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 apparent affinities of endogenous opioid peptides for noncompetitively interacting mu and delta receptors, inhibitorily linked to dopamine (DA) D-1 receptor-stimulated adenylate cyclase, were investigated in superfused rat striatal slices exposed to 40 microM DA in the presence of 10 microM of the selective D-2 receptor antagonist (-)sulpiride. In the presence of peptidase inhibitors, a comparison was made with the apparent affinities of opioid peptides toward independent presynaptic opioid receptors in brain slices. beta-Endorphin had an about 100-fold higher apparent affinity (EC50: 1 nM) toward presynaptic mu-opioid receptors, mediating inhibition of the electrically evoked neocortical [3H]norepinephrine release, than for the striatal adenylate cyclase-coupled mu receptors. In contrast, the kappa-opioid receptor agonist dynorphin A1-13 displayed a similar apparent affinity (EC50: 0.1 microM) toward these functionally different mu receptors. Both Leu- and Met-enkephalin showed only a 3-fold higher apparent affinity (EC50: 30 nM) for presynaptic delta-opioid receptors, mediating inhibition of striatal [14C]acetylcholine release, than for presynaptic mu receptors. However, whereas Leu-enkephalin had a similar apparent affinity for presynaptic and adenylate cyclase-coupled delta receptors, Met-enkephalin displayed a 30-fold selectivity toward the latter receptors. Studying the inhibitory effect of Met-enkephalin on striatal adenylate cyclase stimulated by endogenously released (amphetamine-induced) DA, its very high affinity appeared to be inversely related to the activation of inhibitory DA D-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Mu- and delta-opioid receptors inhibitorily linked to dopamine-sensitive adenylate cyclase in rat striatum display a selectivity profile toward endogenous opioid peptides different from that of presynaptic mu, delta and kappa receptors. 822 47

Prolonged exposure of neuroblastoma x glioma (NG 108-15) hybrid cells to inhibitory acting drugs results in sensitization of adenylate cyclase. We now report that chronic activation (3 days) of either inhibitory delta-opioid receptors, alpha 2B-adrenoceptors, or muscarinic M4 receptors significantly decreases the number of stimulatory, adenylate cyclase-coupled prostaglandin E1 receptors. Pharmacological characterization further revealed that the loss of [3H]prostaglandin E1-binding sites most likely corresponds to a reduction of the number of high-affinity, G protein-coupled prostaglandin E1 receptors. The decline in functionally active prostaglandin E1 receptors developed in a time- and dose-dependent manner and could be prevented by pretreatment of the cells with pertussis toxin. Heterologous prostaglandin E1 receptor regulation was blocked by concomitant exposure of the cells to antagonists for inhibitory receptors and was rapidly reversed (t 1/2 < 30 min) upon termination of chronic inhibitory drug treatment. The decrease in high-affinity prostaglandin E1 receptors developed regardless of whether full or partial agonists were used for pretreatment. In addition, the concentrations of inhibitory drugs required to maximally affect prostaglandin E1 receptor number closely resembled those mediating maximal adenylate cyclase inhibition. The data demonstrate that chronic inhibitory drug treatment of NG 108-15 hybrid cells reduces the number of functionally active, excitatory prostaglandin E1 receptors. Thus, it is proposed that adaptations at the level of stimulatory receptor systems contribute to the regulatory mechanisms associated with drug dependence.
...
PMID:Chronic exposure of NG 108-15 cells to inhibitory acting drugs reduces stimulatory prostaglandin E1 receptor number. 879 Oct 8

