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)

Rat liver plasma membranes are shown to catalyze the formation of adenosine 5'-phosphoroglycerol and adenosine 5'-phosphoromethanol from ATP and glycerol or methanol, respectively. In the presence of 2.7 M glycerol and 1 mM ATP, 30 nmol of adenosine 5'-phosphoroglycerol were formed in 10 min per mg of rat liver plasma membranes. The structures of these phosphodiesters were determined from the following evidence. Radioactivity was incorporated into the nucleotide from [alpha-32P]ATP, [2,8-3H]ATP, or [2-3H]glycerol. Treatment with snake venom phosphodiesterase I converted the nucleotides to AMP. The compound formed from glycerol and ATP co-migrated with adenosine 5'-phosphoroglycerol synthesized from glycerol and adenosine 5'-phosphoromorpholidate in five thin layer chromatography systems. The methyl derivative co-migrated with adenosine 5'-phosphoromethanol synthesized from methanol and adenosine 5'-phosphormorpholidate in several thin layer chromatography systems. The synthesis of these phosphodiesters was also catalyzed by chicken embryo fibroblast membranes and solubilized rat liver plasma membranes but not by rat heart plasma membrane preparations. Formation of significant amounts of these phosphodiesters required relatively high concentrations of the alcohols (greater than 1 M). The alcohol concentration dependence did not exhibit substrate saturation at physiologically meaningful concentrations of glycerol or methacol. It is proposed that either the alcohols examined were not the natural substrates for this enzyme or that the alcohol/AMP phosphodiesters were formed as a result of trapping of an enzyme/nucleotide intermediate. Adenosine 5'-phosphoroglycerol formation was inhibited approximately 50% by 15 mM NaF. Epinephrine, norepinephrine, glucagon, and prostaglandin E1 were without effect. Alloxan, an inhibitor of adenylate cyclase did not inhibit formation of adenosine 5'-phosphoroglycerol. It is concluded that adenylate cyclase was not responsible for formation of these phosphodiesters. The physiological significance of this reaction remains undefined.
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PMID:Formation of adenosine 5'-phosphoroglycerol from ATP and glycerol by rat liver plasma membranes. 83 37

The effect of epinephrine and histamine on adenylate cyclase activity in lungs and hearts of control and ovalbumin-sensitized guinea pigs was investigated. Epinephrine at 10(-6) M concentration stimulated adenylate cyclase from both organs of the sensitized animals but had no effect on the enzyme from control tissues. At 10(-4) M, epinephrine stimulated equally the enzyme activity from the control and sensitized lungs and hearts. Histamine, 10(-6) and 10(-4), stimulated equally adenylate cyclase in tissues from both groups of animals. The results suggest that ovalbumin sensitization leads to hypersensitivity of the beta-adrenergic receptors to epinephrine without changing their sensitivity to histamine.
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PMID:Adenylate cyclase activity in heart and lung: effect of epinephrine and histamine in control and sensitized guinea pigs. 101 92

The effect of various hormones and drugs on the adenyl cyclase system of pig and human epidermal slices was studied in vitro. Adrenaline and isoproterenol in the presence of theophylline increased the epidermal cyclic AMP level 20-fold in 5 min. Noradrenaline also stimulated cyclic AMP accumulation but to a much lesser degree. The adrenaline stimulation was marked even in the absence of the phosphodiesterase inhibitor, theophylline. Theophylline potentiated the effect of adrenaline at the concentration of 2-10 mM although theophylline alone did not elevate the cyclic AMP level significantly. The Km for adrenaline stimulation of the adenyl cyclase system of pig epidermis was 7-7 X 10(-7) M. A beta-adrenergic antagonist, propranolol, markedly inhibited the adrenaline stimulation while alpha-antagonists, phentolamine or priscoline, showed little effect. The results are in accord with the view that the epidermis possesses an active adenyl cyclase system with beta-adrenergic receptors.
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PMID:The effects of catecholamine and related compounds on the adenyl cyclase system in the epidermis. 119 26

The effects of the mixed agonist epinephrine and the beta agonist isoproterenol, each alone and in combination with the alpha adrenergic blocker phentolamine and the beta blocker propranolol on the adenylate cyclase activity of human adipocyte membrane fragments were determined in a calcium free buffer. Neither phentolamine (10 muM) nor propranolol (32 muM) affected basal adenylate cyclase activity. Epinephrine (10 muM) stimulated adenylate cyclase activity and this effect was slightly enhanced by phentolamine. The combination of epinephrine plus propranolol depressed adenylate cyclase below the basal level. Isoproterenol (10 muM) markedly stimulated adenylate cyclase; the addition of phentolamine caused an equivocal further increase while the addition of propranolol depressed adenylate cyclase activity to, but not below, the basal level. These findings are consistent with the hypothesis that human adipocytes have both alpha and beta adrenergic receptors and that these receptors are associated with the cell membrane adenylate cyclase system.
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PMID:The effect of alpha and beta adrenergic receptor stimulation on the adenylate cyclase activity of human adipocytes. 122 39

