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)

White adipose tissue from rats was examined for insulin- responsive vascular endothelial growth factor 165 (VEGF) secretion and mRNA expression. When separated into it constituent fat vs. stromal-vascular cells using collagenase digestion methods, only the adipocytes (or whole fat tissue) responded to physiological insulin concentrations by doubling VEGF release over 4 and 24 h in culture. Adipocyte VEGF mRNA expression increased similarly. Several adipose depots were tested. Although omental fat cells had the highest rates of VEGF release, the differences were not significant. Insulin-stimulated VEGF release was mediated in part via PI3K, but not PKC. Additional hormones/agents were tested, including steroids, leptin, an adenosine analog, and norepinephrine. Only the latter compound increased VEGF production, and this effect was mediated by adenylate cyclase. Adjusting the incubation glucose concentration between 0-20 mM did not alter adipocyte VEGF release. An experimental mimic of hypoxia, CoCl(2), also increased adipocyte VEGF, and this effect was additive with 100 nM insulin. These studies demonstrate that physiological insulin concentrations stimulate VEGF formation and expression in cultured rodent white adipocytes. Although the biological significance of this observation remains to be determined, if white adipocyte-derived VEGF has paracrine or systemic endocrine actions, these might hypothetically impact on adipose expansion or the vascular comorbidities of obesity.
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PMID:White adipocyte vascular endothelial growth factor: regulation by insulin. 1186 17

1. This study characterizes the mouse beta(3a)-adrenoceptor (AR) and the splice variant of the beta(3)-AR (beta(3b)-AR) expressed in Chinese hamster ovary cells (CHO-K1). 2. Stable clones with high (approximately 1200), medium (approximately 500) or low receptor expression (approximately 100 fmol mg protein(-1)) were determined by saturation binding with [(125)I]-(-)-cyanopindolol. Competition binding studies showed no significant differences in affinity of beta-AR ligands for either receptor. 3. Several functional responses of each receptor were measured, namely extracellular acidification rate (EAR; cytosensor microphysiometer), cyclic AMP accumulation, and Erk1/2 phosphorylation. The beta(3)-AR agonists BRL37344, CL316243, GR265162X, L755507, SB251023, the non-conventional partial beta-AR agonist CGP12177 and the beta-AR agonist (-)-isoprenaline caused concentration-dependent increases in EAR in cells expressing either splice variant. CL316243 caused concentration-dependent increases in cyclic AMP accumulation and Erk1/2 phosphorylation in cells expressing either receptor. 4. PTX treatment increased maximum EAR and cyclic AMP responses to CL316243 in cells expressing the beta(3b)-AR but not in cells expressing the beta(3a)-AR at all levels of receptor expression. 5. CL316243 increased Erk1/2 phosphorylation with pEC(50) values and maximum responses that were not significantly different in cells expressing either splice variant. Erk1/2 phosphorylation was insensitive to PTX or H89 (PKA inhibitor) but was inhibited by LY294002 (PI3K gamma inhibitor), PP2 (c-Src inhibitor), genistein (tyrosine kinase inhibitor) and PD98059 (MEK inhibitor). 6. The adenylate cyclase activators forskolin or cholera toxin failed to increase Erk1/2 levels although both treatments markedly increased cyclic AMP accumulation in both beta(3a)- or beta(3b)-AR transfected cells. 7. These results suggest that in CHO-K1 cells, the beta(3b)-AR, can couple to both G(s) and G(i) to stimulate and inhibit cyclic AMP production respectively, while the beta(3a)-AR, couples solely to G(s) to increase cyclic AMP levels. However, the increase in Erk1/2 phosphorylation following receptor activation is not dependent upon coupling of the receptors to G(i) or the generation of cyclic AMP.
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PMID:Mouse beta 3a- and beta 3b-adrenoceptors expressed in Chinese hamster ovary cells display identical pharmacology but utilize distinct signalling pathways. 1195 93

Here we report antimitogenic mechanisms activated by the adrenocorticotropic hormone (ACTH) in the mouse Y1 adrenocortical tumor cell line. ACTH receptors activate the Galphas/adenylate cyclase cAMP/PKA pathway to promote dephosphorylation of Akt/PKB enzymes, leading to induction of the cyclin-dependent kinases' (CDKs) inhibitor p27(Kip1). Y1 cells display high constitutive levels of phosphorylated Akt/PKB dependent on chronically elevated c-Ki-Ras.GTP and PI3K activity. Expression of the dominant negative mutant RasN17 in Y1 cells results in strong reduction of both c-Ki-Ras.GTP and phosphorylated Akt/PKB, which are restored by FGF2 treatments. Inhibitors of PI3K lead to rapid dephosphorylation of Akt/PKB and block phosphorylation of Akt/PKB promoted by FGF2. ACTH rapidly promotes dephosphorylation of Akt/PKB in Y1 adrenal cells, while constitutively high levels of c-Ki-Ras.GTP remain unchanged. ACTH and cAMP elevating agents fail to cause Akt/PKB dephosphorylation in PKA-deficient clonal mutants of Y1 cells. In addition, cholera toxin, forskolin, and 8BrcAMP all mimic ACTH, causing dephosphorylation of Akt/PKB in wild-type Y1 cells. ACTH is unable to prevent Akt/PKB phosphorylation, promoted by FGF2 in clonal lines of RasN17-Y1 transfectants displaying negligible levels of c-Ki-Ras.GTP. ACTH promotes strong p27(Kip1) protein induction in wild-type Y1 adrenocortical cells but not in PKA-deficient Y1-clonal mutants nor in RasN17-Y1 transfectants. PI3K inhibitors induce p27(Kip1) protein in all cells studied, i.e., wild type and transfectants. The inverse correlation between levels of phosphorylated Akt/PKB and of p27(Kip1) protein caused by ACTH suggests a novel antimitogenic pathway activated by ACTH and mediated by cAMP/PKA in the mouse Y1 adrenocortical tumor cell line.
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PMID:ACTH promotion of p27(Kip1) induction in mouse Y1 adrenocortical tumor cells is dependent on both PKA activation and Akt/PKB inactivation. 1214 78

