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 epididymal tubules maintained in organ culture for 3 days respond to the addition of androgens to the culture media (testosterone and dihydrotestosterone 1 x 10-minus 5 m and 1 x 10-minus 7 m) with an increased incorporation of amino acids into acid-insoluble material. Significant androgenic stimulation is observed only 24 h after addition of hormone, while an inhibitory effect is found at earlier periods. The stimulation seems to be specifically produced by androgens; it is blocked by cyproterone acetate and is not elicited by oestradiol-17beta or corticosterone. The process appears to involve RNA synthesis since actinomycin D suppresses the stimulatory effect of androgen. Evidence suggests that cAMP production is not a primordial step in the response to androgen since dibutyryl cAMP did not mimick the androgenic effect, theophylline did not potentiate the response and alpha,beta-methylene ATP, which competitively inhibits adenyl cyclase, failed to alter the androgenic effect. Radioactive testosterone and dihydrotestosterone added to the culture media showed a preferential intranuclear localization as well as extensive metabolism. DHT was found to be the principal intranuclear steroid.
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PMID:The influence of androgens on protein synthesis by cultured rat epididymal tubules. 16 37

The present studies were undertaken to characterize further the role of serotonin (5-HT) in the regulation of the norepinephrine (NE) beta adrenoceptor coupled adenylate cyclase system in the rat cortex. Although 5-HT in vitro did not influence maximum binding and Kd values of [3H]dihydroalprenolol binding or the IC50 value for isoproterenol as estimated from competition binding curves in cortical tissue from control animals, 5-HT abolished the increase in beta adrenoceptor number and the marked elevation of the IC50 value for isoproterenol in cortical membrane preparations after selective lesions with 5,7-dihydroxytryptamine (5,7-DHT). Nonlinear regression analysis of competition binding curves revealed that the increase in the maximum binding of beta adrenoceptors after 5,7-DHT is due exclusively to an increase in beta adrenoceptors in the agonist low affinity conformation and that it is this receptor population that is reduced by nanomolar concentrations of 5-HT. The increase in the density of beta adrenoceptors in the low affinity conformation occurred approximately 11 days after the lesions and remained elevated throughout the experimental period of 28 days. Ritanserin in a dose that virtually abolished 5-HT2 receptor binding in cortex did not mimic the effect of 5,7-DHT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The serotonin/norepinephrine-link in brain. II. Role of serotonin in the regulation of beta adrenoceptors in the low agonist affinity conformation. 282 64

The effects of subchronic administration of various psychotropic agents on the density of 5HT 2 receptor binding sites in rat cerebral cortex were investigated. In addition to antidepressant agents, some neuroleptic drugs including chlorpromazine (CPZ), spiperon, and cisflupentixol reduced the numbers of 5HT-2 receptor binding sites after 21 days treatment. The more selective D-2 antagonist haloperidol and sulpiride were totally ineffective in this regard. Anxiolytic agents, benzodiazepine derivatives were also ineffective. Central 5, 7-DHT-induced lesion of 5HT neurons demonstrated that intact 5HT neurons were not required for the reduction of 5HT-2 receptors by desipramine (DMI). Co-administration of DMI and alpha-2 antagonist yohimbine (YOH) produced down-regulation of 5HT-2 receptors within 3 days, whereas each agent alone did not produce such effect. The effect of 3-day treatment with mianserin (MIA, alpha-2 and 5HT-2 antagonist) alone and DMI plus YOH producing 5HT-2 down-regulation, were not prevented by the pretreatment with DSP-4 which selectively destroyed NE neurons. These results suggest that the synaptic availability of 5HT may not be required for DMI-induced down regulation of 5HT-2 receptor binding sites, and the mechanisms mediated through postsynaptic alpha-2 and 5HT-2 receptors are important factors in the regulation of 5HT-2 receptor density. Evidence suggests that the 5HT-1 receptor site is functionally linked to adenylate cyclase in the brain, but a biochemical effector system which is linked to the 5HT-2 receptor site has not been found. The metabolism of inositol phospholipids in response to 5HT was, therefore, investigated in human platelets using sensitive radioisotopic method of Berridge (1983). In platelets prelabeled with 3H-myo-inositol, in Ca++ free HEPES buffer containing 10 mM LiCl, 5HT caused a dose-dependent accumulation of inositol-1-phosphate (IP1) during 15 min incubation. A maximal increase in IP1 formation was observed at 30 microM of 5HT and the EC50 value was 4 microM. Ketanserin, a selective 5HT-2 receptor antagonist was a potent inhibitor of 5HT-stimulated IP1 accumulation, with a Ki value of 12 nM, but a selective 5HT-1 antagonist, (-)-propranolol (1 microM) failed to block the 5HT response. These results indicate that 5HT is activating 5HT-2 receptors, but not 5HT-1 in human platelets. CPZ and imipramine inhibited 5HT-stimulated IP1 accumulation, with Ki values of 124 nM and 2.56 microM, respectively.
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PMID:[Mechanism of action of various psychotropic agents on serotonin receptors and the transmembrane signal control]. 361 34

