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)

Vasoactive intestinal peptide (VIP) and peptide (P) with N-terminal histidine and C-terminal isoleucine (PHI) stimulated prolactin (PRL) secretion from GH4C1 cells equipotent with ED50 values of 30-50 nM. In a parafusion system optimized to give high time resolution both VIP and PHI increased PRL secretion with a delay of about 60 s and subsequent to the activation of the adenylate cyclase. Thyroliberin (TRH) increased PRL secretion within 4 s. The dose-response curves for VIP- and PHI-stimulated cAMP accumulation were superimposable on those for PRL secretion. At submaximal concentrations the effects of VIP and PHI on both cAMP accumulation and PRL secretion were additive, whereas the effects were not additive at concentrations giving maximal effects. VIP and PHI increased [Ca2+]i measured by quin-2 in a different way than TRH, without inducing changes in the electrophysiological membrane properties of the GH4C1 cells. We conclude that both VIP and PHI stimulate PRL secretion via a cAMP-dependent process involving an increase in [Ca2+]i.
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PMID:Vasoactive intestinal peptide and peptide with N-terminal histidine and C-terminal isoleucine increase prolactin secretion in cultured rat pituitary cells (GH4C1) via a cAMP-dependent mechanism which involves transient elevation of intracellular Ca2+. 243 88

The effects of prolactin (PRL), alone and together with human chorionic gonadotropin (hCG), on steroidogenesis and cAMP accumulation in the preovulatory ovary were studied. Cultured granulosa cells obtained from large preovulatory follicles of pregnant mare serum gonadotropin (PMSG)-treated immature rats were used. The results indicated that PRL inhibited, in a dose-dependent manner, hCG-induced cAMP accumulation and 17 beta-estradiol (E2) secretion. When added to 0.4 IU/ml hCG (designated as 100% activity), 1, 10 and 100 ng/ml PRL decreased cAMP accumulation to 86, 64 and 59%, respectively, following 1 h incubation and to 87, 81 and 66% E2 secretion, respectively, following 48 h incubation. PRL alone failed to cause any significant change in cAMP or E2 concentrations. The inhibition of PRL was apparently not at the hCG receptor level, since a similar inhibitory effect was observed in prostaglandin E1 (PGE1)-induced cAMP accumulation. Nor was the inhibitory pathway of adenylate cyclase involved, since pertussis toxin--an inactivator of the Gi regulatory protein--failed to abolish the suppressive effect of PRL on hCG-induced cAMP accumulation. The phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methyl-xanthine, abolished the inhibitory effect of PRL on hCG- and PGE1-induced cAMP accumulation and on hCG-induced E2 secretion, indicating that PRL might be inhibiting cAMP accumulation and steroidogenesis in preovulatory granulosa cells by enhancement of PDE activity.
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PMID:Prolactin inhibits hCG-stimulated steroidogenesis and cAMP accumulation, possibly by increasing phosphodiesterase activity, in rat granulosa cell cultures. 247 81

A-69024 HBr, 1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-methyl-1,2,3,4- tetrahydroisoquinoline hydrobromide, is a selective antagonist of the dopamine D-1 receptor. A-69024 HBr shows an apparent affinity toward the D-1 receptor (identified using [125I]SCH 23390) of 12.6 (4.15-38.3) nM (mean (90% CL), n = 3); the apparent affinity toward the D-2 receptor (identified using [3H]spiroperidol is 1 290 (1,200-1,380) nM (n = 3); using [125I]lysergic acid diethylamine to identify the 5-HT1C receptor gives apparent affinity of 17,800 (9,700-32,600) nM (n = 3). In assays of adenylate cyclase activity, A-69024 HBr antagonizes the D-1 receptor with a calculated affinity of 43.9 (17.5-110) nM (n = 5), while the molecule antagonizes the D-2 receptor with a calculated affinity greater than 400 nM. Behavioral studies demonstrate that A-69024 HBr (5 mg/kg s.c.) is able to block both amphetamine-induced locomotor activity and apomorphine-induced stereotypy. Furthermore, A-69024 HBr blocks SF&F 38393-, but not quinpirole-, induced rotation in rats having unilateral 6-hydroxydopamine lesions of the substantia nigra. When administered at behaviorally effective doses. A-69024 HBr neither increases the concentration of serum prolactin nor potentiates dihydroxyphenylalanine (DOPA) accumulation in the caudate-putamen of rats pretreated with the DOPA decarboxylase inhibitor NSD 1015. Because A-69024 is a dopamine receptor antagonist discriminating between the D-1 and D-2 receptors, it may be a useful research tool.
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PMID:A-69024: a non-benzazepine antagonist with selectivity for the dopamine D-1 receptor. 250 17