GLP-1, incretin with insulin-independent antidiabetic properties, is insulinomimetic upon glucose metabolism in extrapancreatic tissues, acting through specific receptors not associated to adenylate cyclase activation. We investigated the role of enzymes mediating insulin actions, in the GLP-1-induced glycogen synthase a activation in rat hepatocytes. GLP-1, like insulin, activates PI3K/PKB, p70s6k, p44 and p42 MAP-kinase. Wortmannin (PI3K/PKB inhibitor) blocked the stimulatory action of insulin on glycogen synthase a and reduced that of GLP-1; rapamycin (p70s6k inhibitor) was ineffective and PD98059 (MEK/MAPK inhibitor) decreased only the insulin effect; okadaic acid (PP-2A inhibitor) was ineffective, while TNFalpha (PP-1 inhibitor) blocked the action of insulin and reduced that of GLP-1; H-7 or Ro 31-8220 (PKC inhibitors) decreased the GLP-1 effect, while only H-7 reduced that of insulin. The activation of PI3K/PKB, PKC and PP-1, but not PP-2A, seems to mediate the GLP-1 stimulatory action on glycogen synthase a in rat hepatocytes, while MAPKs and p70s6k could participate in other GLP-1 effects.
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PMID:Cell signalling of the GLP-1 action in rat liver. 1285 Feb 80

Genes encoding numerous proto-oncogenes and cytokines, as well as a number of G-protein coupled receptors, are regulated post-transcriptionally at the level of mRNA stability. A common feature of all of these genes is the presence of A + U-rich elements (AREs) within their 3' untranslated regions. We, and others, have demonstrated previously that mRNAs encoding beta-adrenergic receptors (beta-ARs) are destabilized by agonist stimulation of the beta-AR/Galphas/adenylylcyclase pathway. However, in addition to PK-A, beta-ARs can also activate or inhibit mitogen activated kinase (MAPK) cascades, in a cell-type dependent basis. Recent evidence points to an important role for MAPKs in regulating the turnover of cytokine mRNAs, such as TNFalpha. We hypothesized that activation of MAPK's may also regulate beta-AR mRNA stability. The studies conducted herein demonstrate that generalized stimulation of MAPKs (JNK, p38) with anisomycin resulted in marked stabilization of beta-AR mRNA. Reciprocally, selective inhibition of JNK with SP600125 significantly decreased beta-AR mRNA half-life. Similarly, inhibition of the MEK/ERK pathway with either PD98059 or U0126 decreased beta-AR mRNA stability substantially. However, inhibition of p38 MAPK with SB203580 produced destabilization of beta-AR mRNA only at higher, non pharmacologically selective concentrations. In contrast to their effects on several other ARE containing mRNAs, inhibition of tyrosine kinases by genistein or PI3K by wortmannin, had no detectable effect on beta-AR mRNA stability. In summary, these results demonstrate for the first time that modulation of MAPK pathways can bi-directionally influence beta-AR mRNA stability.
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PMID:Reciprocal regulation of beta-adrenergic receptor mRNA stability by mitogen activated protein kinase activation and inhibition. 1503 Jan 75

Communication between receptor tyrosine kinase and G protein-coupled receptor (GPCR)-mediated signaling is recognized as a common integrator linking diverse aspects of intracellular signaling systems. Here, we report that G protein-coupled beta-adrenergic receptor activation leading to stimulation of salivary phospholipid release occurs with the involvement of epidermal growth factor receptor (EGFR). Using sublingual gland acinar cells, we show that prosecretory effect of isoproterenol on phospholipid release was subjected to suppression by EGFR kinase inhibitor, PD153035, and wortmannin, an inhibitor of PI3K, but not by PD98059, an inhibitor of extracellular signal regulated kinase (ERK). Furthermore, wortmannin, but not the ERK inhibitor, caused the reduction in the acinar cell secretory responses to beta-adrenergic agonist-generated cAMP as well as adenyl cyclase activator, forskolin. The acinar cell phospholipid secretory responses to isoproterenol, moreover, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR phosphorylation. Taken together, our data are the first to demonstrate the requirement for Src kinase-dependent EGFR transactivation in regulation of salivary phospholipid secretion in response to beta-adrenergic GPCR activation.
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PMID:Salivary phospholipid secretion in response to beta-adrenergic stimulation is mediated by Src kinase-dependent epidermal growth factor receptor transactivation. 1511 Jul 80

