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)

Dwarf (dw/dw) rats exhibit a 40% reduction in body growth, isolated GH deficiency (less than 5% of normal pituitary content), and a decreased number of pituitary somatotrophs (15-20% of normal). Since GH-releasing factor (GRF) stimulates GH synthesis and secretion and somatotroph proliferation, and its effects are probably mediated by cAMP, we have assessed GH secretion and cAMP production in dw rat pituitaries in response to various GH secretagogues. Dispersed pituitary cells from dw rats were less sensitive (2.5-fold) to stimulation of GH secretion by GRF and showed a 25% reduction in the maximal GH response even after normalization of their reduced GH content. Intracellular cAMP was elevated 63-fold over basal levels in normal cells after 4 h in response to maximal GRF stimulation, but only 1.9-fold in dw cells, and even larger differences between the groups were found at earlier time points. The GH responses of dw cells to exogenous cAMP, however, were indistinguishable from normal. Forskolin, a direct stimulator of adenylate cyclase, elicited comparable maximal GH and cAMP responses, but an increased ED50, in dw cells. Activation of GS alpha by cholera toxin showed an increased ED50 and reduced GH and cAMP responses in dw cells, and marked decreases in these responses were observed in response to prostaglandin E1. Phorbol ester stimulation resulted in a reduced maximal GH response in dw cells without a change in sensitivity. These results provide evidence for a defect in the GRF signal transduction pathway associated with a decreased ability of GS alpha to stimulate adenylate cyclase in dw rat somatotrophs that may be causally linked to their GH deficiency.
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PMID:Evidence for a defect in growth hormone-releasing factor signal transduction in the dwarf (dw/dw) rat pituitary. 164 12

Two human parathyroid hormone-related protein (hPTHrP) fragments were tested for effects on maternofetal transfer of 45Ca and Mg across the in-situ perfused rat placenta at 21 days of gestation (term = 23 days). The fetal placental circulation was perfused with a Mg-free Krebs-Ringer solution and the unidirectional maternofetal clearance (Kmf) of 45Ca and Mg compared with that of 51Cr-EDTA, the latter being employed as a paracellular diffusional marker. Placental perfusion with hPTHrP(1-34) (100 ng/ml) or hPTHrP(75-86)amide (50 ng/ml) did not significantly alter the Kmf of 45Ca or that of Mg. In separate rats, however, hPTHrP(1-34) but not hPTHrP(75-86)amide stimulated marked placental cyclic AMP (cAMP) release, the peak response of 63 +/- 7 pmol/min occurring 10 min after the beginning of the peptide perfusion. A lower dose of hPTHrP(1-34) (4 ng/ml) produced a similar peak release of cAMP, as did [Nle8,21, Tyr34]-rPTH(1-34)amide (4 ng/ml) and the adenylate cyclase agonist forskolin (17 mumol/l). Forskolin also rapidly increased the Kmf of 45Ca but not that of Mg or 51Cr-EDTA. The present study indicates that hPTHrP does not acutely affect maternofetal transfer of Ca or Mg across the perfused rat placenta. The data also question the role played by cAMP in the stimulatory actions of forskolin on placental Ca transport.
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PMID:Effects of two synthetic parathyroid hormone-related protein fragments on maternofetal transfer of calcium and magnesium and release of cyclic AMP by the in-situ perfused rat placenta. 164 89

Little is known about the relative stoichiometry of guanine nucleotide-binding (G) proteins relative to the effector systems to which they link. We addressed this question for the stimulatory G protein (Gs) linked to adenylate cyclase. Forskolin stimulates the catalytic subunit of adenylate cyclase (C), but it has a higher efficacy and potency when C also interacts with the G protein Gs. Accordingly, we measured high-affinity [3H]forskolin binding to intact cells to assay alpha s-C complexes. No high-affinity specific binding occurred with unstimulated cells. The beta-adrenergic agonist isoproterenol promoted the binding of [3H]forskolin to about 3000 sites per cell, suggesting that each receptor on average activates at least several Gs molecules. Activating Gs directly with cholera toxin maximally promoted [3H]forskolin binding to a similar number of sites, suggesting that this is the maximal number of alpha s-C complexes formed per cell. We conclude that each cell likely contains only a few thousand functional copies of C, and that the availability of C (rather than Gs, which exists in more than 100,000 copies per cell) is likely to be limiting for agonist stimulation of adenylate cyclase activity.
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PMID:Stoichiometry of receptor-Gs-adenylate cyclase interactions. 165 Mar 14

