Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An important factor in regulating secretion from endocrine cells is the cytoplasmic concentration of cyclic-AMP. Many regulatory substances are known to either stimulate or inhibit the production of this second messenger through activation of their receptors. In the present study, we have monitored changes in cyclic-AMP efflux from melanotrope cells of Xenopus laevis in response to established neurochemical regulators of alpha-MSH secretion. In vitro superfusion of neurointermediate lobes allows for a dynamic recording of cyclic-AMP production in relation to hormone secretion. Unlike alpha-MSH secretion, the efflux of cyclic-AMP was not dependent on the concentration of extracellular calcium, indicating that hormone release and cyclic-AMP efflux are mediated by different mechanisms. The phosphodiesterase inhibitor IBMX and the adenylate cyclase activator forskolin stimulated cyclic-AMP efflux, but had no stimulatory effect on alpha-MSH release. This indicates that an increase in cyclic-AMP production in melanotrope cells is not necessarily accompanied by an increase in the rate of alpha-MSH release. Corticotropin-releasing factor stimulated cyclic-AMP efflux with dynamics similar to that induced by the amphibian peptide sauvagine. Dopamine and the GABAB receptor agonist baclofen both inhibited cyclic-AMP efflux and alpha-MSH release, with similar dynamics of inhibition and similar dose-response relationships. It is proposed that an inhibition of cyclic-AMP efflux is coupled to an inhibition of alpha-MSH secretion.
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PMID:Dynamics of cyclic-AMP efflux in relation to alpha-MSH secretion from melanotrope cells of Xenopus laevis. 127 39

Release of alpha-MSH from the pars intermedia melanotrope cells of Xenopus laevis is regulated by various classical neurotransmitters and neuropeptides. We have examined the effect of two of these regulatory substances, the neurotransmitter GABA and the CRF-related peptide sauvagine, on the adenylate cyclase system of the melanotrope cells. Sauvagine treatment, which stimulates alpha-MSH release, lead to an elevation in the level of cyclic-AMP, an effect which was potentiated by cholera toxin. Treatment with baclofen, a GABAB receptor agonist, gave a pertussis toxin-sensitive decrease in the cyclic-AMP level and an inhibition of alpha-MSH release. We conclude that sauvagine stimulates alpha-MSH secretion through activation of adenylate cyclase and that GABAB receptor activation inhibits secretion through inhibition of cyclic-AMP production. Baclofen treatment sensitized melanotrope cells to the stimulatory action of 8-bromo-cyclic-AMP on the secretion of alpha-MSH. This observation supports the conclusion that GABAB receptor activation inhibits cyclic-AMP production.
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PMID:The CRF-related peptide sauvagine stimulates and the GABAB receptor agonist baclofen inhibits cyclic-AMP production in melanotrope cells of Xenopus laevis. 185 60

Some newer knowledge concerning the metabolism of the ascorbic acid as well as its importance for the pituitary gland, the adrenal glands, the immune system and the bone formation are described. A large enrichment of the ascorbic acid is present in the pituitary gland and in the adrenal glands. In the pituitary gland the compound is constituent of the Cu-containing peptidyl-glycine-alpha-amidizating-monooxygenase which among others is necessary for the formation of alpha-MSH a lack of ascorbic acid diminishes the formation of alpha-MSH at stress the increased binding of ACTH to the cells of the middle and inner layer of the adrenal cortex leads to the fact that about 40 to 60% of the quantity of ascorbic acid are delivered. This evokes an increase of the activity of the adenylate cyclase as well as of the C21-hydroxylase: The synthesis and secretion of glucocorticosteroids increases. When there is a deficiency of ascorbic acid the content of cortisol in the plasma increases. The ascorbic acid is a constituent of the dopamine-beta-hydroxylase.
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PMID:[Some recent discoveries of metabolism and function of ascorbic acid]. 219 15

The role of protein phosphorylation in MSH-induced melanogenesis was investigated with an in vivo phosphorylation assay using intact cultured Cloudman S91 mouse melanoma cells preincubated with [32P]orthophosphate. Exposure of the cells to alpha-MSH increased the extent of labelling of two protein bands on SDS gel electrophoresis with estimated molecular weights of 43 and 34 kDa, respectively. The 32P incorporation was concentration-dependent and reached a maximal value at 10(-8) M alpha-MSH for the 43 kDa band (156% of controls) and at 10(-5) M alpha-MSH for the 34 kDa band (250% of controls). The corresponding ED50s were 5 X 10(-10) M (43 kDa) and 3 X 10(-8) M (34 kDa). The 32P incorporation into the 34 kDa band reached a maximum after a 5 min exposure to alpha-MSH whereas 43 kDa phosphorylation was maximal after a 30-60 min incubation with hormone. The effect was completely reversible after removal of the hormone and specific for melanotropic peptides. Dibutyryl cAMP (10(-3) M) and forskolin (10(-4) M) together with isobutylmethylxanthine (10(-4) M) mimicked the effect of alpha-MSH, pointing to an involvement of adenylate cyclase activation in the phosphorylation of both the 34 kDa and the 43 kDa protein. Preliminary observations showed that the 34 kDa protein is membrane-bound whereas the 43 kDa protein is of mitochondrial or melanosomal origin.
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PMID:alpha-MSH-induced changes in protein phosphorylation of Cloudman S91 mouse melanoma cells. 243 92