Recent advances in understanding the nature of cellular responses mediated by G protein-coupled receptor (GPCR) activation indicate that integration of the converging regulatory signals into functional cellular pathways requires epidermal growth factor receptor (EGFR) transactivation. In this study, we report that G protein-coupled beta-adrenergic receptor activation leading to stimulation in gastric mucus phospholipid secretion occurs with the involvement of EGFR. Using [14C]choline-labeled gastric mucosal cells in culture, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on phospholipid release was subject to a dose-dependent suppression by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, caused the reduction in the gastric mucosal cell phospholipid secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenyl cyclase activator, forskolin. The gastric mucosal phospholipid secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR phosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in phospholipid secretory responses to cAMP and forskolin. The findings underline the central role of EGFR in mediation of gastric mucosal secretory processes, and demonstrate the requirement for Src kinase-dependent EGFR transactivation in regulation of gastric mucosal phospholipid secretion in response to beta-adrenergic GPCR activation.
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PMID:Secretion of gastric mucus phospholipids in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. 1538 32

The principal regulatory factors that control the flow and make-up of salivary secretion are neurotransmitters, released by parasympathetic and sympathetic innervation, that trigger activation of G protein-coupled receptors (GPCRs) on the acinar cells of salivary glands and stimulate the generation of soluble second messengers. In this study, we report that activation of GPCR by beta-adrenergic agonist leading to stimulation in salivary mucin secretion occurs with the involvement of epidermal growth factor receptor (EGFR). Using [(3)H]glucosamine-labeled mucous acinar cells of sublingual salivary gland in culture, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited in a concentration-dependent manner by EGFR kinase inhibitor, PD153035, as well as wortmannin, an inhibitor of PI3K. Moreover, both inhibitors caused the impedance in the acinar cell mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP, as well as adenylate cyclase activator, forskolin. The acinar cell secretory responses to isoproterenol, furthermore, were blunted in a concentration-dependent fashion by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation. However, no significant alterations in the acinar cell mucin secretory responses to isoproterenol, cAMP or forskolin were attained with an inhibitor of the ERK pathway, PD98059. Our findings underline the role of EGFR as a convergence point in modulation of salivary mucin secretion triggered by beta-adrenergic agonist GPCR activation and demonstrate the importance of Src kinase in the EGFR transactivation process.
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PMID:Src-kinase-dependent epidermal growth factor receptor transactivation in salivary mucin secretion in response to beta-adrenergic G-protein-coupled receptor activation. 1552 48

In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation.
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PMID:Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. 1598 6

The neuropeptide pituitary adenylate cyclase-activating protein (PACAP) acts via the G protein-coupled receptor vasoactive intestinal peptide/PACAP receptor-1 to induce phospholipase C/calcium and MAPK-dependent proinflammatory activities in human polymorphonuclear neutrophils (PMNs). In this study, we evaluate other mechanisms that regulate PACAP-evoked calcium transients, the nature of the calcium sources, and the role of calcium in proinflammatory activities. Reduction in the activity of PMNs to respond to PACAP was observed after cell exposure to inhibitors of the cAMP/protein kinase A, protein kinase C, and PI3K pathways, to pertussis toxin, genistein, and after chelation of intracellular calcium or after extracellular calcium depletion. Mobilization of intracellular calcium stores was based on the fact that PACAP-associated calcium transient was decreased after exposure to 1) thapsigargin, 2) Xestospongin C, and 3) the protonophore carbonyl cyanide 4-(trifluoromethoxy) phenyl hydrazone; inhibition of calcium increase by calcium channel blockers, by nifedipine and verapamil, indicated that PACAP was also acting on calcium influx. Such mobilization was not dependent on a functional actin cytoskeleton. Homologous desensitization with nanomoles of PACAP concentration and heterologous receptors desensibilization by G protein-coupled receptor agonists were observed. Intracellular calcium depletion modulated PACAP-associated ERK but not p38 phosphorylation; in contrast, extracellular calcium depletion modulated PACAP-associated p38 but not ERK phosphorylation. In PACAP-treated PMNs, reactive oxygen species production and CD11b membrane up-regulation in contrast to lactoferrin release were dependent on both intra- and extracellular calcium, whereas matrix metalloproteinase-9 release was unaffected by extracellular calcium depletion. These data indicate that both extracellular and intracellular calcium play key roles in PACAP proinflammatory activities.
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PMID:Differential calcium regulation of proinflammatory activities in human neutrophils exposed to the neuropeptide pituitary adenylate cyclase-activating protein. 1614 59


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