Thrombin-induced platelet aggregation is associated with an increase in intracellular calcium. Epinephrine provokes aggregation in the absence of a rise in intracellular calcium. Adenosine has been postulated as an endogenous inhibitor of platelet aggregation. In this study, the authors examine the effect of adenosine on the rise in intracellular calcium and on platelet aggregation, and the role of cyclic AMP (cAMP) in these actions. Human platelets were obtained from citrated plasma containing 5 micrograms/mL of indomethacin. Intracellular calcium was determined by fura-2 fluorescent dye. Adenosine inhibited thrombin-induced platelet aggregation and the rise in intracellular calcium in a dose-dependent manner. At a concentration of 100 mumol/L, adenosine completely inhibited thrombin-induced aggregation, but only partly inhibited the rise in intracellular calcium (55%). Adenosine also partially inhibited the rise in calcium produced by thrombin in both calcium-containing and calcium-free media, suggesting that adenosine inhibits both calcium influx and calcium mobilization. The effects of adenosine on intracellular calcium, as in the case of platelet aggregation, appear to be linked to adenylate cyclase, since they were prevented by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine (1-mmol/L) and were potentiated by phospho-diesterase inhibition with papaverine (1 mumol/L). Adenosine and dibutyryl-cAMP also inhibited epinephrine-stimulated platelet aggregation in a dose-dependent manner. Thus, it appears that adenosine may inhibit platelet aggregation independently of its ability to decrease cytosolic free calcium.
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PMID:Role of cyclic AMP in adenosine inhibition of intracellular calcium rise in human platelets. Comparison of adenosine effects on thrombin- and epinephrine-induced platelet stimulation. 132 39

Catecholamines inhibit adenylate cyclase in pancreatic B-cells, but the importance of the resulting fall in cAMP concentration for the decrease in insulin release remains controversial. Adrenaline caused a dose-dependent inhibition (EC50 = 5.7 nM) of insulin release by mouse islets incubated in a medium containing 15 mM glucose. Supplementation of the medium with 500 microM dibutyryl-cAMP or 1 microM forskolin potentiated the effect of glucose on release and attenuated the inhibition by 1 and 10 nM adrenaline; the EC50 value was increased 2-fold. The inhibitory action of 100 nM or 1 microM adrenaline was, however, not affected. This apparent change in adrenaline potency was not simply due to the larger rate of release since it was not observed when the effect of glucose was potentiated by cytochalasin-B. However, when the same rate of insulin release as that produced by 15 mM glucose alone was achieved by combining 10 mM glucose and 250 microM dibutyryl-cAMP, the inhibitory potency of adrenaline was unaffected. Intracellular microelectrodes were used to determine whether the changes in B-cell membrane potential brought about by adrenaline are mediated by a fall in cAMP levels. Addition of dibutyryl-cAMP or forskolin to a medium containing 10 or 15 mM glucose increased the Ca(2+)-dependent electrical activity triggered by the sugar. However, this did not prevent adrenaline from hyperpolarizing the membrane transiently and causing a steady-state decrease in the intensity of the electrical activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adrenaline inhibition of insulin release: role of cyclic AMP. 166 76

The ocular hypotensive effects of medetomidine, a relatively selective alpha 2-agonist, and its analogs were tested in rabbits and cats and their inhibition of adenylate cyclase in the isolated bovine ciliary process was also studied. It was found that topical unilateral administration of medetomidine (0.5-2.0%) to the normotensive rabbits produced a dose-dependent bilateral decrease in IOP with peak reduction in IOP at 2 hr in the treated eye and 1 hr in the untreated eye. A dose-dependent mydriasis was also observed in the treated eye. The dose-response curves of medetomidine and its analogs showed that the ranked order of intrinsic activity at lowering IOP was medetomidine greater than or equal to MPV-1440 greater than detomidine greater than MPV-1441 and MPV-305 BII. At concentrations lower than those used in rabbits, topical application of medetomidine to the normotensive cats lowered IOP in both treated and untreated eyes. Medetomidine and detomidine caused a dose-dependent inhibition of isoproterenol-stimulated adenylate cyclase activity. Detomidine was found to be a partial agonist producing about 43% of maximum inhibition obtained by medetomidine. The IOP efficacy of these alpha 2-agonists paralleled their effects on adenylate cyclase activity. The results demonstrated that these imidazoline derivatives are effective ocular hypotensive agents which may be useful in understanding the contribution of alpha 2-receptors to the regulation of IOP.
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PMID:Ocular hypotensive effects of medetomidine and its analogs. 168 23

