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

---

Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of protein kinase C (PKC) activation on cyclic AMP production in GH3 cells has been studied. The stimulation of cyclic AMP accumulation induced by forskolin and cholera toxin was potentiated by 4 beta-phorbol 12,13-dibutyrate (PDBu). Moreover, PDBu, which causes attenuation of the maximal response to vasoactive intestinal polypeptide (VIP), also induced a small right shift in the dose-response curve for VIP-induced cyclic AMP accumulation. PDBu-stimulated cyclic AMP accumulation was unaffected by pretreatment of cells with pertussis toxin or the inhibitory muscarinic agonist, oxotremorine. PDBu stimulation of adenylate cyclase activity required the presence of a cytosolic factor which appeared to translocate to the plasma membrane in response to the phorbol ester. The diacylglycerol-generating agents thyroliberin, bombesin and bacterial phospholipase C each stimulated cyclic AMP accumulation, but, unlike PDBu, did not attenuate the stimulation induced by VIP. These results suggest that PKC affects at least two components of the adenylate cyclase complex. Stimulation of cyclic AMP accumulation is probably due to modification of the catalytic subunit, whereas attenuation of VIP-stimulated cyclic AMP accumulation appears to be due to the phosphorylation of a different site, which may be the VIP receptor.
...
PMID:Regulation of GH3 pituitary tumour-cell adenylate cyclase activity by activators of protein kinase C. 248 Jan 8

The B subunit of cholera toxin, a protein which binds specifically to ganglioside GM1 on the cell surface, stimulates DNA synthesis in quiescent Swiss 3T3 fibroblasts as measured by an increase in [3H]thymidine incorporation. Pertussis toxin pretreatment markedly inhibits B subunit-induced DNA synthesis. The inhibitory effects of pertussis toxin were observed even in the presence of insulin which greatly potentiates the mitogenic response to the B subunit. Treatment with either pertussis toxin or insulin did not alter the binding of the B subunit to the cells. The dose-response for pertussis toxin-induced inhibition of DNA synthesis correlated closely with the dose-response for ADP-ribosylation of a 41-kDa membrane protein, suggesting the involvement of a GTP-binding protein that is a substrate for pertussis toxin (Gi) in mitogenesis induced via cross-linking of endogenous gangliosides. Pertussis toxin, in a similar concentration-dependent manner, also inhibited the mitogenic response to unfractionated fetal calf serum and to bombesin in the absence or presence of insulin. The inhibitory effect of pertussis toxin was clearly unrelated to any effects on known G proteins coupled to adenylate cyclase or phospholipase C. In addition, pertussis toxin did not impair the early increase in cytosolic free Ca2+ induced by the B subunit or bombesin. Pertussis toxin-induced inhibition of DNA synthesis could still be observed even when the toxin was added as late as 6 h after addition of the growth-promoting agents. This suggests the involvement of a GTP-binding protein in a late step of the B subunit- and bombesin-mediated pathways of mitogenesis. The possibility that other growth factors bypass this pathway is shown by their lack of sensitivity to pertussis toxin.
...
PMID:Possible involvement of a GTP-binding protein in a late event during endogenous ganglioside-modulated cellular proliferation. 249 20

Cellular proliferation of rat glioma C6 BU1 cells in tissue culture is dependent on the presence of either calf or foetal-calf serum in the medium. Foetal-calf serum stimulated a high-affinity GTPase in membranes derived from C6 BU1 cells. Pretreatment of the cells with pertussis toxin decreased the high-affinity GTPase activity substantially, and attenuated the foetal-calf-serum-stimulated increase in this GTPase activity. Cholera toxin, in contrast, did not modulate the response to foetal-calf serum. Foetal-calf serum did not inhibit adenylate cyclase activity in membranes of these cells, indicating that the G-protein that was stimulated by foetal-calf serum was not Gi (the inhibitory one). Although the nature of the specific component of foetal-calf serum responsible for this pertussis-toxin-sensitive receptor-mediated stimulation of high-affinity GTPase activity has not been identified, it was mimicked neither by bombesin, which can stimulate inositol phospholipid turnover via a guanine nucleotide binding protein, nor by platelet-derived growth factor, which is present in substantial concentrations in foetal-calf serum. This report represents the first demonstration of a pertussis-toxin-substrate-mediated response in this cell line and provides further evidence that G-proteins other than Gi can be functionally inactivated by pertussis toxin.
...
PMID:Foetal-calf serum stimulates a pertussis-toxin-sensitive high-affinity GTPase activity in rat glioma C6 BU1 cells. 282 23

