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 AtT-20/D16-16 mouse pituitary tumor cell secretes corticotropin (ACTH) in response to corticotropin-releasing factor (CRF), (-)-isoproterenol, and vasoactive intestinal peptide (VIP). These responses are associated with a rapid increase in cyclic AMP formation. Somatostatin (SRIF) markedly decreases the stimulatory effect of CRF, (-)-isoproterenol, and VIP on both cyclic AMP formation and immunoreactive ACTH secretion. Forskolin and cholera toxin, adenylate cyclase activators, also stimulate cyclic AMP formation and ACTH secretion in AtT-20 cells and these responses are all inhibited by SRIF. The ACTH secretory responses to melittin and to the calcium ionophore A23187, neither of which increases cyclic AMP in AtT-20 cells, were not inhibited by SRIF. SRIF did not affect the binding of a tritiated beta-adrenergic receptor antagonist to AtT-20 membranes nor did it decrease basal cyclic AMP formation even in the presence of excess phosphodiesterase inhibitor, indicating that the reduction of cyclic AMP levels by SRIF did not involve either an interference with beta-adrenergic agonist binding to receptors or stimulation of cyclic AMP degradation. These results indicate that the inhibition of CRF-, (-)-isoproterenol-, and VIP-stimulated ACTH secretion by SRIF may be regulated by its inhibitory action on adenylate cyclase.
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PMID:Somatostatin inhibits multireceptor stimulation of cyclic AMP formation and corticotropin secretion in mouse pituitary tumor cells. 612 32

Studies were conducted to explore the effects of vasoactive intestinal peptide (VIP), histamine, somatostatin-14 and -28 (S-14 and S-28), and prostaglandin E2 (PGE2) on cAMP production in gastric glands isolated from the guinea pig. VIP (EC50 = 5 X 10(-10) M) and PGE2 (EC50 = 10(-8) M) induced cAMP accumulation in glands isolated by means of EDTA from the fundus or antrum. The structurally related peptides PHI (peptide with N-terminal histidine and C-terminal isoleucine amide) and secretin also increased cAMP production in the system, but with 200 to 2000 times lower potencies than VIP. Combinations of VIP with PHI or secretin do not produce additive stimulation, indicating that PHI or secretin interact with the receptor-cAMP system highly sensitive to VIP. Histamine was about 10 times more potent in fundus (EC50 = 10(-5) M) than in antrum (EC50 = 9 X 10(-5) M) and did not produce any stimulation in enterocytes isolated from the upper part of the duodenum. Complete inhibitions caused by the H2 receptor antagonist cimetidine (Ki = 0.15-0.16 X 10(-6) M) (Ki is the inhibition constant) or by the H1 receptor antagonist diphenhydramine (DPH) (Ki = 13-17 X 10(-6) M) indicate that H interacts with typical H2 receptors mediating adenylate cyclase activation in fundic (Ka = 10(-5) M) (Ka is the association constant) or antral membranes (Ka = 3 X 10(-5) M). In fundus, S-14 inhibited partially (about 60%) cAMP production evoked by H or by its H1 or H2 agonists. The kinetics and the inhibitory potencies (2 X 10(-8) M) or efficacies of S-14 and -28 were identical. No effect of S-14 was found on basal or on cAMP production induced by VIP or PGE2 in either fundic or antral glands or by H in antral glands. The results support the hypothesis of a regulatory role for VIP and/or secretin in mucous and/or peptic secretions via a cAMP-dependent mechanism in gastric mucosa in mammals. Second, we propose that S-14 as well as S-28 may inhibit gastric acid secretion by a direct and selective control of H-induced cAMP production in parietal cells, through a common recognition site (receptor?) distinct from the H2 receptor. Third, not only parietal cells, but also nonparietal cells of the antrum possess an H2 receptor-cAMP system. This finding could be related to the in vivo regulation by cimetidine of endocrine (somatostatin) and exocrine (pepsin) secretions by the stomach.
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PMID:Regulation by vasoactive intestinal peptide, histamine, somatostatin-14 and -28 of cyclic adenosine monophosphate levels in gastric glands isolated from the guinea pig fundus or antrum. 613 13