The acrosome reaction of spermatozoa appears to be analogous to various somatic cell exocytotic events which involve cascade reactions, i.e., transmission of an external signal across the cell membrane resulting in activation of an "amplifier" enzyme and the generation of a second messenger. Using a synchronous acrosome reaction system (De Jonge et al., J. Androl., 10:232-239, '89a), it was found that analogues of the second-messenger cAMP, dibutyryl cAMP (dbcAMP) and 8-bromo cAMP, stimulated the acrosome reaction of capacitated spermatozoa. Additionally, treatment of spermatozoa with either xanthine or non-xanthine phosphodiesterase inhibitors induced a significant (P less than 0.05) increase in the percent acrosome reaction after a period of capacitation in comparison to untreated controls. These results indicate that analogues of cAMP or inhibitors which prevent cAMP hydrolysis can induce the human sperm acrosome reaction. Subsequent experiments were conducted to test whether the amplifier enzyme in the cascade reaction, adenylate cyclase, has a role in the acrosome reaction. Forskolin, an adenylate cyclase stimulator, caused a significant (P less than 0.01) increase in the percent acrosome reaction in comparison to controls. Modulators of adenylate cyclase--adenosine, 2'-0-methyladenosine, and 2',3'-dideoxyadenosine--significantly (P less than 0.01) inhibited the forskolin-induced acrosome reaction. dbcAMP was able to overcome the inhibition by adenosine. Two inhibitors of protein kinase A, the Walsh inhibitor and H-8, caused a significant (P less than 0.01) inhibition of the dbcAMP-induced acrosome reaction. Finally, in the absence of extracellular calcium, dbcAMP induced a significant (P less than 0.01) increase in the acrosome reaction in contrast to A23187. These results suggest that: 1) a molecular mechanism for the human sperm acrosome reaction involves the cAMP second-messenger system; i.e., activation of adenylate cyclase, the amplifier enzyme that produces cAMP, production of cAMP as a second messenger, and activation of cAMP-dependent kinase A; and that 2) activation of adenylate cyclase occurs after calcium influx.
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PMID:Modulation of the human sperm acrosome reaction by effectors of the adenylate cyclase/cyclic AMP second-messenger pathway. 165 65

The ecto-5'-nucleotidase activity of rat glomerular mesangial cells increases after exposure to prostaglandin E2 (PGE2) via cAMP stimulation (Savic et al., 1990, Immunology 70, 321). Therefore we examined whether other cAMP-stimulating agents had a similar effect. Forskolin (1 microM), PGE2 (10 microM), and isoproterenol (10 microM), three products stimulating rat mesangial cell adenylate cyclase activity, enhanced cAMP accumulation within 5 min and 5'-nucleotidase activity after a lag time of at least 24 h, 3-Isobutyl-1-methylxanthine (IBMX) and Ro 20-1724, two drugs inhibiting cAMP degradation, also stimulated cAMP accumulation and 5'-nucleotidase activity. The effects of these agents on 5'-nucleotidase activity were additive with those of the three products stimulating adenylate cyclase activity, except for Ro 20-1724 and forskolin which acted synergistically. Cycloheximide, a blocker of protein synthesis, suppressed the cAMP-dependent increase of 5'-nucleotidase activity. Because ecto-5'-nucleotidase activity is a marker of cell differentiation, the effect of the same cAMP-stimulating agents on cell proliferation was also studied. Forskolin, PGE2, and isoproterenol inhibited [3H]thymidine incorporation into rat mesangial cells in a dose-dependent manner. The same effect was obtained with IBMX (100 microM) and Ro 20-1724 (50 microM). Stimulation of 5'-nucleotidase activity and inhibition of [3H]thymidine incorporation occurred over the same range of concentrations for the various agonists tested. Taken together, these results indicate that expression of ecto-5'-nucleotidase in rat mesangial cells is induced by cAMP whatever the reason for its accumulation. The simultaneous inhibition of DNA synthesis may occur independently or be associated with the stimulation of 5'-nucleotidase expression.
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PMID:Cyclic adenosine monophosphate-stimulating agents induce ecto-5'-nucleotidase activity and inhibit DNA synthesis in rat cultured mesangial cells. 165 63

