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)

A role for cAMP in the process of LHRH release was suggested several years ago, but only recently has the validity of this notion come under close scrutiny. In the present experiments we have used three probes, which stimulate adenylate cyclase activity via different mechanisms, to determine whether an increase in endogenous cAMP results in LHRH release from the hypothalamus of prepubertal female rats. Median eminences from juvenile, 28-day-old animals were incubated in vitro with either forskolin (F), cholera toxin (CT), or pertussis toxin (PT). All three substances enhanced LHRH release. The estimated ED50 values were 28.7 microM and 20.0 ng/ml, for F and PT, respectively. The effect of CT appeared biphasic and thus no ED50 could be calculated. None of these agents increased the release of prostaglandin E2 (PGE2), an obligatory component in the process of norepinephrine-induced LHRH secretion. Doses of PGE2 and F, which were maximally effective in stimulating LHRH release when administered separately, did not produce any further response when administered concomitantly, thus suggesting that PGE2 and F act along a common pathway. Blockade of phosphodiesterase activity with 1-methyl-3-isobutylxanthine increased LHRH secretion without enhancing PGE2 release, implying that cAMP metabolism was elevated in the median eminence nerve terminals in vitro. Addition of 1-methyl-3-isobutylxanthine augmented the LHRH response to CT and PT, but it did not increase further the already marked LHRH response to PGE2 or F. The results indicate that both an increase in adenylate cyclase activity and a decrease in phosphodiesterase activity lead to LHRH release from the median eminence. They also suggest that, upon proper (neurotransmitter?) stimulation, cAMP production increases subsequent to the activation in PGE2 synthesis, which itself causes LHRH release. Furthermore, the capacity of PT to induce LHRH release suggests the involvement of an inhibitory guanine nucleotide-binding regulatory protein in transducing inhibitory inputs impinging on LHRH-secreting neurons.
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PMID:Stimulation of cyclic adenosine 3',5'-monophosphate production enhances hypothalamic luteinizing hormone-releasing hormone release without increasing prostaglandin E2 synthesis: studies in prepubertal female rats. 241 Feb 36

Voltage-dependent Ca2+ currents appear to be involved in the actions of hormones that regulate pituitary secretion. In order to investigate modulation of Ca2+ currents by release-inducing and release-inhibiting hormones, we performed whole-cell clamp experiments in the pituitary cell line GH3. The resting potential was approximately -40 mV; spontaneous action potentials were observed in the majority of cells. Superfusion of cells with the stimulatory hormone, LHRH, depolarized the plasma membrane to approximately -10 mV, whereas the inhibitory hormone, somatostatin, caused hyperpolarization to approximately -60 mV; both hormones suppressed spontaneous action potentials. Under voltage clamp conditions, GH3 cells exhibited slowly and fast inactivating Ca2+ currents. LHRH increased whereas somatostatin decreased the slowly inactivating currents; fast inactivating currents were not affected by these hormones. The stimulatory effect of LHRH was not mimicked by intracellularly applied cAMP. In contrast to vasoactive intestinal peptide and forskolin, LHRH did not activate adenylate cyclase in membranes of GH3 cells, but rather appeared to cause inhibition of the enzyme. Hormonal stimulation and inhibition of inward currents were abolished by pretreatment of the cells with pertussis toxin. In membranes of GH3 cells, we identified a pertussis toxin-sensitive G-protein of the Gi-type and Go. We conclude that LHRH and somatostatin modulate voltage-dependent Ca2+ currents via cAMP-independent mechanisms involving pertussis toxin-sensitive G-proteins. The occurrence of both pertussis toxin-sensitive hormonal stimulation and inhibition of voltage-dependent Ca2+ currents in one cell type suggest that these opposite regulations are mediated by distinct G-proteins.
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PMID:Cyclic AMP-independent, dual regulation of voltage-dependent Ca2+ currents by LHRH and somatostatin in a pituitary cell line. 245 19