Addition of somatostatin-14 (SRIF) inhibits corticotropin releasing factor (CRF) and forskolin-stimulated cyclic AMP formation and ACTH release from tumor cells of the mouse anterior pituitary (AtT-20/D16-16). After long-term pretreatment of these cells with SRIF, the ability of SRIF to inhibit CRF and forskolin-stimulated cyclic AMP accumulation or ACTH secretion is markedly reduced. SRIF pretreatment also increases the formation of cyclic AMP in response to forskolin. This increase is delayed in onset, slow to recover, and blocked by the protein synthesis inhibitor, cycloheximide. SRIF pretreatment did not affect basal cyclic AMP and cyclic GMP levels or phosphodiesterase activity. It is proposed that prolonged treatment of AtT-20 cells with SRIF desensitizes SRIF receptors and induces a compensatory sensitization of adenylate cyclase through a process requiring protein synthesis.
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PMID:Prolonged somatostatin pretreatment desensitizes somatostatin's inhibition of receptor-mediated release of adrenocorticotropin hormone and sensitizes adenylate cyclase. 613

Somatostatin (SRIF) release from rat hypothalamus was investigated in vitro with a perifusion system. Glucagon (1 microM) and high potassium concentrations (56 mM) stimulated SRIF release in a calcium-dependent manner. Pretreatment of the rat with cysteamine (30 mg/100 g body weight, 7 h earlier) significantly reduced SRIF release from the hypothalamus in glucagon- and high potassium-stimulated states as well as in the basal state. SRIF release from rat hypothalamus was also stimulated by both dibutyryl cyclic AMP (1 mM) and theophylline (3 mM). These results suggest that glucagon, acting in a calcium-dependent manner and possibly through the adenylate cyclase-cyclic AMP system, stimulates SRIF release from rat hypothalamus and that cysteamine treatment reduces releasable SRIF in the hypothalamus.
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PMID:Glucagon-induced somatostatin release from perifused rat hypothalamus: calcium dependency and effect of cysteamine treatment. 613 40

Somatostatin-14 (SRIF) inhibits both hormone- and forskolin-stimulated cyclic adenosine 3':5'-monophosphate (cyclic AMP) formation in tumor cells of the mouse anterior pituitary (AtT-20/D16-16). However, long-term pretreatment of cells with SRIF modifies the responsiveness of this system in two ways: The response of adenylate cyclase to stimulatory agents is enhanced, whereas the ability of SRIF to inhibit stimulated cyclic AMP formation is reduced. The supersensitive adenylate cyclase response and the SRIF desensitization were dependent on the concentration and duration of SRIF pretreatment. Enhancement of forskolin-stimulated cyclic AMP formation occurred within 4 hr, whereas that of corticotropin-releasing-factor-, (-)-isoproterenol-, and vasoactive intestinal peptide-induced cyclic AMP accumulation required 16 hr of pretreatment. The elevated responses to each of these stimulants were due to increases in their maximal ability to stimulate cyclic AMP formation. Cycloheximide treatment blocked the enhanced cyclic AMP response induced by SRIF pretreatment, suggesting a requirement for protein synthesis. In membrane preparations, SRIF pretreatment facilitated activation of adenylate cyclase by forskolin, sodium fluoride, and guanosine 5'-(beta,tau-imido)-triphosphate without affecting basal activity. These results suggest that desensitization of an inhibitory input to adenylate cyclase is accompanied by a supersensitivity of adenylate cyclase to stimulatory agents through a process requiring protein synthesis.
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PMID:Somatostatin pretreatment desensitizes somatostatin receptors linked to adenylate cyclase and facilitates the stimulation of cyclic adenosine 3':5'-monophosphate accumulation in anterior pituitary tumor cells. 614 35