Chronic exposure of all-trans-retinoic acid-differentiated SH-SY5Y cells to morphine (10 mu M; 2 days) results in sensitization of adenylate cyclase as characterized by a significant increase in both PGE1 receptor-mediated as well as receptor-independent (NaF, 10 mM; forskolin, 100 mu M) stimulation of effector activity. To investigate the underlying biochemical alterations, chronic opioid regulation of each of the components comprising the stimulatory PGE1 receptor system was examined. On receptor level, chronic morphine treatment was found to reduce PGE1 receptor number (Bmax) by approximately 40%, whereas their affinity slightly increased. Binding experiments performed in the presence of GTPgammaS (100 mu M) further indicate that the decrease in PGE1 receptor density is associated with a loss of functionally G protein-coupled receptors. On post-receptor level, chronic morphine treatment substantially increased the abundance and functional activity of stimulatory G proteins, as assessed by cholera toxin-catalyzed ADP-ribosylation of GSalpha and S49 cyc- reconstitution assays. No changes were found on the level of adenylate cyclase. Evaluation of the functional interaction between PGE1 receptors and GS in situ by application of a C-terminal anti-GSalpha antibody revealed a more intense coupling efficiency between these two entities, since a significant higher amount of antibody (2.3-fold) was required in morphine dependent cell membranes to half-maximally attenuate PGE1 receptor-stimulated adenylate cyclase activity. In addition, limitation of the amount of functionally available GSalpha within the PGE1 receptor/adenylate cyclase signal transduction cascade abolished the generation of a supersensitive adenylate cyclase response during the state of naloxone (100 mu M)-precipitated withdrawal. These data demonstrate that in human neuroblastoma SH-SY5Y cells chronic morphine-induced sensitization of adenylate cyclase is associated with distinct quantitative and qualitative adaptations within the stimulatory adenylate cyclase-coupled PGE1 receptor system. Thus, alterations in the functional activity of stimulatory receptor systems are suggested to contribute to the cellular mechanisms underlying opioid dependence.
...
PMID:Morphine dependence in human neuroblastoma SH-SY5Y cells is associated with adaptive changes in both the quantity and functional interaction of PGE1 receptors and stimulatory G proteins. 891 1

5HT1A receptors occur in the retina of various species and the administration of 5HT1A agonists results in the inhibition of outgrowth from postcrush goldfish retinal explants. The levels of cyclic AMP (cAMP) play a role in the modulation of the outgrowth of the nevous system. Moreover, the stimulation of central 5HT1A receptors with the agonist 8-hydroxy-2-(di-n-propylamino)tetralin has been reported to produce an increase or decrease in the activity of adenylate cyclase. In the present investigation we studied the effect of adenylate cyclase stimulation by forskolin, as well as the modulatory effects of 5HT1A receptor agonists and antagonists on the production of cAMP in the goldfish retina, and on the outgrowth of this tissue in vitro. 8-Hydroxy-2-(di-n-propylamino)tetralin produced a significant and dose-dependent increase in cAMP concentration. This effect was not additive to the stimulation produced by forskolin. By contrast, as previously described, the 5HT1A agonist decreased cAMP concentration in the hippocampus of the rat. Both effects were significantly impaired by the 5HT1A antagonist WAY-100,135. A significant effect of the antagonist alone was observed only in the goldfish retina. The increase in cAMP levels was greater in the intact than in the postcrush retina. In addition, forskolin decreased the outgrowth of postcrush retinal explants in a dose-dependent manner, suggesting the importance of critical levels of cAMP in this process. Taken together, 5HT1A receptors seem to be positively coupled to adenylate cyclase in the goldfish retina, where cAMP plays a role as a modulator of outgrowth and regeneration. The inhibitory effect of 5HT1A receptor agonists on retinal outgrowth might be mediated through the production of cAMP. The activation of other subtypes of 5HT receptors positively coupled to adenylate cyclase by the 5HT1A agonist, such as 5HT7, cannot be discarded.
...
PMID:5HT1A receptor agonist differentially increases cyclic AMP concentration in intact and lesioned goldfish retina. In vitro inhibition of outgrowth by forskolin. 893 55