Properties of a clonal line of SV40-transformed rat granulosa cells (DC3 cells) were elucidated. DC3 cells were maintained in vitro in Iscove Modified Dulbecco Medium that contained 20% fetal bovine serum. The cells had a logarithmic growth phase doubling time of approximately 18 h and produced detectable quantities of estrone, estradiol, and progesterone. Steroidogenesis was increased by supplementation with either steroidogenic substrates or agents that stimulated activity of adenylate cyclase. Production of progesterone and estrogens was enhanced when medium was supplemented with 25-hydroxycholesterol, and production of estradiol was enhanced by medium supplementation with androstenedione. Treatments with forskolin and cholera toxin resulted in marked increases of cyclic adenosine 3',5'-monophosphate (cAMP) in medium and cells and enhanced steroidogenesis. Isoproterenol and vasoactive intestinal peptide, but not follicle-stimulating hormone (FSH), luteinizing hormone (LH), insulin or prolactin, stimulated cAMP secretion by suspended cells. DC3 cells had small but detectable levels of binding to FSH, but binding of LH and epidermal growth factor could not be detected. DC3 cells possess characteristics expected of granulosa cells arrested in an early stage of differentiation and may provide a useful model for studies of "immature" granulosa cell functions.
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PMID:Physiologic characterization of transformed and cloned rat granulosa cells. 254 13

In cultured rat anterior pituitary cells incubated for 30-180 min, PHNO caused a concentration-dependent inhibition of prolactin release (IC50 approximately 0.5 nM) with maximal suppression at 5 nM. Forskolin increased cyclic adenosine 3',5'-monophosphate (cAMP) generation by stimulating adenylate cyclase and PHNO inhibited this effect with the same concentration profile as for inhibition of prolactin release. Inhibitory effects of 0.5 nM PHNO on prolactin release and cAMP generation were abolished by coincubation with 10 nM haloperidol, a D2 dopamine receptor antagonist. Within 30 min, 0.5 nM PHNO blunted the stimulation of prolactin release due to 10 nM thyrotropin-releasing hormone (TRH) or angiotensin II (AII). Thus, PHNO appears to activate the D2 dopamine receptor to inhibit the formation of cAMP and the secretion of prolactin.
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PMID:The dopamine agonist, PHNO ((+)-4-propyl-9-hydroxynaphthoxazine), inhibits cyclic adenosine 3',5'-monophosphate formation and prolactin release from anterior pituitary cells. 254 81

The present review is dealing with the five major hypothalamic hypophysiotropic neuropeptides (H.H.N.P.) purified and synthesized so far. Four of them specifically stimulate the secretion of one or several anterior pituitary (A.P.) hormones, i.e. thyroliberin (TRH) on TSH and prolactin, gonadoliberin (GnRH) on LH and FSH, corticoliberin (CRF) on ACTH and precursor peptides and somatocrinine (GRF) on GH. The fifth one, somatostatin (SRIF), inhibits the secretion of all A.P. hormones, excepted LH and FSH. All H.H.N.P. affect, positively or negatively, in a dose- and time-dependent manner, the release of stored hormones and their neosynthesis. These responses are submitted to multihormonal modulations. They are initiated by the occupancy of high affinity specific binding sites which have been extensively characterized and morphologically localized. Informations concerning molecular characterization and cloning of receptors for any H.H.N.P. are still awaited. By contrast, the transduction mechanisms which are activated by the occupation of receptors have been extensively studied. They vary depending on H.H.N.P.: TRH and GnRH activate the catabolism of polyphosphoinositides and ensuing pathways, CRF and GRF activate and SRIF inhibits adenylate cyclase dependent pathways. In addition, Ca2+, from extracellular and intracellular sources, play a pivotal role in all cases. The intracellular mechanisms responsible for the last steps of H.H.N.P. action, i.e. exocytosis of secretory granules and transcription of target genes, are however still unknown.
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PMID:[Hypothalamic hypophysiotropic neuropeptide receptors]. 255 5