Addition of somatostatin (SRIF) inhibits corticotropin-releasing factor- and forskolin-stimulated cyclic AMP accumulation and adrenocorticotropin hormone secretion from mouse anterior pituitary tumor cells (AtT-20/D16-16). However, prior exposure of these cells to SRIF reduced the potency of SRIF to inhibit both corticotropin-releasing factor- and forskolin-stimulated cyclic AMP accumulation and adrenocorticotropin hormone release. This SRIF desensitization is time- and concentration-dependent and reversible. Cross-desensitization to SRIF analogs also occurred whereas SRIF pretreatment did not affect the inhibition by SRIF of 8-bromo-cyclic AMP-stimulated adrenocorticotropin hormone release or did it affect basal cyclic AMP levels, protein content or phosphodiesterase activity. These data indicate that SRIF can regulate the sensitivity of its own receptor and that SRIF desensitization may involve either a down-regulation of SRIF receptors or an uncoupling of these inhibitory receptors from adenylate cyclase.
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PMID:Somatostatin desensitization: loss of the ability of somatostatin to inhibit cyclic AMP accumulation and adrenocorticotropin hormone release. 614 43

Somatostatin (SRIF) inhibits vasoactive intestinal peptide (VIP)-stimulated cAMP accumulation in the GH4C1 strain of rat pituitary tumor cells, and this effect is responsible for SRIF inhibition of VIP-stimulated hormone release. In this study we examined the interaction between the SRIF receptor and adenylate cyclase in GH4C1 cell membranes. Maximal concentrations of VIP (50 nM) increased membrane adenylate cyclase activity 4.2-fold; half-maximal stimulation was observed with 0.75 nM VIP. SRIF noncompetitively inhibited the stimulatory effect of VIP, but it did not alter basal adenylate cyclase activity. The relative potencies of SRIF and two SRIF analogs as inhibitors of VIP-stimulated adenylate cyclase activity in membranes and of VIP-stimulated cAMP accumulation in intact cells were similar. Furthermore, the concentration of SRIF that caused half-maximal inhibition of adenylate cyclase activity (ED50 = 2.3 nM) was close to the equilibrium dissociation constant for SRIF (Kd = 0.40 nM) measured in membrane preparations in the presence of GTP. Therefore, SRIF inhibition of adenylate cyclase appears to be receptor mediated. As with receptors known to regulate adenylate cyclase by interaction with a guanine nucleotide regulatory subunit, SRIF receptor binding was decreased in the presence of guanine nucleotides. Addition of GTP (150 microM) or the nonhydrolyzable GTP analog guanyl-5'-yl-imidodiphosphate (100 microM) decreased the specific binding of [125I-Tyr1]SRIF to 31% and 13% of the control value, respectively. This decrease in specific binding was due entirely to decreased receptor affinity for SRIF. GTP (150 microM) increased the equilibrium dissociation constant for SRIF from 0.11 to 0.40 nM, whereas the number of binding sites was unaffected by the nucleotide (Bmax = 0.2 pmol/mg protein). Analysis of dissociation kinetics demonstrated that in the absence of guanyl nucleotides, the rate of [125I-Tyr1]SRIF dissociation was first order (t 1/2 = 180 min). However, in the presence of a half-maximal concentration of guanyl-5'-yl-imidodiphosphate (0.3 microM), [125I-Tyr1]SRIF dissociation occurred with biphasic kinetics. Fifty percent of the specifically bound peptide dissociated at the same rate as that observed in the absence of nucleotide, whereas the remainder dissociated 15 times more rapidly (t 1/2 = 9.6 min).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The somatostatin receptor is directly coupled to adenylate cyclase in GH4C1 pituitary cell membranes. 614 60