The neuropeptide bombesin acts on a variety of target cells to stimulate the processes of secretion and cell proliferation. In this study we determined whether bombesin receptors interact with known guanine nucleotide-binding proteins in four different cell types: GH4C1 pituitary cells, HIT pancreatic islet cells, Swiss 3T3 fibroblasts, and rat brain tissue. Maximal concentrations of nonhydrolyzable GTP analogs decreased agonist binding to bombesin receptors in membranes from all four sources. In GH4C1 and HIT cell membranes GTP analogs inhibited bombesin receptor binding with IC50 values of about 0.1 microM, whereas GDP analogs were approximately 10-fold less potent. In contrast, GMP and the nonhydrolyzable ATP analog adenylyl-imidodiphosphate had no effect at 100 microM. Equilibrium binding experiments in GH4C1 and HIT cell membranes indicated a single class of binding sites with a dissociation constant (Kd) for [125I-Tyr4]bombesin of 24.4 +/- 7.0 pM and a binding capacity of 176 +/- 15 fmol/mg protein. Guanine nucleotides decreased the apparent affinity of the receptors without significantly changing receptor number. Consistent with this observation, guanine nucleotides also increased the rate of ligand dissociation. Pretreatment of GH4C1 or HIT cells with either pertussis toxin (100 ng/ml) or cholera toxin (500 ng/ml) for 18 h did not affect agonist binding to membrane bombesin receptors, its regulation by guanine nucleotides, or bombesin stimulation of hormone release. Although pertussis toxin pretreatment has been reported to block bombesin stimulation of DNA synthesis in Swiss 3T3 cells, it did not alter the binding properties of bombesin receptors in Swiss 3T3 membranes or inhibit the rapid increase in intracellular [Ca2+] produced by bombesin in these cells. In summary, our results indicate that the bombesin receptor interacts with a guanine nucleotide-binding protein which exhibits a different toxin sensitivity from those which regulate adenylate cyclase as well as those which couple some receptors to phospholipases.
...
PMID:The bombesin receptor is coupled to a guanine nucleotide-binding protein which is insensitive to pertussis and cholera toxins. 283 Feb 64

We examined the effects of several in vitro experimental systems on the apparent potencies of putative secretagogues for stimulating ACTH release from rat anterior pituitary cells. Cells were prepared by trypsin digestion and gentle mechanical dispersion. Aliquots of the same cell preparations were tested in 1) a microperifusion system immediately after dispersion (day 0), 2) the same microperifusion system after 4 days of static suspension culture on a layer of Sephadex G-10 gel particles (day 4), 3) a static suspension system after 4 days of static suspension culture, and 4) a static monolayer system after 4 days of monolayer culture. Ovine CRF stimulated release of similar amounts of ACTH in all of the systems on days 0 and 4, except in one experiment, in which the response was less on day 4. Arginine vasopressin (AVP), oxytocin, and angiotensin II all appeared to be more potent in day 4 than in day 0 cells in the perifusion system, and the synergism of AVP with ovine CRF was also increased. Dioctanoylglycerol, which directly activates protein kinase-C, and forskolin, which directly activates adenylate cyclase, both stimulated greater release in day 4 cells. The mechanism(s) responsible for the difference in the responses of day 0 and day 4 cells is unknown. Epinephrine had only a small effect in the microperifusion system, but both epinephrine and norepinephrine had potencies comparable to AVP in the static suspension and monolayer systems. This was not due to prolonged exposure to the catecholamines, suggesting that these agents may act on other anterior pituitary cells to release metabolic products that secondarily stimulate the corticotrophs to release ACTH. The same situation appears to be true for atrial natriuretic factor. Gastrin-releasing peptide, its bioactive COOH-terminal half, which was active in a rat urinary bladder smooth muscle assay, its amphibian analog, bombesin, and cholecystokinin (26-33) were devoid of ACTH-releasing activity in all of the systems, in contrast to the findings of others. Since 4-day culture of dispersed cells improved most of their responses and diminished none, we postulate that they may more closely resemble normal pituitary cells in function, and since cellular metabolites are unlikely to accumulate in the interstitial fluid of the pituitary gland, we propose that the secretory functions of cells in perifusion systems may more closely resemble those in the pituitary gland in situ than they do in static incubation systems.
...
PMID:Effects of several in vitro systems on the potencies of putative adrenocorticotropin secretagogues on rat anterior pituitary cells. 283 88

