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 gene encoding proopiomelanocortin(POMC) offers an interesting model for negative regulation of gene transcription by glucocorticoids. A fragment of human genomic DNA containing the entire POMC gene, together with the neo marker gene, was introduced by transfection into the ACTH-producing mouse pituitary tumor cell line, AtT-20, and the mouse fibroblast L cell line. In the transformed AtT-20 cells the human POMC gene was transcribed correctly and the transcript was spliced faithfully. Furthermore, the addition of dexamethasone to the transformed AtT-20 cells resulted in a 40% reduction of the human POMC mRNA levels. Deletion analysis demonstrated that no more than 417 bp in the 5'-flanking region of the human POMC gene are required for transcriptional repression by glucocorticoid. This region was also responsible for the transcription induction of the human POMC gene by cyclic AMP (cAMP). In the transformed L cells, however, most of the transcripts of the human POMC gene were not correctly initiated. The addition of dexamethasone to the transformed L cells did not significantly affect the content of human POMC mRNA, although these cells expressed glucocorticoid receptor(GR). However, the increase of the transcripts by forskolin, a post-receptor adenylate cyclase-activating agent, was partially but significantly suppressed by dexamethasone in the transformed L cells. These results suggest that binding of GR to the negative glucocorticoid response element (nGRE) could lead to steric occlusion of positive transcription factors, such as cAMP-response element binding protein and tissue specific factors or that GR bound to nGRE could interact with DNA-bound positive factors in such a way as to prevent their transcriptional stimulatory activity.
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PMID:Molecular mechanisms of glucocorticoid inhibition of human proopiomelanocortin gene transcription. 195 35

The effects of angiotensin II (A II) on adenylate cyclase activities in membranes of the zona glomerulosa (the capsular fraction) and the zona fasciculata (the decapsulated fraction) from rat adrenocortical glands were investigated. A time- and GTP-dependent stimulation by A II of adenylate cyclase activity was observed in the capsular fraction but not in the decapsulated fraction. The activation of adenylate cyclase by ACTH and A II was additive. Stimulation by A II was inhibited by an angiotensin antagonist, DD-3487 (DD). Moreover, the addition of a prostaglandin antagonist, a mixture of polyesters of polyphloretin phosphate (PPP) and an inhibitor of prostaglandin synthesis, indomethacin, was effective in inhibiting A II-induced stimulation of the capsular adenylate cyclase activity, suggesting that the activation of A II receptors located on the capsular membrane leads to the release of prostaglandins, which in turn stimulates the adenylate cyclase.
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PMID:Angiotensin stimulates adenylate cyclase activity via prostaglandins in the adrenal glomerulosa membrane. 196 37

The effects of CRH and somatostatin (SRIH) on adenylate cyclase (AC) activity, intracellular free calcium concentrations [( Ca2+]i) and in vitro ACTH release were investigated in six human ACTH-secreting pituitary adenomas. In all tumors, CRH induced a marked stimulation (from 69-210% at 10 nM), whereas SRIH caused a definite inhibition (from 29-50% at 100 nM) of membrane AC. When added together, CRH and SRIH caused a purely additive effect on AC. In adenomatous corticotrophs CRH (10 nM) caused [Ca2+]i to rise from 160 +/- 30 nM (mean +/- SD) to 410 +/- 95 nM. CRH-induced transients were biphasic, with an initial peak predominantly due to redistribution from intracellular Ca2+ stores and a secondary phase due to Ca2+ influx. The effects of CRH on [Ca2+]i were totally independent of the stimulation of AC. In fact, cAMP-elevating agents other than CRH did not modify [Ca2+]i. SRIH (100 nM) decreased resting [Ca2+]i (approximately 20-40%) as well as [Ca2+]i rises induced by CRH, arginine vasopressin, or high K+. The effect of SRIH on [Ca2+]i was maintained in presence of high cAMP levels, while was totally abolished after pertussis toxin pretreatment. CRH (10 nM) stimulated ACTH release (from 22.5 +/- 3.5 to 45.0 +/- 8.5 pmol/L) by an extent similar to that elicited by calcium ionophore and forskolin. By contrast, SRIH (0.1 microM) inhibited both basal and CRH-stimulated ACTH release. In conclusion, in human adenomatous corticotrophs SRIH exerts an inhibitory action by reducing both AC activity and, independently, [Ca2+]i. In this way, SRIH can efficiently counteract the stimulatory action of CRH that in these cells involves activation of both cAMP and Ca2+ pathways.
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PMID:Inhibition of basal and corticotropin-releasing hormone-stimulated adenylate cyclase activity and cytosolic Ca2+ levels by somatostatin in human corticotropin-secreting pituitary adenomas. 197 Aug 28

