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)

Three types of adrenergic receptors, beta, alpha-1, and alpha-2, were identified in human adipocytes, isolated from properitoneal adipose tissue, using both the binding of radioactive ligands and the effects of adrenergic agents on receptor-specific biochemical responses. Adrenergic binding studies showed the following results: [(3)H]dihydroalprenolol binding (beta adrenergic) B(max) 280 fmol/mg protein, K(D) 0.38 nM; [(3)H]para-aminoclonidine binding (alpha-2 adrenergic) B(max) 166 fmol/mg protein, K(D) 0.49 nM; [(3)H]WB 4101 binding (alpha-1 adrenergic) B(max) 303 fmol/mg protein, K(D) 0.86 nM. In adipocytes from subcutaneous adipose tissue, [(3)H]dihydroergocryptine binding indicated the presence of alpha-2 but not alpha-1 receptors. Beta and alpha-2 adrenergic receptors appeared to be positively and negatively coupled to adenylate cyclase, respectively. Cells or cell membranes were incubated with epinephrine (10 muM) alone and in combination with the antagonists yohimbine (alpha-2) and prazosin (alpha-1). Epinephrine alone prompted a modest increase in adenylate cyclase activity, cyclic AMP, and glycerol release, an index of lipolysis. Yohimbine (0.1 muM) greatly enhanced these actions whereas prazosin was without effect. The beta agonist, isoproterenol, stimulated glycerol release, whereas the alpha-2 agonist, clonidine, inhibited lipolysis and cyclic AMP accumulation. To assess further alpha-1 receptors, cells were incubated with [(32)P]phosphate and epinephrine (10 muM) alone and in combination with prazosin and yohimbine. Epinephrine alone caused a three- to fourfold increase in (32)P incorporation into phosphatidylinositol. Prazosin (0.1 muM) blocked this action whereas yohimbine (0.1 muM) was without effect. Thus, in a homogeneous cell preparation, the human adipocyte appears to have three different adrenergic receptors, each of which is coupled to a distinct biochemical response.
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PMID:Pharmacological characterizations of adrenergic receptors in human adipocytes. 625 62

A specific and sensitive assay for determining the binding of adrenocorticotropin (ACTH) to isolated rat adipocytes has been developed and utilized to study the effect of glucocorticoids on ACTH receptor. Measurement of the binding of tritiated ACTH (spec. act. 90 Ci/mmol) to adipocytes isolated from normal, adrenalectomized, and adrenalectomized dexamethasone-treated rats indicated that there are no differences among these three populations in either the magnitude or the affinity of the binding reaction. The binding interaction was found to be of high affinity (Kd = 5.23 + 1.92 . 10(-9) M and paralleled closely the stimulation of lipolysis (Km = 2.09 +/- 0.35 . 10(-9) M. About 16,300 receptors were calculated to be presented per adipocyte. Hormone-induced cyclic 3',5'-adenosine monophosphate production remained intact after adrenalectomy, thereby confirming that receptors are not lost during steroid deprivation. The lipolytic response did, however, become less sensitive to both ACTH and epinephrine following adrenalectomy. Pre-treatment of adrenalectomized rats with dexamethasone resulted in an increase in basal and hormone-stimulated levels of cyclic AMP and glycerol production to super-normal values. In adipocyte ghost preparations, ACTH and epinephrine sensitive adenylate cyclase activity was not decreased by adrenalectomy and dexamethasone administration did not result in a selective enhancement of ACTH sensitive adenylate cyclase activity. Our results indicate that glucocorticoids do not cause their permissive effects by specific regulation of the ACTH receptor on the adipocyte.
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PMID:The effect of glucocorticoids on adipocyte corticotropin receptors and adipocyte responses. 626 Feb 29