We and others have recently reported an involvement of calcium (Ca2+)-mediated intracellular pathways in the release of antral gastrin in response to bombesin (BBS), while cyclic adenosine 3'5'-monophosphate (cAMP) potentiated the gastrin response to BBS. In this study we examined the effect of cyclic nucleotides on BBS-induced gastrin release from isolated perfused rat stomachs. Dibutyryl cyclic AMP (dbcAMP, 1 mM), and Rolipram (a phosphodiesterase inhibitor, 0.5 microM), stimulated basal gastrin secretion and potentiated BBS-induced gastrin release. The stimulation of gastrin release by BBS was not altered by Wiptide (a cAMP dependent protein kinase inhibitor, 1.0 microM), but was surprisingly inhibited by dbcGMP (1 mM). The cAMP content in antral mucosa or in the perfusates was not changed after infusion of BBS. These findings coupled with previous results suggest that BBS-provoked gastrin release is principally coupled to a Ca2+-mediated intracellular pathway, and that an activation of the adenylate cyclase mediated pathway is not involved. Intracellular cGMP, however, may participate in the negative regulation of gastrin release induced by BBS.
...
PMID:Effect of cyclic nucleotides on bombesin-evoked gastrin release from isolated perfused rat stomach. 284 54

Growth factors can be divided into two classes which act through distinct signal transduction pathways. One class including epidermal growth factor, platelet derived growth factor and fibroblast growth factor activates receptor tyrosine kinases, and the second class, including thrombin, bombesin, bradykinin and vasopressin activates a phosphoinositide-specific phospholipase C through GTP-binding proteins which can be inactivated by pertussis toxin. In Chinese hamster lung fibroblasts, thrombin-induced mitogenicity seems to correlate well with phospholipase C activation and both events are sensitive to pertussis toxin. Thrombin, like the other mitogens in this class, simultaneously inhibits adenylate cyclase. This involves an inhibitory G protein (Gi), a well established pertussis toxin substrate. The relative contributions of the two signalling pathways to mitogenicity has not been evaluated so far. We report here that the neurotransmitter serotonin (5-hydroxytryptamine), a contracting agent and mitogen for smooth muscle cells, activates phospholipase C, inhibits adenylate cyclase and stimulates DNA synthesis in fibroblasts. These events are sensitive to pertussis toxin. We show that the mitogenicity of 5-hydroxytryptamine can be uncoupled from phospholipase C activation that is mediated by 5-HT2 receptors, but correlates perfectly with inhibition of adenylate cyclase through 5-HT1B receptor. We propose that inhibition of adenylate cyclase or activation of an undefined effector system by Gi is important in 5-hydroxytryptamine induced DNA synthesis and contributes to the strong mitogenicity of the other members of this family of growth factors.
...
PMID:Serotonin stimulates DNA synthesis in fibroblasts acting through 5-HT1B receptors coupled to a Gi-protein. 304 68

1. The biogenic amines 5-hydroxytryptamine (5-HT) and histamine, and the peptides bombesin, gastrin-releasing peptide (GRP), vasoactive intestinal peptide (VIP), cholecystokinin (CCK), substance P and calcitonin gene-related peptide (CGRP) each mimicked slow synaptic excitation (slow e.p.s.p.) when applied to myenteric neurones of the guinea-pig small intestine. 2. Stimulation of the catalytic activity of adenylate cyclase by forskolin and intraneuronal elevation of cyclic 3',5'-adenosine monophosphate (cyclic AMP) also mimicked the slow e.p.s.p. and the actions of the aminergic and peptidergic messengers. 3. Adenosine prevented stimulation of adenylate cyclase by forskolin and abolished the slow e.p.s.p.-like actions of forskolin. 4. Exposure of the neurones to adenosine prior to or during application of bombesin, GRP, VIP, CCK or histamine blocked the actions of these substances. 5. Pre-treatment with adenosine did not suppress the slow e.p.s.p.-like actions of substance P, CGRP or 5-HT. 6. The results suggest that signal transduction for bombesin, GRP, VIP, CCK and histamine involves stimulation of adenylate cyclase and second messenger function of cyclic AMP. Transduction mechanisms for 5-HT, substance P and CGRP appear not to involve second messenger function of cyclic AMP.
...
PMID:Transduction of aminergic and peptidergic signals in enteric neurones of the guinea-pig. 365 77