Pro-opiomelanocortin-derived peptides, alpha-MSH and beta-endorphin, are synthesized and secreted by Leydig cells, and are believed to have paracrine effects on Sertoli cells in the testis. Peptides with MSH activity stimulate adenylate cyclase and cAMP accumulation in Sertoli cell-enriched cultures. The purpose of the present study was to determine whether such peptides would affect Sertoli cell parameters, such as aromatase and plasminogen activator activities, that are known to be regulated by cAMP. alpha-MSH stimulated aromatase activity in Sertoli cell-enriched cultures prepared from 10-day-old rats and this effect was potentiated by methyl isobutylxanthine (MIX). The combination of alpha-MSH plus MIX was not as potent as FSH. alpha-MSH, des-acetyl-alpha-MSH, beta-MSH, ACTH(1-13), and ACTH(1-24) stimulated aromatase activity to a similar extent, suggesting that Sertoli cells do not distinguish between the activities of these peptides. alpha-MSH potentiated the action of dbcAMP and forskolin on Sertoli cell aromatase, but unexpectedly had no effect on the action of either half-maximal or maximal doses of FSH. The regulation of plasminogen activator was examined next; urokinase was markedly suppressed by FSH in 10-day-old Sertoli cells. Although neither alpha-MSH nor MIX alone had an effect on urokinase secretion, in combination they were as effective as FSH. In 10-day-old Sertoli cells each of these peptides had little or no effect on tissue plasminogen activator.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Estradiol and plasminogen activator secretion by cultured rat Sertoli cells in response to melanocyte-stimulating hormones. 247 57

We examined the cultured mouse melanoma cell line B16 (clone F1) and its wheat germ agglutinin-resistant variant Wa4 that suffers from abnormal protein glycosylation (a high fucose:sialic acid ratio in glycoproteins). In both cell lines the adenylate cyclase system was endowed with a functional guanine nucleotide binding protein Gs and was efficiently coupled to alpha-MSH receptors. In the B16 cell line F1 studied we also observed an efficient stimulation of adenylate cyclase activity by helodermin, VIP and the VIP analogue [acetyl-His1]VIP, and also by PGE1. In membranes from the lectin-resistant variant Wa4, the stimulations by VIP-like peptides and by PGE1 were reduced by 60% and 50%, respectively, while the stimulation by alpha-MSH remained normal. As other components of the adenylate cyclase system (Gs site, catalytical unit) appeared unchanged in the Wa4 variant, we conclude that impaired glycosylation essentially affected the number of both VIP-like peptide receptors and PGE1 receptors.
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PMID:Decreased adenylate cyclase activation by helodermin and PGE1 in the lectin-resistant variant Wa4 of the mouse melanoma cell line B16. 255 62

At the final step of melanocyte differentiation in mouse hair follicles, the cells produce melanin. The type of melanin they produce is, however, determined by the tissue environment of hair follicles. In wild-type mice, melanocytes located in hair bulbs synthesize eumelanin at the beginning of hair growth. They subsequently produce pheomelanin and finally produce eumelanin again. Therefore, the hair is characterized by a subterminal band of yellow, with the rest of it displaying black. This characteristic is called the agouti pattern and is known to be determined by the wild-type allele, A at the a (agouti) locus, which is considered to function in the follicular cells. Expression of the agouti pattern is altered by genetic substitutions at the a locus and the e (extension) locus. Animals heterozygous for the Ay (lethal yellow) allele exhibit yellow coat color; those homozygous for the e (recessive yellow) also produce yellow hair exclusively. By using an organ culture method, we demonstrated that alpha-MSH and cholera toxin, as well as forskolin, induced eumelanin synthesis in explants from lethal yellow mice (Ay/a). On the other hand, these reagents did not induce eumelanogenesis in the hair follicles of recessive yellow (e/e) mice. Therefore, we assume that the product of the a locus, which probably functions in follicle cells, interacts with alpha-MSH at the alpha-MSH receptor and that the e locus controls the functionality of adenylate cyclase in the membrane of mouse melanocytes.
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PMID:Genetic control of signal transduction in mouse melanocytes. 271 58