The selective 5-HT1A receptor ligand ipsapirone (IPS) induces corticotropin (ACTH) and cortisol secretion in humans. To explore 5-HT1A receptor-mediated hypothalamic-pituitary-adrenal (HPA) system activation in depression, 24 subjects (12 patients with unipolar depression and 12 individually matched controls) were given 0.3 mg/kg IPS or placebo in random order. Compared with controls, the depressed patients exhibited significantly decreased ACTH and cortisol responses to IPS in association with increased basal cortisol secretion. The impaired HPA response following 5-HT1A receptor challenge in unipolar depression could have resulted from glucocorticoid-dependent subsensitivity of the (post-synaptic) 5-HT1A receptor itself and/or from a defective postreceptor signaling pathway [inhibitory guanine nucleotide-binding protein (Gi)-adenylate cyclase complex function], thus supporting the hypothesis that a disintegrated 5-HT and HPA system interaction may be present in depression. Future studies of the HPA response to direct-acting 5-HT1A ligands, such as IPS, should facilitate the assessment of 5-HT/HPA system integrity in various affective disorders and its involvement in psychotropic drug effects.
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PMID:5-HT1A receptor responsivity in unipolar depression. Evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls. 197 79

We measured cortisol and precursor steroid production in response to ACTH, cholera toxin, and forskolin by the dispersed adrenocortical cells prepared from the adrenal glands of 10 patients with different forms of Cushing's syndrome. The cells prepared from the hyperplastic adrenal glands from 4 patients with Cushing's disease responded in a dose-dependent manner to ACTH, cholera toxin, and forskolin. The adrenal cells prepared from 4 encapsulated adrenal adenomas showed no (n = 2), a lowered (n = 1), or a clear (n = 1) response of cortisol release to ACTH. The cells prepared from the adrenal glands of 1 patient with dysplastic micronodular adrenal glands showed a limited response to ACTH, while the cells from an adrenocortical carcinoma, which secreted very little cortisol per cell, were unresponsive to ACTH, cholera toxin, and forskolin. The reaction of the dispersed adrenal cells from these 10 patients to ACTH, cholera toxin, and forskolin showed a close correlation (P less than 0.001 in all instances). This suggests that the defect in autonomous glands is not located at the level of the ACTH receptor, but, rather, involves the adenylate cyclase complex as a whole or its coupling to cAMP-dependent protein kinase. The release into the medium of the cortisol precursors deoxycortisol, 17-hydroxyprogesterone, and progesterone showed that the four autonomous nodules were characterized by a significantly higher deoxycortisol/cortisol ratio in the medium (P less than 0.01), suggesting a relative blockade of 11 beta-hydroxylase in these adrenal adenomas. This was further substantiated in cells from several adrenals by a significant increase in the release of these precursors in response to ACTH in the absence of a cortisol response. We conclude the following. 1) Adrenal adenoma formation in patients with Cushing's syndrome is accompanied by a parallel decrease in the stimulation of the release of steroid hormones in response to ACTH, cholera toxin, and forskolin. This points to a defect in the adenoma cells beyond the ACTH receptor. 2) Adrenal adenoma formation in patients with Cushing's syndrome is accompanied by a relative blockade of 11 beta-hydroxylase activity. 3) By comparing the preoperative dynamic tests of the pituitary-adrenal axis, the plasma ACTH concentration, the morphology of the adrenal glands, and their in vitro responsiveness, a gradual transition from pituitary to (partial) adrenal autonomy could be recognized in several patients.
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PMID:Characterization of adrenal autonomy in Cushing's syndrome: a comparison between in vivo and in vitro responsiveness of the adrenal gland. 215 30

We describe here a new method for the identification of adenylate cyclase-regulating receptors using the morphological response of Y1 cells to cAMP. The efficiency of this method was demonstrated with a cloned beta 2-adrenergic receptor: the coding region of a genomic beta 2-adrenergic receptor clone was amplified using the polymerase chain reaction, so that in vitro RNA transcripts of this DNA could be obtained. Y1 cells were microinjected with this RNA and assayed for sensitivity to isoproterenol. In the presence of this agonist, the microinjected cells rapidly showed morphological changes identical to those observed in the presence of ACTH, forskolin, or cholera toxin, agents that enhance cAMP accumulation in the control uninjected cells. This suggests the integration, within the injected cell membrane, of a functional beta 2-adrenergic receptor, whose activation by isoproterenol resulted in the intracellular formation of cAMP. This new qualitative screening method for the identification of adenylate cyclase-regulating receptors can be extended to any unknown receptor coupled to adenylate cyclase and absent in these cells. It has been applied to the identification of the dog thyrotropin receptor.
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PMID:An efficient screening morphological test for the identification and characterization of cyclic AMP-coupled hormone receptors. 215 63