The binding properties of p-[125I]iodoclonidine [( 125I]PIC) to human platelet membranes and the functional characteristics of PIC are reported. [125I]PIC bound rapidly and reversibly to platelet membranes, with a first-order association rate constant (kon) at room temperature of 8.0 +/- 2.7 x 10(6) M-1 sec-1 and a dissociation rate constant (koff) of 2.0 +/- 0.8 x 10(-3) sec-1. Scatchard plots of specific [125I]PIC binding (0.1-5 nM) were linear, with a Kd of 1.2 +/- 0.1 nM. [125I]PIC bound to the same number of high affinity sites as the alpha 2-adrenergic receptor (alpha 2-AR) full agonist [3H] bromoxidine (UK14,304), which represented approximately 40% of the sites bound by the antagonist [3H]yohimbine. Guanosine 5'-(beta, gamma-imido)triphosphate greatly reduced the amount of [125I]PIC bound (greater than 80%), without changing the Kd of the residual binding. In competition experiments, the alpha 2-AR-selective ligands yohimbine, bromoxidine, oxymetazoline, clonidine, p-aminoclonidine, (-)-epinephrine, and idazoxan all had Ki values in the low nanomolar range, whereas prazosin, propranolol, and serotonin yielded Ki values in the micromolar range. Epinephrine competition for [125I]PIC binding was stereoselective. Competition for [3H]bromoxidine binding by PIC gave a Ki of 1.0 nM (nH = 1.0), whereas competition for [3H]yohimbine could be resolved into high and low affinity components, with Ki values of 3.7 and 84 nM, respectively. PIC had minimal agonist activity in inhibiting adenylate cyclase in platelet membranes, but it potentiated platelet aggregation induced by ADP with an EC50 of 1.5 microM. PIC also inhibited epinephrine-induced aggregation, with an IC50 of 5.1 microM. Thus, PIC behaves as a partial agonist in a human platelet aggregation assay. [125I]PIC binds to the alpha 2B-AR in NG-10815 cell membranes with a Kd of 0.5 +/- 0.1 nM. [125I]PIC should prove useful in binding assays involving tissues with a low receptor density or in small tissue samples and in studies of cloned and expressed alpha 2-AR.
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PMID:p-[125I]iodoclonidine is a partial agonist at the alpha 2-adrenergic receptor. 197 94

Intracellular Ca2+ ([Ca2+]i) is thought to act as a second messenger of transmembrane signalling systems. However, no measurement of [Ca2+]i has been made in intact epidermal keratinocytes. We have developed a method for measuring [Ca2+]i in human keratinocytes from pure epidermal sheet by the application of digital imaging fluorescence microscopy with the use of Fura 2-AM. Normal human pure epidermal sheets were obtained by dispase treatment. Epinephrine and salbutamol induced transient [Ca2+]i increases. Propranolol, a beta-antagonist, inhibited this response, while prazosin and yohimbine (alpha 1- and alpha 2-antagonists, respectively) did not affect the response. Histamine and adenosine, also receptor agonists of the epidermal adenylate cyclase system, induced a similar [Ca2+]i increase, as did forskolin, a direct activator of adenylate cyclase. These data coincide with those previously presented for cultured human epidermal keratinocytes, and reveal that adenylate cyclase activation induces an increase of [Ca2+]i in intact epidermal cells. This technique enables the kinetics of [Ca2+]i in various skin disorders to be investigated.
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PMID:Adenylate cyclase induces intracellular Ca2+ increase in single human epidermal keratinocytes of the epidermal sheet as measured by digital imaging microscopy using Fura 2-AM. 206 17

Epinephrine, histamine and prostaglandin E1 stimulated adenylate cyclase activity in lung membranes and their stimulation of the enzyme activity was completely blocked by propranolol, metiamide and indomethacin, respectively. A partially-purified activator from the adult rat lung also enhanced adenylate cyclase activity in membranes. However, stimulation of adenylate cyclase by the rat lung activator was not abolished by the above receptor antagonists. Further, epinephrine, NaF and Gpp(NH)p stimulated adenylate cyclase activity rather readily, whereas stimulation of the enzyme activity by the lung activator was evident after an initial lag phase of 10 min. Also, the lung activator produced additive activation of adenylate cyclase with epinephrine, NaF and Gpp(NH)p. These results indicate that the lung activator potentiates adenylate cyclase activity in membranes by a mechanism independent from those known for epinephrine, NaF and Gpp(NH)p. Incubation of lung membranes for 30 min at 40 degrees C resulted in a loss of adenylate cyclase activation by NaF and Gpp(NH)p. Addition of the released proteins to the heat-treated membranes did not restore the enzyme response to these agonists. However, heat treatment of lung membranes in the presence of 2-mercaptoethanol or dithiothreitol prevented the loss of adenylate cyclase response to NaF and Gpp(NH)p. N-ethylmaleimide abolished adenylate cyclase activation by epinephrine, NaF, Gpp(NH)p and the lung activator. These results indicate that the sulfhydryl groups are important for adenylate cyclase function in rat lung membranes.
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PMID:Mechanism of adenylate cyclase activation by the rat lung cytoplasmic factors. 207 93


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