize beta-adrenergic receptors. Significant age-related differences were noted in beta-receptor affinity (Kd) and density (RD) of neonatal and adult animals; the adult Kd was 3.7-fold greater and the RD 2-fold higher than the neonates. No significant differences in these parameters were detected among the 27-day old fetus and the 1- and 7-day old neonates. Age-dependent differences in agonist isoproterenol affinity for the receptor were not observed in contrast to the significant changes in antagonist (DHA) affinity. Age-related changes in receptor affinity were also quantitated by determining the inhibitory potency of alprenolol on isoproterenol stimulated adenylate cyclase enzyme activity. A decreased affinity of the beta-adrenergic receptor for alprenolol in the adult heart was indicated by a 3.7-fold greater Ki for the adult than the 1-day old neonate. Ontogenic variations in the coupling efficiency between the receptor and catalytic components of the adenylate cyclase complex were also evaluated. The Kd of the beta-adrenergic receptor for isoproterenol and the EC50 for adenylate cyclase stimulation were determined under similar conditions. The corresponding coupling index (Kd/EC50) was found to be 2.4-fold greater in the 1-day old neonate than adult, suggesting that for a given percentage increase in adenylate cyclase activity, a lower percentage of beta-adrenergic receptor sites need be occupied in the neonate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biological maturation and beta-adrenergic effectors: development of beta-adrenergic receptors in rabbit heart. 632 58

Pressure overload left ventricular (LV) hypertrophy was produced by banding the ascending aorta of puppies and allowing them to grow to adulthood. LV free wall weight per body weight increased by 87% from a normal value of 3.23 +/- 0.19 g/kg. Hemodynamic studies of conscious dogs with LV hypertrophy and of normal, conscious dogs without LV hypertrophy showed similar base-line values for mean arterial pressure, heart rate, and LV end-diastolic pressure and diameter. LV systolic pressure was significantly greater, P less than 0.01, and LV stroke shortening was significantly lss, P less than 0.01, in the LV hypertrophy group. In both normal and LV hypertrophy groups, increasing bolus doses of norepinephrine or isoproterenol produced equivalent changes in LV dP/dt. beta-adrenergic receptor binding studies with [3H]-dihydroalprenolol ( [3H]DHA) indicated that the density of binding sites was significantly elevated, P less than 0.01, in the hypertrophied LV plasma membranes (111 +/- 8.8, n = 8), as compared with normal LV (61 +/- 5.6 fmol/mg protein, n = 11). The receptor affinity decreased, i.e., disassociation constant (KD) increased, selectively in the LV of the hypertrophy group; the KD in the normal LV was 6.8 +/- 0.7 nM compared with 10.7 +/- 1.8 nM in the hypertrophied LV. These effects were observed only in the LV of the LV hypertrophy group and not in the right ventricles from the same dogs. The plasma membrane marker, 5' -nucleotidase activity, was slightly lower per milligram protein in the LV hypertrophy group, indicating that the differences in beta-adrenergic receptor binding and affinity were not due to an increase in plasma membrane protein in the LV hypertrophy group. The EC50 for isoproterenol-stimulated adenylate cyclase activity was similar in both the right and left ventricles and in the two groups. However, maximal-stimulated adenylate cyclase was lower in the hypertrophied left ventricle. Plasma catecholamines were similar in the normal and hypertrophied groups, but myocardial norepinephrine was depressed in the dogs with LV hypertrophy (163 +/- 48 pg/mg) compared with normal dogs (835 +/- 166 pg/mg). Thus, severe, but compensated LV hypertrophy, induced by aortic banding in puppies, is characterized by essentially normal hemodynamics in adult dogs studied at rest and in response to catecholamines in the conscious state. At the cellular level, reduced affinity and increased beta-adrenergic receptor number characterized the LV hypertrophy group, while the EC50 for isoproterenol-stimulated adenylate cyclase activity was normal. By these mechanisms, adequate responsiveness to catecholamines is retained in conscious dogs with severe LV hypertrophy.
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PMID:Effects of pressure overload, left ventricular hypertrophy on beta-adrenergic receptors, and responsiveness to catecholamines. 632 5


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