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)

When bovine adrenocortical cells from the zona fasciculata/reticularis (zfr) are maintained in primary culture, cortisol secretion in response to acute stimulation with ACTH and adrenaline (which activate adenylate cyclase) is seen to increase steadily over the first 48 h, while secretion in response to angiotensin II and acetylcholine (which activate phosphoinositidase C) shows an initial decline in the first 24 h and a recovery to maximum after 48 h. We have investigated whether these discrepant changes in cortisol secretory response to the different agonists are due to changes in formation of the associated second messengers (cAMP or inositol phosphates), or altered coupling of these second messenger signals to steroid secretion. Increases in steroid secretion in response to ACTH and adrenaline were paralleled by increased cAMP. Steroid secretion in response to exogenous 8-bromoadenosine 3':5'-cyclic monophosphate also increased steadily during this 48-h period. Thus increased responsiveness was due to both increased second messenger formation and increased coupling to the steroid secretory response. The decreased steroid secretory response to angiotensin and acetylcholine after 24 h, and subsequent recovery after 48 h in culture, were accompanied by an increased formation of phosphoinositols after 24 h and a further increase by 48 h. However, the steroid secretory response to a combination of calcium ionophore and the protein kinase C activator, phorbol 12-myristate 13-acetate, was reduced after 24 h and recovered by 48 h of culture. Fura-2-loaded cells also showed an increase in intracellular [Ca2+] after 24 h in culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Further characterization of the steroidogenic responsiveness of purified zona fasciculata/reticularis cells from bovine adrenal cortex before and after primary culture: changing responsiveness to phosphoinositidase C agonists. 132 34

Hepatocyte growth factor (HGF) is the most potent known mitogen for hepatocytes in primary culture. However, the mechanisms through which HGF induces hepatocyte proliferation have not been defined. Here we have investigated the role of the adenylate cyclase, phosphoinositidase C and tyrosine kinase signalling systems in the control of hepatocyte proliferation by HGF using freshly isolated or cultured adult rat hepatocytes. We show that human recombinant HGF caused a dose-dependent increase in hepatocyte DNA synthesis with a maximal effect at 10 ng/mL and an EC50 of 5.9 ng/mL. HGF had no effect on hepatocyte adenylate cyclase activity or intracellular cAMP levels. Elevation of hepatocyte cAMP levels resulted in inhibition of HGF-stimulated DNA synthesis. HGF stimulated inositol phospholipid hydrolysis with a maximal effect at 25 ng/mL and potentiated the effect of vasopressin (10(-8) and 10(-9)M). HGF (100 ng/mL) caused an increase in the phosphorylation on tyrosine of an unknown hepatocyte protein with a molecular mass of 36 kDa. Thus, we have shown that HGF, like epidermal growth factor (EGF), can activate the phosphoinositidase C and tyrosine kinase systems in rat hepatocytes. As with EGF, these intracellular signalling systems may underlie HGF-induced hepatocyte proliferation.
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PMID:Role of the adenylate cyclase, phosphoinositidase C and receptor tyrosyl kinase systems in the control of hepatocyte proliferation by hepatocyte growth factor. 132 55

Basic fibroblast growth factor (bFGF) stimulates mitogenesis of Balb/c 3T3 fibroblast cells. This stimulation may be mediated by multiple signal pathways as it is accompanied by the formation of inositol phosphates, activation of PKC (protein kinase C) and a decrease in intracellular cAMP levels. The multiple positive and negative pathways implicated for FGF-induced mitogenesis may interact and each may contribute in varying degrees to the final cellular response. At least two types of G-proteins may be involved in the intracellular signalling pathways of FGF. Pertussis toxin blocks FGF and TPA (12-O-tetradecanoylphorbol-13-acetate) induced. PKC-mediated mitogenesis and also the associated fall in intracellular cAMP levels. However, pertussis toxin has no effect upon FGF-induced inositol phosphates formation. Thus, inhibition of mitogenesis by pertussis toxin may involve pertussis toxin sensitive G-proteins which may affect at least two separate putative signal pathways involving adenylate cyclase and protein kinase C. Pertussis toxin insensitive G-proteins may also be involved in coupling the FGF receptor to phosphoinositidase C.
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PMID:Studies on the mechanisms of signalling and inhibition by pertussis toxin of fibroblast growth factor-stimulated mitogenesis in Balb/c 3T3 cells. 165 71