The effects of human chorionic gonadotropin (hCG) and prostaglandin F2 alpha (PGF2 alpha) on the adenylate cyclase-cAMP and inositol phospholipid-phospholipase C-inositol trisphosphate and diacylglycerol transmembrane signalling systems were evaluated in cultured human granulosa-luteal cells. Granulosa-luteal cells obtained from patients undergoing in vitro fertilization were cultured for 72 h prior to addition of hormones. During the last 24 h of culture granulosa-luteal cells were incubated with [3H]inositol. Neither hCG nor gonadotropin-releasing hormone (GnRH) stimulated the inositol phospholipid-phospholipase C signalling system. PGF2 alpha stimulated increases in inositol mono-, bis-, and trisphosphate accumulation in 30 min incubations. NaF (20 mM) mimicked the stimulatory effect of PGF2 alpha on inositol phosphate accumulation suggesting the involvement of a guanine nucleotide regulatory protein in the activation of phospholipase C. In contrast, hCG but not PGF2 alpha or NaF stimulated cAMP accumulation in 30 min incubations. Simultaneous treatment with hCG and PGF2 alpha did not alter the stimulatory effect of PGF2 alpha on inositol phosphate accumulation but reduced (37%) the stimulatory effect of hCG on cAMP accumulation. The protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA) inhibited the stimulatory effects of hCG (76%) and PGF2 alpha (62%) on cAMP and inositol phosphate accumulation, respectively. Thus, cultures of human granulosa-luteal cells possess multiple transmembrane signalling systems which may be modulated by the activation of protein kinase C.
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PMID:Effects of human chorionic gonadotropin, prostaglandin F2 alpha and protein kinase C activators on the cyclic AMP and inositol phosphate second messenger systems in cultured human granulosa-luteal cells. 255 Feb 98

One single injection of ethylene dimethane sulfonate (EDS) to mature rats causes specific degeneration of testicular Leydig cells which is complete after 3 days. At this time no steroidogenic activities can be detected, indicating that Leydig cells are the source of steroids. The mechanism of this cytotoxic effect of EDS has been investigated with isolated cells. Extensive protein alkylation has been shown to occur in Leydig cells, Sertoli cells and hepatocytes. Steroid production by Leydig cells is always inhibited by EDS, but cytotoxic effects of EDS could only be demonstrated in Leydig cells from mature rats or tumour tissue and not in Leydig cells from immature rats. A new population of Leydig cells develops during the next 2-5 weeks after EDS treatment. In hypophysectomized rats this repopulation only occurs when hCG is given daily. FSH has no effects. The proliferative activity in the interstitial tissue increases within 2 days after administration of hCG or EDS and there are indications that LH and locally produced factors are involved in the proliferation of Leydig cells or Leydig cell precursor cells. Inhibition of cAMP production with inhibitors of adenylate cyclase results in an enhancement of the LH-stimulated steroid production similar to that observed with an LHRH agonist and phospholipase C (PLC). Since the effects of LHRH and PLC on protein phosphorylation and steroid production are similar and different from LH or active phorbol esters, it is proposed that LHRH and PLC may stimulate steroid production via liberation of calcium from a specific intracellular pool. Sterol carrier protein2 (SCP2) which is specifically localized in Leydig cells and regulated by LH probably plays a role in the delivery of cholesterol to the mitochondria although the mechanism of this carrier function is not clear. The results indicate that regulation of Leydig cell development and the steroidogenic activities by gonadotrophins and locally produced factors occur via different transducing systems and regulatory pathways.
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PMID:Multiple regulation of testicular steroidogenesis. 282 90