beta-adrenergic binding ([3H]dihydroalprenolol), adenylate cyclase activity, and cAMP accumulation were measured in adipocytes to investigate whether the mechanism of decreased hormone-sensitive lipolytic response with age was mediated through membrane-associated events. The dose of epinephrine required for half maximal stimulation of glycerol release (ED50) was significantly lower in 2-month-old rats (0.8 +/- 0.2 microM)than in matur (6- and 12-month-old) rats (5.2 +/- 1.5 and 6.2 +/- 1.5 microM, respectively). In 24-month-old rats the ED50 (0.7 +/- 0.2 microM) was less than in mature rats. maximum rates of hormone-stimulated glycerol release (per 10(6) cells) was highest in the two mature groups and decreased by 50% in the old rats (P less than 0.01). Lipolytic changes were independent of cell size. beta-adreanergic raeceptor number (50-90 thousand sites/call) and affinity (KD 4-5 nM) were the same in each age group. ED50 and maximum level of hormone-stimulated adenylatae cyclase activity did not change with age. The ED50 of cAMP accumulation of young rats was 3 +/- 5 microM compared with 24 +/- 4 and 25 +/- 5 microM in 6- and 12-month-old rats, respectively. In old rats, the ED50 of cAMP accumulation was 2 +/- 1 microM (P less than 0.001 compared with mature rats). Maximally stimulated cAMP levels were the same in old and mature animals. Phosphodiesterase activity in the presence and absence of 10(-5) M isoproterenol did not change with age. The results suggest that age-related decrease of epinephrine-sensitive lipolysis in old rats may be due to alterations of the lipolytic pathway distal to the receptor-adenylate cyclase complex and the generation of cyclic AMP.
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PMID:Mechanism of the age-related decrease of epinephrine-stimulated lipolysis in isolated rat adipocytes: beta-adrenergic receptor binding, adenylate cyclase activity, and cyclic AMP accumulation. 626 27

We examined the process of desensitization in the isolated rat adipocyte. When adipocytes were exposed to isoproterenol (10(-7) or 10(-5) M) or ACTH (250 mU/ml) for 2 h, there was a marked decline of as much as 77% in response upon restimulation by hormone, as measured by glycerol release or cAMP levels. This desensitization was both heterologous as well as homologous. Thus, for example, exposure of adipocytes to isoproterenol desensitized them to further stimulation by both isoproterenol and ACTH. The process was time dependent, since augmentation rather than desensitization was seen if cells were initially exposed to hormone for 30 min rather than 2 h. No desensitization was seen when the cells were restimulated with the nonhormonal lipolytic agent dibutyryl cAP. Similarly, no desensitization was seen when cells were first exposed to dibutyryl cAMP and then restimulated with hormone. We draw the following conclusions. First, desensitization in the adipocyte is a time- and dose-dependent process that is specific for adenylate cyclase-activating hormones. Secondly, the process is heterologous as well as homologous. Initial exposure of the adipocyte to one adenylate cyclase-activating hormone reduces its adenylate cyclase or lipolytic response upon reexposure to either the same or a different adenylate cyclase-activating hormone. Finally, the reduction in the end result of hormone activation, lipolysis, is due in part to a decrease in inducible levels of cAMP.
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PMID:Hormone-induced homologous and heterologous desensitization in the rat adipocyte. 626 36

The interaction of FSH with membrane receptors from rat and calf testis has been studied in some detail. The FSH receptor has been solubilized through use of the nonionic detergent Triton X-100 and highly purified by affinity chromatography on Affigel-10 coupled to ovine FSH. Hormone binding activity of the solubilized receptor has been preserved for extended periods through use of the structure-stabilizing agent glycerol. Other components of the FSH testes receptor system including the guanyl nucleotide binding protein and adenylate cyclase have been solubilized by nonionic detergents and also found to be stabilized by glycerol. FSH binding activity has been observed in testes cytosol and represents a putative class of receptors prepared from testes in the absence of detergent. The concentration of this buffer-soluble component decreased with age and increased concomitantly with loss of membrane receptors consequent to their down-regulation after administration of exogenous FSH. Phospholipids seem involved in the interaction of FSH with membrane-bound, detergent-solubilized, and buffer-soluble FSH binding activity. Phospholipids may maintain or stabilize a particular receptor conformation necessary for interaction with the hormone. A specific role for GTP seems indicated in regulation of FSH-stimulated adenylate cyclase activity in immature rat testis. Follitropin binding to testes receptor appears modulated by a variety of factors present in serum, testes extracts, follicular fluid, and seminal plasma, which are poorly understood at present. Inhibition of FSH binding by seminal plasma best-fit by a model proposing two hormone binding sites per receptor molecule, where binding to one site decreases the affinity of the other site for FSH. As a result of studies in this and other laboratories, the molecular endocrinology of FSH interaction with testis receptors is becoming increasingly understood.
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PMID:Biochemical properties of the testicular follitropin-receptor system. 628 87