The extracellular environment is a major factor in determining the responsiveness of a cell to particular stimuli. For example, E series prostaglandins suppress B cell responses to T-independent antigens, mitogen stimulation of DNA synthesis and proliferation, and the primary immune response. We investigated the effects of prostaglandins on the intracellular signals generated by receptor-coupled effector systems in B lymphocytes. Pretreating splenocytes from athymic nude mice with forskolin, PGE1, or PGE2 decreased the magnitude of anti-IgM-induced changes in cytosolic free [Ca2+]. Addition of 8-Br-cAMP, forskolin, PGE1, or PGE2 following stimulation with anti-IgM resulted in a decrease in the intracellular calcium signal measured by fluorescence-activated cell sorting using Indo-1 as a Ca2+ indicator. This decrease was not a result of an inhibition of influx across the plasma membrane. Thus activation of adenylate cyclase by prostaglandins modifies the generation of signals by phosphoinositidase C. This effector system cross-talk between adenylate cyclase and phosphoinositidase C is consistent with and may account for the inhibitory effects of prostaglandins in B cell responses.
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PMID:Modulation of the B cell response to T-independent antigens by prostaglandins: evidence for effector system cross-talk. 165 21

Dictyostelium cells use extracellular cyclic AMP both as a chemoattractant and as a morphogen inducing cell-type-specific gene expression. Cyclic AMP binds to surface receptors, activates one or more G-proteins, and stimulates adenylate cyclase, guanylate cyclase and phosphoinositidase C. Mutant fgdC showed aberrant chemotaxis, and was devoid of cyclic AMP-induced gene expression and differentiation. Both the receptor- and G-protein-mediated stimulation of adenylate cyclase and guanylate cyclase were unaltered in mutant fgdC as compared to wild-type cells. In wild-type cells phosphoinositidase C was activated about twofold by the cyclic AMP receptor. In mutant fgdC cells, however, the enzyme was inhibited by about 60%. These results suggest that phosphoinositidase C is regulated by a receptor-operated activation/inhibition switch that is defective in mutant fgdC. We conclude that activation of phosphoinositidase C is essential for Dictyostelium development.
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PMID:Abberant chemotaxis and differentiation in Dictyostelium mutant fgdC with a defective regulation of receptor-stimulated phosphoinositidase C. 166 62

Leukotriene B4 is one of a number of agents which stimulate bone resorption by acting on osteoblasts. Some agonists, such as PTH or prostaglandins, are known to activate adenylate cyclase in osteoblasts, whereas others, such as vitamin D3, have no effect on adenylate cyclase. Recent evidence suggests that both classes of agonist may raise the intracellular calcium concentration, although the relative importance for bone resorption of calcium mobilization and adenylate cyclase activity in the osteoblast is not clear. Here it is shown 1) that leukotriene B4 does not activate but may be inhibitory toward adenylate cyclase in intact osteoblasts or membrane preparations, 2) that leukotriene B4 causes an elevation of intracellular calcium levels in osteoblast monolayers, 3) leukotriene B4 rapidly activates phosphatidylinositol bisphosphate breakdown in osteoblast membranes and intact osteoblasts, and 4) that leukotriene B4 stimulates phosphatidylinositol kinase activity concurrently with phosphoinositidase C in intact osteoblasts over a similar timescale. These results suggest that leukotriene B4 may increase the concentration of intracellular calcium in osteoblasts by stimulating phosphoinositide turnover, and support the proposal that calcium signaling rather than activation of adenylate cyclase in osteoblasts may be of overriding importance in the regulation of bone resorption.
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PMID:Leukotriene B4 increases intracellular calcium concentration and phosphoinositide metabolism in mouse osteoblasts via cyclic adenosine 3',5'-monophosphate-independent pathways. 171 59

Nine distinct alpha subunits of guanine nucleotide binding proteins (G-proteins) have now been identified by cDNA cloning. Each of these functions to allow transduction of information between hormone-activated receptors in the plasma membrane and effector systems which are either ion channels or enzymes which regulate the intracellular concentration of second messengers. As the individual G-proteins are highly similar in primary sequence, it is pertinent to ask what degree of specificity of interaction each of these display with the various receptors and effector systems. Specificity of tissue location defines that the rod and cone transducins (TD1 and TD2, respectively) act as the coupling proteins between rhodopsin and cone opsins and their cyclic nucleotide phosphodiesterase effectors and that G(olf) is the G-protein which tranduces signals from odorant receptors to adenylate cyclase in olfactory sensory neurones. However, many of the other identified G-proteins are co-expressed in a single tissue or cell. Whilst sensitivity to ADP-ribosylation catalysed by bacterial toxins from Bordetella pertussis and Vibrio cholerae has allowed a further subdivision of the G-protein family, this approach is limited as these toxins have multiple G-protein substrates. As the extreme C-terminus of the alpha subunit of each G-protein appears to be a key domain for the interactions of receptors and G-proteins we have generated a series of G-protein-selective antipeptide antisera against this region and then have used these antisera to attempt to interfere with receptor-G-protein coupling. With this approach we have been able to demonstrate that a delta opioid receptor-mediated inhibition of adenylate cyclase in neuroblastoma x glioma, NG108-15, cell membranes is transduced specifically by Gi2 and in the same cell that alpha 2 adrenergic inhibition of Ca2+ currents is transduced by Go. Similar strategies are likely to be of universal significance, for example in the identification of the G-protein (Gp) which regulates the receptor-mediated activation of phosphoinositidase C. Methods to allow pharmacological manipulation of the levels of expression of various G-proteins in the membranes of cells are also discussed. Such approaches are also likely to assist in the identification of G-proteins of defined functions.
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PMID:The role and specificity of guanine nucleotide binding proteins in receptor-effector coupling. 196 33