Previous studies from this laboratory showed that treatment with 17-beta-estradiol (E2) caused an acquisition of inhibitory effect of somatostatin (SRIF) on prolactin release with an increased number of SRIF-binding sites in the rat anterior pituitary. The aim of this study was to characterize the E2-dependent SRIF receptor in comparison with the E2-independent one, which was expressed in ovariectomized rats. The following observations were obtained: 1) both of the E2-dependent and E2-independent SRIF receptors, measured with 125I-Tyr11-SRIF as a radiolabeled ligand, were enriched in the plasma membrane fraction of the cells, displaying a single class of binding site (E2-dependent: Kd, 32 pM, Bmax, 2.3 pmol/mg protein; E2-independent: Kd, 83 pM, Bmax, 0.26 pmol/mg protein). The ligand binding to both receptors was sensitive to monovalent and divalent cations, and GTP. 2) Among the SRIF analogs tested, the relative potencies of SRIF28 and its analog and cyclosomatostatin compared with SRIF were lower in the E2-dependent receptor than in the E2-independent one. 3) A cross-linking study with N-hydroxysuccinimidyl-4-azido-benzoate revealed that the molecular weight of the cross-linked E2-dependent receptor was approximately 94,000, whereas that of the E2-independent one was 82,000, irrespective of the presence of a reducing reagent. The molecular weight of SRIF receptor from normal male or female rat pituitary was similar to the E2-independent type. 4) Both types of the cross-linked SRIF receptors were solubilized by sucrose monolaurate, adsorbed to a wheat germ agglutinin-agarose column, and eluted with N-acetyl-glucosamine. 5) SRIF inhibited the forskolin-stimulated adenylate cyclase activity in the pituitary membranes from E2-treated rats, but it did not in the E2-depleted membranes. These results demonstrate that there are at least two subtypes of SRIF receptor in the rat anterior pituitary, one of which is exclusively expressed by the treatment with E2, and that these subtypes are distinct with respect to ligand binding specificity, molecular weight, and coupling to adenylate cyclase inhibition.
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PMID:Characterization of 17-beta-estradiol-dependent and -independent somatostatin receptor subtypes in rat anterior pituitary. 256 36

Somatostatin (SRIF) actions in the brain and pituitary are mediated by specific receptors. Using radioiodinated ligands it has been possible to characterize the kinetics of specific binding sites in the brain and pituitary, and to determine their cellular localization by autoradiography. At the pituitary level, the inhibition of growth hormone, prolactin and thyrotropin secretions induced by SRIF is mediated through a single binding site which is coupled to the inhibition of adenylate cyclase. In the brain, SRIF receptors are localized on neurons and glial cells and are also coupled to adenylate cyclase inhibition. Two sites are differentiated in the brain with an analogue of somatostatin, SMS 201995. In humans, SRIF-binding sites have been related to a number of pathologies. At the pituitary level, it has been shown that the number of binding sites was negatively correlated to growth hormone levels in acromegaly. Furthermore, SRIF-binding sites were undetectable in a patient which did not respond to SMS 201995 therapy. In the brain, meningiomas and gliomas are rich in SRIF binding sites. This suggests a possible role for SRIF on glia. In neurodegenerative diseases, cortical SRIF concentrations are decreased in Alzheimer's and Parkinson's disease associated with dementia while SRIF-binding sites are only affected in Alzheimer's disease. In conclusion, the physiological role of SRIF in the brain and pituitary can be evaluated by studying the receptors of the peptide. Such studies allow to question the implication of SRIF in endocrine and neuropathologies.
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PMID:Somatostatin receptors in brain and pituitary. 256 73