The polyamine biosynthetic enzymes, ornithine decarboxylase (EC 4.1.1.17) (ODC) and arginine decarboxylase (EC 4.1.1.19) (ADC), are negatively controlled by cAMP in Escherichia coli. The specific activities of ODC and ADC were determined in crude extracts prepared from E. coli strains carrying a mutation in the adenylate cyclase (EC 4.6.1.1) structural gene (cya) and wildtype strains. These strains were cultured on various carbon sources in the presence and absence of cAMP. In wild-type strains, ODC and ADC activities were diminished in cells grown on glycerol compared to these strains cultured on glucose. When cya strains were grown on glucose or glycerol, ODC and ADC activities were the same. Addition of 1 mM cAMP to glucose-based medium repressed ODC and ADC activities in both the wild-type and cya strains. Furthermore, cAMP exerts its negative control through the cAMP receptor protein, since strains carrying a mutation in the crp structural gene fail to repress ODC and ADC activities in response to increased cAMP obtained by carbon source manipulation or cAMP supplementation of the growth medium. This evidence suggests that negative control of ODC and ADC by cAMP occurs at the level of transcription.
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PMID:Negative control of ornithine decarboxylase and arginine decarboxylase by adenosine-3':5'-cyclic monophosphate in Escherichia coli. 629 Aug 46

To test the hypothesis that alterations of adipocyte beta-adrenergic receptors provide a molecular mechanism for enhanced catecholamine-stimulated lipolysis in physically trained animals, we studied adipocytes derived from rats subjected to 14 wk of swimming and from sedentary controls. Peak glycerol release and peak adenylate cyclase activity in response to epinephrine were increased in swimmers to 255% (P less than 0.01) and 156% (P less than 0.01) of control values, respectively, but neither basal glycerol release, basal cyclase activity, NaF-stimulated cyclase activity, beta-receptor number, nor receptor affinity for [3H]dihydroalprenolol were altered. Epinephrine-stimulated adenylate cyclase activity remained increased in adipocytes from swimmers in the presence of theophylline or adenosine. In the absence of exogenous guanine nucleotide, we observed no differences in the dissociation constants for either the high-affinity (KD = 0.025 microM) or the low-affinity (KL = 11 microM) classes of binding sites for (-)-epinephrine, but the proportion of high-affinity sites was greater in membrane preparations from swimmers than from controls (74 vs. 42%; P less than 0.01). We conclude that receptor-cyclase coupling is enhanced in adipocytes from exercising rats, perhaps due to an improved ability of adrenergic agonists to form the guanine nucleotide reversible high-affinity agonist-receptor complex.
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PMID:Enhanced receptor-cyclase coupling and augmented catecholamine-stimulated lipolysis in exercising rats. 629 2

