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At least 307 records · Page 17Linked to original sources
PubMed2004

Human adipose angiotensinogen gene expression and secretion are stimulated by cyclic AMP via increased DNA cyclic AMP responsive element binding activity.

Components of the adipose renin-angiotensin system (RAS) have been suggested as providing a potential path-way linking obesity to hypertension. In adipose cells, the biological responses to beta-adrenergic stimulation are mediated by an increase in intracellular cAMP. Because an association exists among body fat mass, hypertension, and increased sympathetic stimulation, we examined the influence of cAMP on angiotensinogen (ATG) expression and secretion in human adipose tissue and in parallel we studied the DNA binding activity of CRE transcriptional factors. A 24 h exposure to the cAMP analog 8Br-cAMP resulted in significant increases in ATG mRNA levels (+176+/-60%) and protein secretion (+40+/-27%). The ability of 8Br-cAMP to promote ATG gene expression was unaltered by H89, a protein kinase A inhibitor, because H89 per se was found to stimulate ATG mRNA levels and protein secretion. Moreover, 8Br-cAMP stimulated the specific CRE DNA binding activity (+115+/-14%) in human adipocyte nuclear extracts as assessed by electrophoretic mobility shift assays. These results indicate that cAMP upregulates in vitro ATG expression and secretion in human adipose tissue and that the induction in ATG mRNA levels appears to result, at least in part, from positive effects on the DNA binding activity of CRE transcription factors. Further studies are required to determine whether this regulatory pathway is activated in human obesity and to elucidate the importance of adipose ATG to the elevated blood pressure observed in this pathological state.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMedDate not supplied

[Effect of cortisol on adenylate cyclase and 3',5'-AMP phosphodiesterase activity and 3',5'-AMP concentration in tissues and biological fluids in experimental atherosclerosis].

Administration of hydrocortisone into healthy rabbits activated adenilate cyclase and phosphodiesterase in liver tissue; activity of the enzymes was normalized within 5 days after the treatment. The hormone, administered into animals with experimental cholesterol-induced atherosclerosis, caused an activation of adenilate cyclase and inhibition of phosphodiesterase; due to the phenomenon more distinct and long-term increase in cAMP concentration was observed in kidney, liver and fatty tissues. Concentration of cAMP exceeded considerably its initial content in the tissues within 5 days after the hydrocortisone administration. Hydrocortisone inhibited the adenilate cyclase system activity in adrenal cortex of experimental and control animals at early period of the experiment. In health rabbits content of cAMP was increased in adrenal cortex within 5 days after the hormone administration. As the similar effect was not found in animals with experimental atherosclerosis these data suggest that the hypophysis-adrenal cortex system under the experimental conditions studied was inhibited.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1978

Possible participation of glucocorticoid in elevation of 3',5'-cyclic AMP levels through inhibition of cyclic AMP phosphodiesterase.

Administration of prednisolone and cholate to rats elevated levels of cAMP (adenosine 3',5'-cyclic monophosphate) by 1.5- to 2.0-fold. Compounds such as prednisolone, hydrocortisone, cholate, and deoxycholate were found to be potent inhibitors of partially purified cAMP phosphodiesterase prepared from rat liver. Kinetic analysis showed that the prednisolone inhibition was noncompetitive with a Ki of 8.9 x 10(-4) M. These results suggest that in addition to increasing DNA-dependent RNA polymerase activity in vivo, a large application of glucocorticoid may incur elevation of intracellular cAMP levels.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Arginine substituted for leucine at position 195 produces a cyclic AMP-independent form of the Escherichia coli cyclic AMP receptor protein.

Mutant forms (CRP*) of the Escherichia coli cAMP receptor protein (CRP) that activate CRP-dependent promoters in the absence of the normal allosteric effector (cAMP) have been described. A previous report (Harman, J. G., McKenney, K., and Peterkofsky, A. (1986) J. Biol. Chem. 261, 16332-16339) detailed the properties of three CRP* mutant proteins. One protein, 220 CRP, has amino acid substitutions at positions 127 and 170 and low CRP* activity in vivo. A second protein, 222 CRP, has the amino acid substitutions present in 220 CRP and a third substitution (arginine for leucine) at position 195. 222 CRP has high CRP* activity in vivo and high apparent affinity for lacP DNA relative to the 220 CRP in vitro. In this report, we evaluate the effect of a single amino acid substitution at position 195 (leucine to arginine) on CRP activity both in vivo and in vitro. Cells (cya delta crp delta/pJH8crpR195) containing R195 CRP were found to exhibit a CRP* phenotype, expressing a variety of CRP-dependent genes in the absence of added cAMP. R195 CRP exhibited both CRP* activity in vitro and increased apparent affinity for cAMP relative to wild-type CRP. CRP titration experiments performed using an in vitro lac transcription system suggest that the isolated substitution of arginine at position 195 does not confer on CRP the high lacP affinity that distinguishes the 220 and 222 forms of CRP. These findings lead us to the conclusion that the effects of multiple mutations in CRP can be both cumulative and interactive.

Arginine↗
PubMed1985

Identification and cyclic AMP-induced modification of the cyclic AMP receptor in Dictyostelium discoideum.