ATP stimulation of surfactant secretion in type II cells is mediated by both a P2Y2 receptor coupled to phospholipase C and a receptor coupled to adenylate cyclase. UTP also activates the P2Y2 receptor but does not stimulate adenosine 3',5'-cyclic monophosphate (cAMP) formation. We have examined surfactant secretion and signaling parameters in response to ATP and UTP in type II cells from newborn rats. There was a developmental increase in the response to both agonists. However, whereas ATP increased secretion as early as day 1, the effect of UTP did not become significant until 4 days after birth. ATP increased cAMP formation as early as day 1 but did not promote diacylglycerol formation or phospholipase D activation until day 4. Thus the adenylate cyclase-coupled ATP signaling mechanism is functional early in development but the P2Y2 pathway is not. We therefore used type II cells from 1- to 2-day-old rats to investigate the adenylate cyclase-coupled mechanism in the absence of interactions with the P2Y2 system. Effects of ATP and 5'-(N-ethylcarboxamido)adenosine (NECA) on surfactant secretion and cAMP formation were not additive, and their effects on secretion were antagonized by the same adenosine receptor antagonists. Overnight culture of the cells with NECA almost completely abolished the subsequent increase in cAMP formation in response to NECA, adenosine, and ATP but not to terbutaline. These data suggest that ATP, NECA, and adenosine activate the same receptor. Effects of ATP were not decreased by adenosine deaminase, showing that they are not mediated by adenosine acting directly at adenosine receptors. We suggest that ATP directly activates an adenosine receptor on the type II cell.
...
PMID:Adenylate cyclase-coupled ATP receptor and surfactant secretion in type II pneumocytes from newborn rats. 912 68

The relationship between receptor number and agonist-induced intracellular responses has been well studied in receptors coupled to adenylate cyclase; however, for receptors coupled to phospholipase C (PLC), very little is known about the effect of receptor number on receptor-mediated processes. To explore this issue, we investigated the effect of the number of receptors for gastrin-releasing peptide (GRP) on ligand affinity and on the ability to activate intracellular messengers [PLC, tyrosine phosphorylation of p125 focal adhesion kinase (p125FAK)] and cause receptor modulation (internalization, desensitization, down-regulation) and ligand degradation. Three BALB 3T3 cell lines were made that stably expressed the gastrin-releasing peptide receptor (GRP-R) with receptor numbers varying by 280-fold (GRP-R-Low, GRP-R-Med, and GRP-R-Hi). Each cell line had the same affinity for agonist. The efficacy for bombesin to increase [3H]inositol phosphates but not tyrosine phosphorylation of p125FAK correlated well with receptor number. In contrast, the EC50 value for [3H]inositol phosphate generation for bombesin was the same in each cell line. Receptor number did not alter internalization. In the absence of protease inhibitors, there was an inverse correlation between receptor number and receptor down-regulation and desensitization. However, with protease inhibitors present, GRP-R-Med and GRP-R-Hi down-regulated significantly less than the GRP-R-Low. Similarly, GRP-R-Low desensitized significantly more than GRP-R-Med or GRP-R-Hi. GRP-R-Hi caused significantly greater ligand degradation than GRP-R-Low, and protease inhibitors completely inhibited degradation by GRP-R-Low and inhibited degradation by 70% for GRP-R-Hi. In conclusion, we show that for the PLC-coupled GRP-R, receptor number had little or no effect on binding affinity, potency for activating PLC, tyrosine phosphorylation of p125FAK, or extent of receptor internalization. In contrast, receptor number had an effect on ligand degradation, down-regulation, desensitization, and efficacy of PLC activation without altering the efficacy of tyrosine phosphorylation of p125FAK. These results demonstrate that the effect of receptor number differs for the different functions mediated by the GRP receptor and differs from that reported for adenylate cyclase-coupled receptors such as receptors mediating the action of adrenergic agents, secretin, and opioids.
...
PMID:Effect of gastrin-releasing peptide receptor number on receptor affinity, coupling, degradation, and modulation. 914 10