1. A comparison was made of the binding of 5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one) and cyclic AMP in the rat prostate gland. Distinct binding mechanisms exist for these compounds, and cyclic AMP cannot serve as a competitor for the 5alpha-dihydrotestosterone-binding sites and vice versa. In contrast with the results obtained with 5alpha-dihydrotestosterone, very small amounts of cyclic AMP are retained in nuclear chromatin and the overall binding of this cyclic nucleotide is not markedly affected by castration. 2. Androgenic stimulation does not lead to major increases in the adenylate cyclase activities associated with any subcellular fraction of the prostate gland. Accordingly, changes in the concentration of cyclic AMP in the prostate gland after hormonal treatment are likely to be small, but these were not measured directly. 3. When administered to whole animals in vivo, small amounts of non-degraded cyclic AMP are found in the prostate gland but sufficient to promote an activation of certain carbohydrate-metabolizing enzymes in the cell supernatant fraction. The stimulatory effects of cyclic AMP were not evident with cytoplasmic enzymes engaged in polyamine synthesis or nuclear RNA polymerases. These latter enzymes were stimulated solely by the administration of testosterone. 4. By making use of antiandrogens, a distinction can be drawn between the biochemical responses attributable to the binding of 5alpha-dihydrotestosterone but not of cyclic AMP. Evidence is presented to suggest that the stimulation of RNA polymerase, ornithine decarboxylase and S-adenosyl-l-methionine decarboxylase is a consequence of the selective binding of 5alpha-dihydrotestosterone. Only the stimulation of glucose 6-phosphate dehydrogenase can be attributed to cyclic AMP or other metabolites of testosterone. 5. Overall, this study indicates that the formation of cyclic AMP is not a major feature of the androgenic response and affects only a restricted number of biochemical processes. Certainly, cyclic AMP cannot be considered as interchangeable with testosterone and its metabolites in the control of the function of the prostate gland. This difference is additionally emphasized by the failure of cyclic AMP to restore the morphology of the prostate gland in castrated animals; morphological restoration only follows the administration of androgens.
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PMID:A reappraisal of the effects of adenosine 3':5'-cyclic monophosphate on the function and morphology of the rat prostate gland. 435 82

To date, it is unknown whether intrapancreatic serotonergic nerves can influence pancreatic somatostatin (SS) content and the SS receptor/effector system in the exocrine pancreas. In this study, the intrapancreatic serotonergic nerves were chemically ablated by injecting a specific serotonin (5-HT) neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the substance of the gland. Three days after the injection, the 5-HT-like immunoreactive levels in the pancreas were reduced by more than 85% whereas somatostatin-like immunoreactive levels had increased (86%). The number of SS receptors in the pancreatic acinar cell membranes of the 5,7-DHT-treated rats was also increased (72%). No significant differences were seen in basal or forskolin-stimulated adenylate cyclase (AC) enzyme activities in the control and the 5,7-DHT-treated groups. In spite of the increase in the number of SS receptors in the pancreatic acinar cell membranes of 5,7-DHT-treated rats, SS caused a significantly lower inhibition of AC activity in these membranes. This finding is related to the observed decrease of a 41 kD pertussis toxin-sensitive substrate, presumably the alpha i subunit of the guanine nucleotide inhibitory protein, in pancreatic acinar cell membranes 3 days after intrapancreatic 5,7-DHT administration when compared with the corresponding controls. The functions of pancreatic serotonergic nerves seem to be associated with enteropancreatic communication. These data together with the present results suggest that pancreatic SS content and the SS receptor/effector system in the exocrine pancreas may be regulated by enteropancreatic serotonergic nerve fibers and may participate in enteropancreatic reflexes.
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PMID:Pancreatic changes in somatostatin content and receptor/effector system after intrapancreatic injection of 5,7-dihydroxytryptamine. 761 56

In plasma, most steroid hormones are bound and transported by the specific binding protein, testosterone-estradiol-binding globulin (TeBG). For years, it was believed that the only function of this protein was to regulate the concentration of free steroids in plasma. However, a number of reports have provided evidence for the presence of specific TeBG receptors on plasma membranes. Furthermore, the interaction of TeBG with its receptor was shown to be inhibited when steroids are bound to TeBG, suggesting that TeBG is an allosteric protein. The purpose of this manuscript is to review the evidence that androgen-binding proteins bind to membrane receptors, and, in some cells, this binding stimulates cAMP accumulation, and transfer TeBG/ABP into tissue as a consequence of receptor mediated endocytosis. Recent studies from our laboratories have demonstrated binding and uptake of TeBG by MCF-7 breast cancer cells. The interaction of unligated rabbit TeBG with membranes from MCF-7 cells resulted in a time and concentration-dependent increase in adenylate cyclase activity. The TeBG alone also had a reproducible effect on intact cells by increasing cAMP accumulation by 30-35%. The addition of DHT to cells, after TeBG has been allowed to bind, resulted in increases in cAMP of greater than 4-fold. This effect was not blocked by antiandrogens. These data support the hypothesis that extracellular SHBG is a regulator of cellular function through a membrane receptor that is coupled to adenylate cyclase.
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PMID:Receptors for androgen-binding proteins: internalization and intracellular signalling. 762 10