A series of compounds containing combinations of one or two pharmacophores of the agonist type (isoproterenol) or the antagonist type (propranolol or alprenolol) on the same molecule were prepared. The pharmacophores were connected by a derivative of polyethylene glycol with an average length of six atoms (carbon and oxygen). Furthermore, compounds containing two alprenolol residues, separated by chains of average lengths of 70 or 145 atoms, were synthesized. The abilities of these compounds to interact with beta-adrenoceptors of rat heart and lung tissues were examined by measuring the following parameters: competitive binding with [3H]dihydroalprenolol, activation of adenylate cyclase, and inhibition of isoproterenol-stimulated adenylate cyclase. The affinity of the compound with two isoproterenol pharmacophores for receptor was about the same as that with one isoproterenol pharmacophore and between 30 and 200 times weaker than that of (+/-)isoproterenol. Both mono- and bis-pharmacophore compounds partially stimulated catecholamine sensitive adenylate cyclase and at high concentrations inhibited the stimulation produced by (-)isoproterenol. The affinity of the compound with antagonist (propranolol) and agonist (isoproterenol) pharmacophores on the same molecule was intermediate between that of propranolol and isoproterenol. The compound was only able to inhibit adenylate cyclase activity. Compounds containing two antagonist (alprenolol) pharmacophores bound to receptors with affinities from an order of magnitude lower to about equal to that of the compound containing one pharmacophore. When membranes were preincubated with compounds containing two antagonist pharmacophores and then washed extensively, there were persistent effects of all of these compounds on the binding constants of [3H]dihydroalprenolol. All of these compounds were only able to inhibit adenylate cyclase activity and none exhibited any subtype selectivity at beta-adrenoceptors. The results suggest that, in the beta-adrenergic system, compounds with agonist and antagonist substituents on the same molecule exhibit properties of the substituent with the higher affinity for beta-adrenoceptor, and no agonist activity is evident when two antagonist pharmacophores are linked on the same molecule. All of the above results may be explained without recourse to cross-linking of beta-adrenoceptors with two pharmacophores, a phenomenon cited in similar studies of receptors for opiates and gonadotropin-releasing hormone.
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PMID:Two beta-adrenergic pharmacophores on the same molecule. A set of agonist-antagonist combinations. 288 May 91

Over the past twenty years, each of the five major hypothalamic releasing or release-inhibiting hormones has been sequenced and its gene structure determined. With the use of molecular biological techniques, such as in situ hybridization, Northern blot analysis or gene constructs for in vitro or in vivo transfection studies--together with 'traditional' neuroendocrinological techniques, such as immunocytochemistry, radio-immunoassay and portal vessel cannulation--investigators have been able to address major issues in neuroendocrine regulation. Several common themes have emerged: messenger RNA expression is uniformly present in neurons that are immunopositive for the specific hypothalamic hormone. Steady state RNA levels within the hypophysiotropic neuron groups are either increased or reduced by changes in specific target hormones that conform to predictions based on previous physiological data. Regulation by the requisite peripheral hormone is exquisitely anatomically specific and is not evident in extrahypophysiotropic regions. Determining the receptor or genetic basis of this specificity is a major focus of current research. Clarifying the apparently lesser role of afferent neural pathways to the hypothalamus in regulating releasing hormone mRNA levels is also an important challenge. Clinically, the measurement of levels of releasing hormones in the peripheral circulation appears to be of limited usefulness, except in rare cases of ectopic GRH or CRH secretion. For diagnostic purposes, each of the releasing hormones has specific utility in amplifying the release and measurement of pituitary hormones, both to clarify the overall physiological activity of the hypothalamic-pituitary-target hormone axis and to further define the anatomic locus of any underlying disturbance. The usefulness of somatostatin as a diagnostic tool is presently limited, but the development of SS receptor antagonists might have significant impact in future clinical investigation. The molecular mechanisms of action of the hypothalamic hormones have been separated into those whose receptor-effector function is mediated by the cAMP-adenylate cyclase pathway(s), GRH and CRH, and those working through the phosphoinositide-protein kinase C cascade, GnRH and TRH. Each of the hormone receptors is coupled to intermediary G proteins, somatostatin uniquely to the inhibitory subclass. The mechanisms responsible for sensitization (priming) or desensitization are not fully understood but are presumably related to receptor down regulation and protein phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular biology and regulation of the hypothalamic hormones. 290 17