We have recently identified a cell surface cAMP-binding protein by specific photoaffinity labeling of intact Dictyostelium discoideum cells with 8-N3-[32P] cAMP. The major photolabeled protein appears as a doublet (Mr = 40,000-43,000) in sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography. In this study, the doublet is shown to have the characteristics of the cAMP receptor responsible for chemotaxis and cAMP signaling. Both specific photoaffinity labeling of the doublet and binding of 8-N3-[32P]cAMP are saturable (KD = 0.3 microM), the levels of both peak at 5 h, and both are inhibited by cAMP and several cAMP analogs in the same order of potency and with K1 values similar to those measured for inhibition of [3H]cAMP binding. When cAMP-binding activity was partially purified (40-fold) and then photoaffinity labeled, the same bands (Mr = 40,000-43,000) were observed. The relative intensities of the upper and lower bands of the doublet alternated at the same frequency as the spontaneous oscillations in cAMP synthesis. When oscillations were suppressed, the lower band of the doublet predominated. Following addition of cAMP, the relative intensity gradually shifted to the upper band. When cAMP was removed, there was a gradual restoration of the lower band form. We propose that the lower band form of the receptor activates chemotaxis and cAMP signaling and that the upper band form does not. This reversible receptor modification may then be the mechanism of adaptation, the process by which the physiological responses cease to be stimulated by persistent cAMP. Several developmentally regulated genes in D. discoideum have been reported to be induced or suppressed by pulses of cAMP (adaptive regulation) and others by continuous cAMP (nonadaptive regulation). These observations may be explained by the receptor modification reported here if the two forms of the receptor, which bind cAMP with the same affinity, independently influence gene expression.

Affinity Labels↗
PubMed1987

A monoclonal antibody that inhibits cyclic AMP binding by the Escherichia coli cyclic AMP receptor protein.

The monoclonal antibody (mAb) 64D1 was found to inhibit cAMP binding by the cAMP receptor protein (CRP) from Escherichia coli (Li, X.-M., and Krakow, J. S. (1985) J. Biol. Chem. 260, 4378-4383). CRP is relatively resistant to attack by the Staphylococcus aureus V8 protease, chymotrypsin, trypsin, and subtilisin whereas both mAb 64D1-CRP and cAMP-CRP are attacked by these proteases yielding N-terminal core fragments. The fragment patterns resulting from proteolysis of mAb 64D1-CRP and cAMP-CRP differ indicating that the CRP in each complex is in a different conformation. The data presented indicate that the preferred conformation of the antigenic site for mAb 64D1 is present in unliganded CRP. Binding of mAb 64D1 to CRP is inhibited at high cAMP concentration. Formation of a stable cAMP-CRP-lac P+-RNA polymerase open promoter complex resistant to dissociation by mAb 64D1 occurs at a much lower cAMP concentration. The observed increase in resistance to mAb 64D1 may reflect a possible conformational change in CRP effected by contact with RNA polymerase in the open promoter complex.

Antibodies, Monoclonal↗
PubMed1994

Arg-242 is necessary for allosteric coupling of cyclic AMP-binding sites A and B of RI subunit of cyclic AMP-dependent protein kinase.

The functional consequences of Arg-242 to Ser or Lys substitutions in type I alpha regulatory (R) subunits of cAMP-dependent protein kinase were analyzed by using recombinant murine R subunits expressed in Escherichia coli. These mutations arose in cAMP-resistant mutants to S49 mouse lymphoma cells and were shown previously to inhibit cAMP binding to site A, the more amino-terminal of two intrachain cAMP-binding sites. Binding of cAMP to site A of the mutant R subunits could be detected by cAMP-dependent quenching of endogenous tryptophan fluorescence, [3H]cAMP binding to mutant R subunits with the Arg-242 mutations without or with an inactivating mutation in site B, or biphasic dissociation of [3H]cAMP from the mutant subunits at low temperature. The mutations reduced site A affinities by about 25-fold, and the reductions were attributable to accelerated rates of cAMP dissociation. While the presence of cAMP in site A retards dissociation of [3H]cAMP from site B of wild-type R subunits, saturation of site A had little or no effect on dissociation of [3H]cAMP from site B of the mutant subunits. The predominant effect of the mutations, therefore, was loss of allosteric coupling between the two cAMP-binding sites. A second allosteric interaction, that coupling occupation of site A with a reduced affinity of R for catalytic subunit, was inhibited only partially by these mutations at Arg-242.

Allosteric Regulation↗
PubMed1988

Cyclic AMP-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212.

Possible cAMP-dependent and cAMP-independent mechanisms of action for the cardiac effects of OPC-8212, a novel piperazinyl-quinolinone derivative, were evaluated. OPC-8212 was tested for in vitro potency as an inhibitor of soluble bovine cardiac phosphodiesterases using a rapid isolation and assay method involving monoclonal antibodies that distinguish among isozymes. The drug was selective for a low-Km, cGMP-inhibited phosphodiesterase (CGI-PDE) with an IC50 (half-maximal inhibition concentration) of 7.4 mumol/l when measured at a substrate level of 0.35 mumol/l cAMP. Under the conditions used, sulfolane, the solvent for OPC-8212, did not affect CGI-PDE activity. In electrophysiological measurements, OPC-8212 prolonged the action potential duration in canine Purkinje strand preparations up to 148% (APD90) at 10 mumol/l. Concomitantly, OPC-8212 produced a 100% increase in developed force. Both prolongation of the action potential duration and the positive inotropic effect were readily reversed after exposure to tetrodotoxin, 3 mumol/l. Using Na-selective microelectrodes, intracellular Na+ ion activity increased 225% upon exposure to 10 mumol/l OPC-8212. OPC-8212 represents a novel type of positive inotropic agent, possessing both cAMP-dependent (selective PDE isozyme inhibition) and cAMP-independent (activation of intracellular Na+) mechanism of action.

Action Potentials↗