The present study revealed the effect of prolactin (PRL) and sex steroid hormones on production of prostatic acid phosphatase (PAP) of the immature rat prostatic epithelial cells in serum-free medium. The results showed that PRL significantly stimulated synthesis and secretion of PAP, but failed to synergize with dihydrotestosterone or estradiol. Dihydrotestosterone or estradiol alone did not promote PAP production. Studies on the mechanism of PRL action indicated that adenyl cyclase was not activated in the action of PRL: Synergistic effect between PRL and prostaglandin E2 and F2 alpha was revealed in the stimulation of PAP production, and the effect of PRL could be blocked by indomethacin (a prostaglandin synthesis inhibitor). In conclusion, PRL directly stimulated PAP production of the cultured rat prostatic epithelial cells in serum-free medium and prostaglandin was involved in PRL action.
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PMID:[Effect of prolactin on production of acid phosphatase in rat prostatic cells and its mechanism]. 819 98

Short-circuit current (I(sc)) technique was used to investigate the role of testosterone in the regulation of chloride secretion in cultured rat efferent duct epithelia. Among the steroids tested, only testosterone, and to a lesser extent, 5alpha-dihydrotestosterone (5alpha-DHT), reduced the basal and forskolin-induced I(sc) in cultured rat efferent duct epithelia when added to the apical bathing solution. Indomethacin, a 3alpha-hydroxysteroid dehydrogenase, did not affect the inhibitory effect of 5alpha-DHT. The effect of testosterone occurred within 10-20 s upon application and was dose dependent with apparent IC(50) value of 1 microM. The effect was abolished by removal of Cl(-) but not HCO from the normal Krebs-Henseleit solution, suggesting that testosterone mainly inhibited Cl(-) secretion. The efferent duct was found to be most sensitive to testosterone, while the caput and the cauda epididymidis were only mildly sensitive. Cyproterone acetate, a steroidal antiandrogen, or flutamide, a nonsteroidal antiandrogen, did not block the effect of testosterone on the forskolin-induced I(sc), nor did protein synthesis inhibitors, cycloheximide, or actinomycin D. However, pertussis toxin, a G(i) protein inhibitor, attenuated the inhibition of forskolin-induced I(sc) by testosterone. Testosterone caused a dose-dependent inhibition of forskolin-induced rise in cAMP in efferent duct cells. It is suggested that the rapid effect of testosterone was mediated through a membrane receptor that is negatively coupled to adenylate cyclase via G(i) protein. The role of nongenomic action of testosterone in the regulation of electrolyte and fluid transport in the efferent duct is discussed.
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PMID:Nongenomic effect of testosterone on chloride secretion in cultured rat efferent duct epithelia. 1128 29

The molecular mechanisms involved in differentiation of prostate cancer cells to a neuroendocrine (NE) cell phenotype are not well understood. Here we used the androgen-dependent human prostate cancer cell line LNCaP to perform a systematic and broad analysis of the expression, pharmacology, and functionality of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) receptors. Reverse transcription polymerase chain reaction experiments, together with pharmacological approaches with a set of specific agonists and antagonists, demonstrated the presence of the three VIP/PACAP receptor subtypes (PAC1, VPAC1, and VPAC2 with a major role for VPAC1, acting through adenylate cyclase (AC) stimulation. An essentially similar pattern was observed by NE differentiated cells (4 days after serum deprivation) in spite of the important morphological changes observed. However, the expression of the prostate-specific antigen (PSA) decreased in NE cells (and increased again by dihydrotestosterone, DHT, treatment). The present demonstration of the induction of NE transdifferentiation in LNCaP cells by increasing concentrations of VIP adds value to previous observations on the role of cAMP in this process, an interesting topic in the comprehension of the molecular changes that are involved in the progression of prostate cancer to androgen independence.
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PMID:Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors. 1172 28

The influence of androgens, especially testosterone and its effector dihydrotestosterone, results in a constitutive disadvantage for male skin, e.g. reduced viability of hair at the scalp and reduced epidermal permeability barrier repair capacity. Dihydrotestosterone can act, among others, as an adenyl cyclase inhibitor. Caffeine on the other hand is an inexpensive and (in regular doses) harmless substance used in various cosmetic products, which can act as a phosphodiesterase inhibitor. To prove the hypothesis that caffeine as a phosphodiesterase inhibitor is able to override testosterone-induced effects on barrier function, we performed a double-blind placebo controlled study with healthy volunteers. In this study, 0.5% caffeine in a hydroxyethylcellulose gel preparation (HEC) was applied on one forearm, HEC without caffeine on the other forearm of male and female volunteers for 7 days and transepidermal water loss (TEWL) was measured before and at the end of the treatment period. Basal TEWL did not differ significantly between male and female subjects but the application of caffeine significantly reduced TEWL in male skin compared with female skin. We conclude that caffeine is beneficial for barrier function in male skin.
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PMID:Caffeine improves barrier function in male skin. 1848 98


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