It is proposed that premenstrual syndrome results from the action of elevated gonadotropin levels in various tissues of body other than their natural target organs. These levels are derived from an increased sensitivity to estrogen after pregnancy, childbirth, etc., particularly with respect to the positive feedback on gonadotropin release from the pituitary. Estrogen in conjunction with gonadotropin-releasing hormone (GnRH) releases excessive amounts of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) at ovulation and in the premenstrual phase (post-menopausal patients have greatly elevated gonadotropins and can also demonstrate cyclic symptoms). Gonadotropin action via adenylate cyclase in the adrenal cortex elevates cortisol, while antagonism of parathyroid hormone action on bone gives rise to hypocalcemia. The physiological and psychological symptoms may thereby be explained.
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PMID:Pre-menstrual syndrome--are gonadotropins the cause of the condition? 300 49

The effects of spent media from seminiferous tubules (STM) on Percoll-purified rat Leydig cells were investigated. Intracellular and extracellular cyclic AMP (cAMP) accumulation and testosterone production were measured. After a 5 h incubation period, STM reduces both the basal and LH-dependent cAMP levels (38 and 20%, respectively for intra- and extracellular cAMP) while, simultaneously, a stimulation of testosterone production is observed (47 to 50%, respectively in the absence or presence of LH). The reduction of cAMP levels observed after 5 h is likely to be due to the potentiating effect of the STM factor on the LH-dependent initial rise of the cAMP level which, in turn, induces a desensitization of the Leydig cell adenylate cyclase. This substance is a thermolabile protein (Mr greater than 50 000) produced by the Sertoli cell, independent of FSH and testosterone controls, and different from the LHRH-like substance.
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PMID:Effects of seminiferous tubule secreted factor(s) on Leydig cell cyclic AMP production in mature rat. 301 82

Adult rat Leydig cell aromatase activity is stimulated 2.5 fold by LH or dbcAMP. Spent media prepared from seminiferous tubules or Sertoli cells of immature rats depress both the basal and the LH stimulated estradiol syntheses (25 and 20% decreases, respectively). These inhibitory effects are further enhanced when FSH is added to the culture medium of seminiferous tubules or Sertoli cells. Rat serum as well as culture media from other cell lines are ineffective while seminiferous tubule media from other immature animals (mouse, guinea-pig, calf) inhibit the aromatase activity. This Sertoli cell factor is a heat stable protein (molecular weight greater than 10 kDa), different from the LHRH-like Sertoli cell compound, which acts on the aromatase activity at a step beyond the adenylate cyclase.
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PMID:Spent media from immature seminiferous tubules and Sertoli cells inhibit adult rat Leydig cell aromatase activity. 303 Sep 13

An in vitro superfusion system was used in an attempt to identify the cellular systems involved in the Ca2+ dependence of gonadotropin-releasing hormone (GnRH) actions in the frog, Rana pipiens. Superfusion with 5 microM A23187 (a calcium ionophore) or phorbol myristate acetate (an analog of diacylglycerides) caused marked increases in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Exclusion of Ca2+ from the medium prevented the stimulatory effects of PMA. The potent stimulator of adenylate cyclase, forskolin, caused only slight stimulation of LH and FSH secretion, which was also prevented by removal of Ca2+. The cytoskeletal disruptive agents colchicine, nocodazole, and cytochalasin B, and the calmodulin inhibitors, trifluoperazine and pimozide, had no significant effects on the action of GnRH. Overall, these results indicate that the major mechanisms of Ca2+ involvement in the response to GnRH by the frog pituitary are similar to that of mammals, with the possible exceptions of lesser roles for calmodulin and the cytoskeleton in the frog. The study suggests that polyphosphatidyl-inositol-diacylglyceride metabolism may be critical in understanding the mechanism of GnRH action in frogs.
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PMID:The cellular basis of the calcium dependence of GnRH-stimulated gonadotropin release from frog, Rana pipiens, pituitaries. 309 96


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