Very little has been known of the biochemical function of a human adrenocortical carcinoma cell line, SW-13. In this study, the production of several adrenal steroids and 3', 5'-cyclic adenosine monophosphate (cAMP) were investigated in this cell line. The cells were incubated in L-15 medium containing 0.1% bovine serum albumin with several reagents in an atmosphere of 5% CO2 and 95% air for 2 hours at 37 degrees C. Aldosterone (Ald), corticosterone (B), cortisol (F), dehydroepiandrosterone sulfate (DHEA-S) and cAMP were simultaneously assayed by specific radioimmunoassays in the medium and cells. Significant increases in cAMP production were observed by cholera toxin (10 ng/ml) and forskolin (10 nM), both direct stimulators of adenylate cyclase, in the cAMP concentration without an increase in the steroids. The DHEA-S concentration in the medium was significantly increased by angiotensin-II (10(-7)M), noradrenalin (3 X 10(-5) M), adrenalin (3 X 10(-5) M) or alpha-melanocyte-stimulating hormone (alpha-MSH, 10(-7) M), none of which was associated with cAMP production. Neither adrenocorticotropin (10(-10) M) nor human chorionic gonadotropin (500 mIU/ml) stimulated the release of the steroids or cAMP production. A calcium ionophore, A23187 (10(-7) M), and 12-O-tetradecanoylphorbol-13-acetate (10(-8) M), a direct stimulator of protein kinase C, stimulated the release of DHEA-S, but not those of Ald, B and F. The results suggest that SW-13 retains functioning adenylate cyclase which, however, is not linked with steroidogenesis and that DHEA-S is produced probably by the mechanisms which involve protein kinase C system or calcium ion. This report provides the first demonstration of cAMP and DHEA-S production in SW-13 and suggests that this cell line is potentially useful for investigating the mechanisms of steroidogenesis in the human adrenal cortex.
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PMID:Dehydroepiandrosterone sulfate (DHEA-S) and 3', 5'-cyclic adenosine monophosphate (cAMP) production in a cultured human adrenocortical carcinoma cell line (SW-13). 284 Feb 74

Photoaffinity labelling of MSH receptors on Anolis melanophores was used as a tool for studying the effects of catecholamines, calcium and forskolin on hormone-receptor interaction and receptor-adenylate cyclase coupling. Covalent attachment of photoreactive alpha-MSH to its receptor was suppressed in calcium-free buffer but was hardly influenced by catecholamines or forskolin. The longlasting signal generated by the covalent MSH-receptor complex was readily and reversibly abolished by adrenaline, noradrenaline, dopamine or clonidine or by the absence of calcium. The suppression of pigment dispersion by catecholamines was blocked by the simultaneous presence of yohimbine but not prazosin, indicating that the catecholamines antagonize the alpha-MSH signal by inhibitory action on the adenylate cyclase system through an alpha-2 receptor. Forskolin, which stimulates melanophores by direct action on the catalytic unit of the adenylate cyclase and at about the same speed as alpha-MSH, produced a slower and weaker response in the presence of noradrenaline. If MSH receptors were covalently labelled and then exposed to noradrenaline, the characteristics of the forskolin-induced response were identical to those of unlabelled cells that had not been exposed to noradrenaline. This may point to a partial restoration of receptor-adenylate cyclase coupling by forskolin. The results show that the longlasting stimulation of Anolis melanophores by photoaffinity labelling proceeds via a permanently stimulated adenylate-cyclase system whose coupling to the receptor depends on calcium and is abolished by alpha-2 receptor agonists. Calcium is also essential for hormone-receptor binding.
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PMID:Photoaffinity labelling of MSH receptors on Anolis melanophores: effects of catecholamines, calcium and forskolin. 286 Feb 47

1. The darkening actions of MCH (melanin concentrating hormone), alpha-MSH and the synthetic analog [Nle4, D-Phe7]-alpha-MSH on the toad, Bufo ictericus ictericus, melanophores were studied regarding the role of calcium in the hormone receptor coupling, signal transduction and intracellular pigment translocation. 2. In the absence of external calcium, MCH and both melanotropins still elicit maximal skin darkening. 3. Verapamil, a calcium-channel blocker, completely abolishes the alpha-MSH-induced response and partially inhibits MCH-induced darkening, although the calcium carrier, ionophore A23187, was unable to promote any pigment translocation. 4. Since darkening responses promoted by cyclic nucleotides proceeded normally in the presence of verapamil and extracellular calcium was not necessary for melanotropin dispersing action, it is suggested that the blocking activity obtained with verapamil is probably due to an impairment of the Ca2+-dependent adenylate cyclase activity. 5. Reversal of melanotropin-induced darkening could be obtained with melatonin, in both normal and Ca2+-free Ringer, whereas MCH darkening is reversed by melatonin only in the absence of calcium. 6. The results seem to indicate that calcium is not required for hormone receptor binding and pigment migration, whereas it is specifically needed for signal transduction.
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PMID:alpha-MSH (melanocyte stimulating hormone) and MCH (melanin concentrating hormone) actions in Bufo ictericus ictericus melanophores. 288 67


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