The concept of multifactorial pituitary control is now well established. As in other cell systems, integration of complex messages involves dynamic interactions of receptors and coupling mechanisms. Regulation of adenohypophyseal secretions has been shown to involve cyclic AMP production, the modulation of phosphatidylinositol phosphate breakdown and Ca2+ mobilization. Dopamine, somatostatin and angiotensin II receptors are negatively coupled to adenylate cyclase in anterior pituitary cells. In the case of angiotensin, this effect on adenylate cyclase appears paradoxical since the peptide markedly stimulates prolactin secretion. In fact, angiotensin II also markedly stimulates inositol phosphate production and this effect could account for the stimulated hormone secretion. In addition, dopamine could inhibit inositol phosphate production stimulated by angiotensin II and thyrotropin-releasing hormone. Dopamine and somatostatin also directly modulate voltage-dependent calcium channels, perhaps through a direct coupling with potassium channels. On the other hand, steroids modulate the sensitivity of adenohypophyseal cells to neurohormones by different mechanisms. In the case of somatostatin, it increases the number of specific binding sites, while in the case of dopamine estradiol affects the transduction mechanisms of D2 dopamine receptors. In conclusion, dopamine and somatostatin receptors appear coupled to various transduction mechanisms through pertussis-sensitive G proteins in anterior pituitary cells.
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PMID:Multiple transduction mechanisms of dopamine, somatostatin and angiotensin II receptors in anterior pituitary cells. 256 74

The phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) and thyroliberin exerted additive stimulatory effects on prolactin release and synthesis in rat adenoma GH4C1 pituicytes in culture. Both TPA and thyroliberin activated the adenylate cyclase in broken cell membranes. When combined, the secretagogues displayed additive effects. TPA did not alter the time course (time lag) of adenylate cyclase activation by hormones, guanosine 5'-[beta,gamma-imino]triphosphate or forskolin, nor did it affect the enzyme's apparent affinity (basal, 7.2 mM; thyroliberin-enhanced, 2.2 mM) for free Mg2+. The TPA-mediated adenylate cyclase activation was entirely dependent on exogenously added guanosine triphosphate. ED50 (dose yielding half-maximal activation) was 60 microM. Access to free Ca2+ was necessary to express TPA activation of the enzyme, however, the presence of calmodulin was not mandatory. TPA-stimulated adenylate cyclase activity was abolished by the biologically inactive phorbol ester, 4 alpha-phorbol didecanoate, by the protein kinase C inhibitor polymyxin B and by pertussis toxin, while thyroliberin-sensitive adenylate cyclase remained unaffected. Experimental conditions known to translocate protein kinase C to the plasma membrane and without inducing adenylate cyclase desensitization, increased both basal and thyroliberin-stimulated enzyme activities, while absolute TPA-enhanced adenylate cyclase was maintained. Association of extracted GTP-binding inhibitory protein, Gi, from S49 cyc- murine lymphoma cells with GH4C1 cell membranes yielded a reduction of basal and hormone-stimulated adenylate cyclase activities, while net inhibition of the cyclase of somatostatin was dramatically enhanced. However, TPA restored completely basal and hormone-elicited adenylate cyclase activities in the Gi-enriched membranes. Finally, TPA completely abolished the somatostatin-induced inhibition of adenylate cyclase in both hybrid and non-hybrid membranes. These data suggest that, in GH4C1 cells, protein kinase C stimulation by phorbol esters completely inactivates the n alpha i subunit of the inhibitory GTP-binding protein, leaving the n beta subunit functionally intact. It can also be inferred that thyroliberin conveys its main effect on the adenylate cyclase through activation of the stimulatory GTP-binding protein, Gs.
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PMID:Protein kinase C stimulates adenylate cyclase activity in prolactin-secreting rat adenoma (GH4C1) pituicytes by inactivating the inhibitory GTP-binding protein Gi. 256 96


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