This study assessed agonist- and post-receptor-stimulated adenylate cyclase (AC) activity in parotid and submandibular salivary glands from female F-344 rats of 3, 12, and 24 months of age. Isoproterenol-stimulated dose-response activation of adenylate cyclase was unchanged between 3 and 12 months but decreased at 24 months (p less than .05). Forskolin-stimulated AC activity, representing catalytic unit activity, was decreased at 24 months in the parotid (p less than .05) and at 12 months (p less than .05) and 24 months (p less than .01) in the submandibular gland. Beta-adrenergic signal transduction in salivary glands stimulates the secretion of salivary proteins that have important functions in the maintenance of oral health.
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PMID:Beta-adrenergic signal transduction in aging parotid and submandibular salivary glands. 165 13

We have previously shown that after peripheral nerve lesion the synthesis of NGF is induced in cells of the nerve sheath (Heumann et al., 1987a). Further analysis led to the identification of growth factors and intracellular mechanisms responsible for this induction in sciatic fibroblasts (Lindholm et al., 1988; Hengerer et al., 1990). The present work aimed at the elucidation of the regulation of NGF synthesis in Schwann cells. A variety of cytokines and peptide growth factors, including interleukin-1 (IL-1) and platelet-derived growth factor (PDGF), which are known to increase NGF-mRNA in fibroblasts and astrocytes, failed to do so in Schwann cell cultures. Forskolin (FK), an activator of adenylate cyclase, increased the level of NGF-mRNA eightfold within 3 hr of incubation. The effect of FK on NGF-mRNA was mimicked by analogs of cAMP but not by dideoxyforskolin, an FK derivative not activating adenylate cyclase. Application of norepinephrine and isoproterenol also augmented the NGF-mRNA content. Pretreatment of Schwann cells with N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride (H-8), an inhibitor of cyclic-nucleotide-dependent protein kinases, decreased both basal and elevated levels of NGF-mRNA. Ionomycin, a Ca2+ ionophore, and phorbol 12-myristate 13-acetate (TPA), an activator of protein kinase C, potentiated the effect of FK in an H-8-sensitive manner. We show that the action of FK is independent of changes in mRNA stability and of protein synthesis. Thus, in cultured Schwann cells upregulation of NGF-mRNA expression seems to be mainly achieved by a cAMP-triggered transcriptional activation of the NGF gene. Another striking difference between various glial cell types was revealed by application of transforming growth factor beta-1 (TGF-beta 1), which is the strongest inducer of NGF-mRNA in cultured astrocytes (Lindholm et al., 1990). Schwann cells responded to TGF-beta 1 by decreasing basal as well as FK-induced NGF-mRNA levels. Together with previously published work, our results show that cell-type-specific mechanisms not only account for the different control of NGF expression in neurons as compared to glial cells, but also reveal a surprising specificity of regulatory mechanisms in different non-neuronal cell types, even those derived from the same tissue such as fibroblasts and Schwann cells of peripheral nerves.
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PMID:Cell-type-specific regulation of nerve growth factor (NGF) synthesis in non-neuronal cells: comparison of Schwann cells with other cell types. 165 45