We have investigated the effects of SRIF and human pancreatic GH-releasing factor-44 (hpGRF-44) on adenylate cyclase (AC) activity of male rat anterior pituitaries (in which somatotrophs are present in large proportion) and of human GH-secreting pituitary adenomas (which are almost homogeneously constituted by somatotrophs). The adenoma's responsiveness to both agents in terms of secretion was previously demonstrated in in vitro experiments. SRIF inhibited in a dose-dependent fashion the GH release from monolayer cultures of the tumors. The inhibition ranged from 32-66% at the maximal effective concentration (10(-6) M). hpGRF-44 stimulated GH release in a dose-dependent fashion. The stimulation was 78-172% at 10(-7) M. SRIF and hpGRF-44 markedly affected AC activity in both systems. SRIF elicited a pronounced inhibition of the enzyme activity in a dose-dependent manner. The inhibition was about 40% in the rat and ranged from 16-49% in adenomas at the maximal effective concentration (10(-5) M SRIF). The inhibitory effect was GTP-dependent. hpGRF-44 markedly stimulated AC activity. The stimulation was dose dependent and GTP dependent. The stimulation was about 650% in the rat and 26-350% in adenomas at the maximal effective concentration (10(-6) M). These results suggest the presence of a dually regulated (by SRIF and hpGRF-44) AC in GH-secreting cells; an involvement of cAMP in the intracellular mechanisms transducing the signals of SRIF and hpGRF-44 in somatotrophs.
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PMID:Presence of an adenylate cyclase dually regulated by somatostatin and human pancreatic growth hormone (GH)-releasing factor in GH-secreting cells. 614 15

Pituitary GH secretion is regulated by Ca+2 and cAMP. We show that human pancreatic tumor GRF (hpGRF) stimulates anterior pituitary adenylate cyclase activity, cAMP accumulation, and GH release. The relationship between Ca+2 and the stimulating effects of the Ca+2 ionophore A23187 on cAMP accumulation and GH release in vitro was studied. To evaluate the role of the Ca+2-binding protein calmodulin in this system, we used the calmodulin antagonist W7, a naphthalene-sulfonamide derivative, and its less active analog W5. W7 inhibited hpGRF-stimulated adenylate cyclase activity, cAMP accumulation, and GH release, whereas W5 was either poorly effective or ineffective. Somatostatin (SRIF) also attenuated hpGRF stimulation of adenylate cyclase. These results suggest that the actions of Ca+2-calmodulin and cAMP are interrelated in modulating GH release. Calmodulin participates in hpGRF stimulation of adenylate cyclase, cAMP formation, and GH release. The attenuation of hpGRF-stimulated adenylate cyclase activity by SRIF may be one of the mechanisms for its GH inhibitory action.
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PMID:Human pancreatic tumor growth hormone-releasing factor stimulates anterior pituitary adenylate cyclase activity, adenosine 3',5'-monophosphate accumulation, and growth hormone release in a calmodulin-dependent manner. 614 31

The interaction of growth hormone-releasing factor (GRF) and somatostatin (SRIF) on adenylate cyclase activity and growth hormone release was investigated in pituitary homogenates and 2-day cultured rat anterior pituitary cells. GRF stimulated growth hormone release by about 3-fold (ED50 1.6 X 10(-12) M) and caused a rapid 15-fold increase in cyclic AMP production (ED50 6.0 X 10(-12) M). The increase in cyclic AMP was due to direct stimulation of adenylate cyclase by GRF, which caused a 4-fold increase in the activity of the enzyme measured in anterior pituitary homogenates. GRF-induced cyclic AMP formation and GRF-stimulated adenylate cyclase activity were maximally inhibited to the extent of about 50% by 10(-8) M somatostatin. In contrast, GRF-stimulated growth hormone release was completely inhibited by somatostatin (ID50 3.2 X 10(-11) M), suggesting a second site of action of somatostatin. These studies demonstrate that GRF stimulates growth hormone release via activation of adenylate cyclase and a rise in intracellular cyclic AMP. In addition, these findings indicate that the inhibitory action of somatostatin on growth hormone release is exerted at two levels, one at the level of adenylate cyclase affecting the production of cyclic AMP, and the other beyond the formation of the nucleotide, at a site which modulates the release of growth hormone from the cell.
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PMID:Actions of growth hormone-releasing factor and somatostatin on adenylate cyclase and growth hormone release in rat anterior pituitary. 614 68


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