Recent evidence has suggested that receptor-mediated phosphoinositide turnover, like that of the adenylate cyclase cAMP pathway, is regulated by guanine nucleotides. It is likely that one or more guanine nucleotide-binding proteins (G-proteins) couple calcium-mobilizing receptors to the activation of phosphoinositidase C. Recent studies utilizing various bacterial toxins have strongly suggested the presence of multiple G-proteins in the regulation of receptor-phosphoinositidase C coupling in a variety of cell types.
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PMID:Receptor-phosphoinositidase C coupling. Multiple G-proteins? 282 38

Several lines of experimental evidence indicate the involvement of a guanine nucleotide-dependent protein (G-protein) in the hormone-stimulated hydrolysis of phosphatidylinositol(4,5)-bisphosphate (PtdIns(4,5)P2). However, the shortcomings of available procedures for cell-free assay of hormone-stimulated phosphoinositidase C (PIC) have limited our current understanding of the molecular and mechanistic details of PIC regulation. We recently have proposed that turkey erythrocyte membranes may provide a valuable model system for studies of G-protein-dependent PtdIns(4,5)P2 hydrolysis. The membranes can be simply prepared from [3H]inositol-labelled erythrocytes and they contain a PIC activity that hydrolyses endogenous phosphoinositides and is exquisitively sensitive to guanine nucleotides. PtdIns(4,5)P2 is the principal substrate for this enzyme, there being relatively little direct hydrolysis of phosphatidylinositol 4-phosphate and no detectable hydrolysis of PtdIns. The membranes also contain a purinoceptor of the P2y subclass that is efficiently coupled to PtdIns(4,5)P2 hydrolysis both in intact cells and in the isolated membranes. 2-Methylthioadenosine trisphosphate (2-methyl-S-ATP), a specific P2y receptor agonist, has no effect upon PtdIns(4,5)P2 hydrolysis in the absence of guanine nucleotides, but greatly enhances both the potency and efficacy of PIC activation by guanine nucleotides such as GTP gamma S. GTP gamma S alone stimulates PIC activity only after a prolonged time-lag; the effect of increasing doses of 2-methyl-S-ATP is progressively to shorten this lag phase. These results suggest that the mechanism of G-protein activation involves acceleration of a nucleotide exchange reaction as has been demonstrated for the activation of adenylate cyclase in the same membrane preparation. As well as contributing valuable information on the substrate specificity of PIC and its mode of regulation by hormones, turkey erythrocytes provide a plentiful source of plasma membranes and may be useful for purification of the appropriate G-protein and PIC activities.
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PMID:Receptor and G-protein-dependent regulation of turkey erythrocyte phosphoinositidase C. 290 38

Pretreatment of human embryonic pituitary tumour cells (Flow 9000) with pertussis toxin significantly reduced carbachol-mediated inhibition of isoprenaline and prostaglandin E2 stimulation of cyclic AMP formation. This is in accord with an action on the inhibitory Gi-protein by pertussis toxin. In contrast, pertussis toxin-pretreatment had no effect on either muscarinic agonist or GTP[S] (a non-hydrolysable GTP analogue) stimulation of [3H]inositol phosphate production in intact and permeabilized [3H]inositol-prelabelled Flow 9000 cells, respectively. These results suggest that muscarinic receptors are linked to the inhibition of adenylate cyclase and the stimulation of phosphoinositidase C via two different G-proteins in Flow 9000 cells.
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PMID:Pertussis toxin distinguishes between muscarinic receptor-mediated inhibition of adenylate cyclase and stimulation of phosphoinositide hydrolysis in Flow 9000 cells. 303 12


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