The adenylate cyclase gene of Escherichia coli has been cloned on the plasmid vector pBR325. The hybrid plasmid pTH4 obtained has a molecular weight of 6,4 megadalton and represents pBR325 plasmid with the insertion of 2,8 megadalton in the Pst1 site. The cya mutant bacteria carrying pTH4 recover their ability to utilize mannitol, lactose and other carbohydrates as carbon sources, and lose this ability again in the case of rare spontaneous excision of the DNA insert from the Pst1 site. The phenotypical effect of pTH4 in cya mutants can be only seen in the crp+ genome. The strains carrying pTH4 are also characterized by the ability of beta-galactosidase induction under conditions of catabolite repression. Besides, the bacteria containing cya+ allele on the plasmid do not grow on glycerol, which seems to be caused by toxic concentrations of methylglyoxal formed as a result of the increased intracellular level of cyclic adenosine monophosphate.
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PMID:[Cloning of the adenylate cyclase gene of Escherichia coli K-12]. 629 20

The effects of epinephrine and electrical stimulation on lipolysis in the skeletal muscles of lean, and obese-diabetic (db/db) mice were studied using the perfused mouse hindquarter preparation. The rate of glycerol release from the obese mouse preparation was two times that of their lean littermates. Epinephrine sensitivity in the db/db mice was reduced only with respect to lipolytic activation, but was unaltered with respect to tissue cyclic AMP elevation and glycogen phosphorylase activation. Electrical stimulation caused a prompt increase in lactate production in both lean and obese mice and elevated glycerol release only in the obese mice. Glycerol release was also increased in the lean mice by stimulating at voltages exceeding 10 volts. Cyclic AMP levels were unaffected by electrical stimulation. Omission of calcium from the perfusion medium severely blunted lipolytic activation by electrical stimulation, which could be restored by calcium readdition. These results suggest that an impairment in lipolytic activation by epinephrine distal to activation of adenylate cyclase exists in the skeletal muscle of young db/db mice. Despite of this impairment, however, lipolysis in the obese mouse muscle was more sensitive to activation by electrical stimulation through a mechanism unrelated to changes in cyclic AMP, but is dependent on extracellular calcium.
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PMID:Activation of lipolysis by epinephrine and electrical stimulation in the perfused hindquarters of lean and obese-diabetic (db/db) mice. 630 33

An Escherichia coli strain which overproduces the lactose permease was used to investigate the mechanism of allosteric regulation of this permease and those specific for melibiose, glycerol, and maltose by the phosphoenolpyruvate-sugar phosphotransferase system (PTS). Thio-beta-digalactoside, a high affinity substrate of the lactose permease, released the glycerol and maltose permeases from inhibition by methyl-alpha-d-glucoside. Resumption of glycerol uptake occurred immediately upon addition of the galactoside. The effect was not observed in a strain which lacked or contained normal levels of the lactose permease, but growth of wild-type E. coli in the presence of isopropyl-beta-thiogalactoside plus cyclic AMP resulted in enhanced synthesis of the lactose permease so that galactosides relieved inhibition of glycerol uptake. Thiodigalactoside also relieved the inhibition of glycerol uptake caused by the presence of other PTS substrates such as fructose, mannitol, glucose, 2-deoxyglucose, and 5-thioglucose. Inhibition of adenylate cyclase activity by methyl-alpha-glucoside was also relieved by thiodigalactoside in E. coli T52RT provided that the lactose permease protein was induced to high levels. Cooperative binding of sugar and enzyme III(Glc) to the melibiose permease in Salmonella typhimurium was demonstrated, but no cooperativity was noted with the glycerol and maltose permeases. These results are consistent with a mechanism of PTS-mediated regulation of the lactose and melibiose permeases involving a fixed number of allosteric regulatory proteins (enzyme III(Glc)) which may be titrated by the increased number of substrate-activated permease proteins. This work suggests that the cooperativity in the binding of sugar substrate and enzyme III(Glc) to the permease, demonstrated previously in in vitro experiments, has mechanistic significance in vivo. It substantiates the conclusion that PTS-mediated regulation of non-PTS permease activities involves direct allosteric interaction between the permeases and enzyme III(Glc), the postulated regulatory protein of the PTS.
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PMID:Cooperative binding of the sugar substrates and allosteric regulatory protein (enzyme IIIGlc of the phosphotransferase system) to the lactose and melibiose permeases in Escherichia coli and Salmonella typhimurium. 635 Feb 68


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