The dwarf (dw) mutation in rats results in 40-50% growth retardation associated with a selective reduction in pituitary somatotroph number, GH content, and GH mRNA levels and a decreased GH secretory response to GH-releasing factor (GRF). Recent studies in freshly dispersed pituitary cells have provided evidence for a defect in adenylate cyclase-linked GRF signal transduction in dw somatotrophs. To further examine this defect in a more specific cell population, we developed a somatomammotroph cell line (DP) derived from anterior pituitaries of male dw rats. A similar cell line from normal rats (Po) was used as control. We studied acute GH (4-h release) and cAMP (30-min intracellular accumulation) responses to GH secretagogues known to interact with the adenylate cyclase system. Basal GH release in both cell lines was 80-130% of the cell content, thus limiting the capacity for further GH responses. GRF (10(-8) M) produced a doubling of cAMP levels in Po and DP cells (P less than 0.01), but inconsistent effects on GH release. (Bu)2cAMP (5 x 10(-3) M) increased GH secretion by 50-100% in both groups (P less than 0.01). Cholera toxin (10(-9) M) increased GH release by 50% in both Po and DP (P less than 0.01), but the cAMP response in DP cells was only half that in Po cells (P less than 0.01). Forskolin (10(-5) M), a direct stimulator of adenylate cyclase, doubled GH release in both groups (P less than 0.01). However, cAMP generation was impaired in DP, with a maximal response to forskolin less than one third that in Po (P less than 0.01). In somatotrophs, cAMP mediates not only GRF-stimulated GH release, but also GH synthesis and mitogenesis. The impairment in maximal cAMP generation in DP cells, while not affecting acute GH release, may underlie the defect in somatotroph cell number and GH content in the dw pituitary gland.
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PMID:Impaired generation of cyclic adenosine 3',5'-monophosphate in a somatomammotroph cell line derived from dwarf (dw) rat anterior pituitaries. 165 31

The possible roles of cyclic AMP and protein kinase C in the release of renin from human decidual cells were investigated by examining renin release from monolayers of decidual cells exposed for 72 h to agents that increase intracellular cAMP or activate protein kinase C. Dibutyryl cAMP (10-1000 microM caused a dose-dependent stimulation of renin release after a 24-h exposure. Maximal stimulation, 410 per cent greater than that of control cells, occurred at 72 h, and 98 per cent of the renin released into the medium was in the form of prorenin. Forskolin (10-1000 microM) and cholera toxin (CT. 20-1000 ng/ml), both of which stimulate adenyl cyclase, also stimulated prorenin release. Phorbol myristate acetate (PMA), an activator of protein kinase C, had little effect on basal prorenin release at 100 nM but potentiated the stimulation of prorenin release by cAMP and CT. The effects on prorenin release were paralleled by stimulation of active renin release. The results of this study therefore implicate cAMP and protein kinase C in the regulation of prorenin release from decidual cells and suggest that prorenin release from the decidua and other tissues is regulated by the same second messengers.
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PMID:Cyclic AMP as a second messenger for prorenin release from human decidual cells. 166 20

The mechanism of adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca(2+)-induced Cl- secretion was studied in monolayers of the colon carcinoma cell line HT-29.cl19A by combined short-circuit current (Isc) and 125I- or 36Cl- efflux measurements. Forskolin, a specific adenylate cyclase activator, was found to induce a large increase in Isc and a two- to threefold increase in 36Cl- efflux solely across the apical border. The fractional efflux of 36Cl-compared with 125I- (basal ratio 1.71 +/- 0.28) did not change significantly in the presence of forskolin (1.91 +/- 0.45). In contrast, the Ca2+ ionophore A23187 did not appreciably affect the Isc but enhanced 36Cl- and 125I- efflux at the apical and basolateral side of the monolayer. Furthermore, the fractional efflux ratio of 36Cl- to 125I- changed dramatically to a value of 0.36 +/- 0.14. Both forskolin- and A23187-induced 36Cl- or 125I- efflux were only weakly inhibited by the putative Cl- channel blocker 5-nitro-2-(3-phenylpropylamino)-benzoicacid. Carbachol, a Ca(2+)-linked agonist, mimicked the effects of A23187 on the 36Cl- and 125I- efflux but additionally provoked a significant increase in Isc. These data show that Ca2+ and cAMP activate different Cl-efflux pathways in HT-29.cl19A cells. Most likely these pathways represent a cAMP-activated conductance in the apical membrane and a separate Ca(2+)-activated Cl- conductance expressed in both apical and basolateral membranes. Apparently cholinergic agonists induce net electrogenic Cl- secretion through an intracellular signaling pathway (e.g., protein kinase C activation) different from the one activated by Ca2+/Ca2+ ionophore alone.
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PMID:Ca2+ and cAMP activate different chloride efflux pathways in HT-29.cl19A colonic epithelial cell line. 166 17


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