The present studies were undertaken to precise the mechanism through which glucocorticoids enhance the responsiveness of ovine adrenocortical cells to ACTH. Experiments using intact cells and crude adrenal membranes have shown that, at the level of the adenylate cyclase system, dexamethasone increases the number of ACTH receptors without modification of the catalytic subunit or of the GTP binding regulatory components Gs and Gi. Cells cultured with dexamethasone secreted more pregnenolone and more corticosteroids in response to 8-BrcAMP than did control cells. By contrast, dexamethasone did not increase corticosterone secretion by cells incubated in the presence of 22-(R)-hydroxycholesterol or of exogenous pregnenolone. Dexamethasone neither affected the incorporation of [14C] acetate into cellular cholesterol nor the amount of cholesterol present in mitochondria of unstimulated cells. However, dexamethasone-treated cells incubated in the presence of both 8-BrcAMP and aminoglutethimide exhibited higher amounts of mitochondrial cholesterol than control cells. These data indicate that dexamethasone enhances the number of cellular ACTH receptors together with increasing the cAMP-induced translocation of cholesterol from the cytoplasm into mitochondria and/or mitochondrial storage of cholesterol.
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PMID:Mechanism of glucocorticoid enhancement of the responsiveness of ovine adrenocortical cells to adrenocorticotropin. 215 73

The effects of prolonged administration of ACTH in vivo on adenylate cyclase activity in the zona glomerulosa (the capsular fraction) and the zona fasciculata-reticularis (the decapsulated fraction) of rat adrenocortical glands were investigated. Hyperresponsiveness of adenylate cyclase activity to ACTH in vitro was observed for both the capsular and the decapsulated fractions from ACTH-treated rats with a similar magnitude of stimulation by NaF, the guanine nucleotide or forskolin. There were no differences in binding sites for ACTH in membranes between the ACTH- and the saline-treated rats. The augmenting effects of the in vivo ACTH treatment on the enzyme stimulated by ACTH were accompanied by an increased sensitivity to the guanine nucleotide, suggesting that ACTH treatment in vivo was followed by an increased efficacy in coupling of the ACTH receptors to the adenylate cyclase complex associated with the guanine nucleotide regulatory components.
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PMID:Effects of chronic treatment with adrenocorticotropin on adenylate cyclase activity in the adrenal cortex. 215 18

In a punished drinking test in rats sclareol glycol (SG) decreased the number of punished responses ("proconflict response") while diazepam had the opposite effect; SG antagonized the "anticonflict response" of diazepam. Post-training administration of SG in rats enhanced retention in active avoidance task evaluated 24 h later. SG produced an increase in plasma ACTH and corticosterone levels in unstressed rats. The stress-induced increase in ACTH and corticosterone secretion was potentiated by SG. All these data suggest that SG behaves as an anxiogenic, memory-facilitator and perhaps adaptogenic agent. The effects of SG may be mediated by different mechanisms of action (stimulation of adenylate cyclase, interaction with GABA-ergic and dopaminergic transmitter mechanisms).
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PMID:Measures of anxiety, retention and stress in the rat following treatment with the diterpene sclareol glycol. 215 19

Inhibitors of calmodulin [trifluoperazine, chlorpromazine, pimozide, and calmidazolium N-(6-aminohexyl)5-chloro-1-napthalenesulphonamide (W7)] and calmodulin antibodies were used to investigate the role of calmodulin in the response of Y-1 mouse adrenal cells to ACTH, with particular reference to events in the plasma membrane. In whole cells it was found that two responses (production of steroids and cAMP) to two stimulating agents (ACTH and forskolin) were inhibited by trifluoperazine at concentrations consistent with those involved in binding of the inhibitor to pure calmodulin (10-25 microM). The steroidogenic responses were also inhibited by the three other inhibitors of calmodulin (chlorpromazine, calmidazolium, and W-7). Trifluoperazine and pimozide (1-500 microM) did not inhibit binding of an [125I]ACTH analog to highly purified plasma membranes of Y-1 cells or to the cells themselves. With Y-1 plasma membranes it was found that trifluoperazine, pimozide, W-7, and calmodulin antibodies inhibited the increase in adenylate cyclase activity in response to ACTH, but not the cyclase responses to cholera toxin or forskolin. Moreover, the effect of cholera toxin on the ADP-ribosylation of specific membrane substrates was independent of the presence or absence of endogenous and/or exogenous Ca2+/calmodulin. The response of adenylate cyclase to ACTH was also decreased in plasma membranes from which calmodulin was removed by washing, and exogenous calmodulin partly reversed this decrease. Anti-calmodulin immunoglobulin inhibited the stimulation of adenylate cyclase produced in plasma membrane by ACTH, but was without effect on the responses to cholera toxin and forskolin. Exogenous calmodulin partly reversed the inhibition of stimulation by ACTH of adenylate cyclase produced by the antibody. It is concluded that calmodulin influences the events taking place in the plasma membrane in response to ACTH, after the binding of the hormone to its receptor and before the action of the G protein (Gs). That is, calmodulin is involved in coupling the occupied receptor to Gs. The effects of inhibitors of calmodulin in whole cells must involve some additional effect(s) requiring the intact cell.
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PMID:The role of calmodulin in the responses to adrenocorticotropin of plasma membranes from adrenal cells. 215 26


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