Somatostatin (SRIF) has previously been shown to inhibit both basal and hormone-stimulated PRL secretion from GH4C1 cells, a clonal strain of rat pituitary tumor cells. In this study we examined the ability of SRIF to modulate cAMP accumulation in GH4C1 cells to determine whether such alterations mediate its biological effects. SRIF did not cause statistically significant changes in basal cAMP accumulation. Of six PRL secretagogues examined, only vasoactive intestinal peptide (VIP) increased cAMP accumulation significantly: TRH, bombesin, epidermal growth factor, insulin, and the tumor promoter, phorbol-12,13-dibutyrate were without effect. When SRIF was added simultaneously with VIP, it inhibited maximal VIP-stimulated cAMP accumulation (55 +/- 3%, mean +/- SE) without changing the ED50 for VIP (3.0 +/- 0.2 nM). Inhibition by SRIF was not due to altered kinetics of VIP stimulation, since the half-time for VIP-stimulated cAMP accumulation was 2 min both in the absence and presence of 100 nM SRIF. SRIF did not inhibit isobutylmethylxanthine-stimulated cAMP accumulation, and the presence of 0-10 mM isobutylmethylxanthine did not alter the inhibitory effect of SRIF on VIP-stimulated cAMP accumulation. Therefore, SRIF must act primarily to modulate VIP activation of adenylate cyclase activity. Inhibition of VIP-stimulated cAMP accumulation occurred at concentrations of SRIF (ID50 = 1.2 +/- 0.1 nM) close to the equilibrium dissociation constant for receptor binding (Kd = 0.6 +/- 0.2 nM). Furthermore, the potencies of a series of SRIF analogs to inhibit VIP-stimulated cAMP accumulation correlated with the apparent Kd of each peptide for binding to the SRIF receptor. In addition, SRIF did not reduce VIP-stimulated cAMP accumulation in GH(1)2C1 cells, which lack SRIF receptors. We conclude that SRIF inhibits VIP-stimulated cAMP accumulation by a receptor-mediated process that may be causally related to the ability of SRIF to inhibit VIP-dependent PRL secretion.
...
PMID:Somatostatin inhibits vasoactive intestinal peptide-stimulated cyclic adenosine monophosphate accumulation in GH pituitary cells. 619 74

We used thapsigargin (TG), 2,5-di-tert-butyl-1,4-benzohydroquinone (BHQ) and cyclopiazonic acid (CPA), each of which inhibits microsomal Ca(2+)-ATPase, to evaluate the effects of this inhibition on cytoplasmic free calcium ([Ca2+]i) and secretagogue-stimulated enzyme secretion in rat pancreatic acini. Using single-cell microspectrofluorimetry of fura-2-loaded acini we found that all three agents caused a sustained increase in [Ca2+]i by mobilizing calcium from inositol-(1,4,5)-trisphosphate-sensitive intracellular calcium stores and by promoting influx of extracellular calcium. Concentrations of all three agents that increased [Ca2+]i potentiated the stimulation of enzyme secretion caused by secretagogues that activate adenylate cyclase but inhibited the stimulation of enzyme secretion caused by secretagogues that activate phospholipase C. With BHQ, potentiation of adenylate cyclase-mediated enzyme secretion occurred immediately whereas inhibition of phospholipase C-mediated enzyme secretion occurred only after several min of incubation. In addition, the effects of BHQ and CPA on both [Ca2+]i and secretagogue-stimulated enzyme secretion were reversed completely by washing whereas the actions of TG could not be reversed by washing. Concentrations of BHQ in excess of those that caused maximal changes in [Ca2+]i inhibited all modes of stimulated enzyme secretion by a mechanism that was apparently unrelated to changes in [Ca2+]i. Finally, in contrast to the findings with TG and BHQ, CPA inhibited bombesin-stimulated enzyme secretion over a range of concentrations that was at least 10-fold lower than the range of concentrations over which CPA potentiated VIP-stimulated enzyme secretion.
...
PMID:Effect of inhibition of microsomal Ca(2+)-ATPase on cytoplasmic calcium and enzyme secretion in pancreatic acini. 750 54


<< Previous 1 2 3 4 Next >>

---