von Willebrand factor (vWf) is released from endothelial cell storage granules after stimulation with thrombin, histamine and several other agents that induce an increase in cytosolic free calcium ([Ca2+]i). In vivo, epinephrine and the vasopressin analog DDAVP increase vWf plasma levels, although they are thought not to induce vWf release from endothelial cells in vitro. Since these agents act via a cAMP-dependent pathway in responsive cells, we examined the role of cAMP in vWf secretion from cultured human umbilical vein endothelial cells. vWf release increased by 50% in response to forskolin, which activates adenylate cyclase. The response to forskolin was much stronger when cAMP degradation was blocked with IBMX, an inhibitor of phosphodiesterases (+200%), whereas IBMX alone had no effect. vWf release could also be induced by the cAMP analogs dibutyryl-cAMP (+40%) and 8-bromo-cAMP (+25%); although their effect was weak, they clearly potentiated the response to thrombin. Epinephrine (together with IBMX) caused a small, dose-dependent increase in vWf release, maximal at 10(-6) M (+50%), and also potentiated the response to thrombin. This effect is mediated by adenylate cyclase-coupled beta-adrenergic receptors, since it is inhibited by propranolol and mimicked by isoproterenol. In contrast to thrombin, neither forskolin nor epinephrine caused an increase in [Ca2+]i as measured by fura-2 fluorescence. In addition, the effects of forskolin and thrombin were additive, suggesting that they act through distinct signaling pathways. We found a close correlation between cellular cAMP content and vWf release after stimulation with epinephrine and forskolin. These results demonstrate that cAMP-dependent signaling events are involved in the control of exocytosis from endothelial cells (an effect not mediated by an increase in [Ca2+]i) and provide an explanation for epinephrine-induced vWf release.
...
PMID:Epinephrine induces von Willebrand factor release from cultured endothelial cells: involvement of cyclic AMP-dependent signalling in exocytosis. 924 55

We determined the relative effects of chemical receptor inactivation on dopaminergic signaling through adenylate cyclase and phospholipase C pathways and evaluated the behavioral implications of such receptor manipulations. Groups of rats were given intraperitoneal injections of 10 mg/kg N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), a reagent that differentially inactivates neurotransmitter receptors. Control and treated animals were used to assess dopaminergic-mediated behaviors or brain tissues were prepared from the animals and used to assay D1-like receptor binding and agonist-stimulated second messenger formation. EEDQ decreased by 75% the number of D1-like binding sites and completely abolished dopamine-stimulated cyclic AMP formation in striatal membranes. Conversely, dopamine-stimulated phosphoinositide hydrolysis was insensitive to inactivation by EEDQ as examined over different durations of EEDQ treatment, in different brain regions, or with different concentrations of the D1-like receptor agonist SKF38393. EEDQ-pretreated animals lost their stereotypic response to apomorphine but showed increased vacuous jaw movements in response to apomorphine or SKF38393. Basal catalepsy was increased and SCH23390 was unable to further enhance catalepsy beyond the basal levels in the lesioned animals. In naive animals, SCH23390 catalepsy was reversed by apomorphine, and apomorphine stereotypy was reversed by SCH23390. Taken together, the present results imply that the dopamine-sensitive phospholipase C system mediates a subset of dopaminergic behaviors, notably vacuous jaw movements, in contrast to stereotypy and catalepsy which appear to be respectively mediated through stimulation and inhibition of the adenylate cyclase-coupled dopaminergic system.
...
PMID:Dopaminergic behaviors and signal transduction mediated through adenylate cyclase and phospholipase C pathways. 1066 21

Inducible nitric oxide synthase (iNOS) plays a significant role in the pathology of central nervous system diseases. Inducible NOS expression is regulated by intracellular adenosine 3',5'-cyclic monophosphate (cAMP) signaling, and astrocytes contain both iNOS and adenylate cyclase-coupled neurotransmitter receptors. The data obtained from the present study indicated that acetylcholine, lambda-amino-n-butyric acid, glutamate, quinolinic acid, N-methyl-D-aspartate and aspartate have no effect on NO(2)(-) production in C6 glioma cells stimulated by lipopolysaccharide and interferon-gamma. However, dopamine (DA) caused inhibition of NO(2)(-) production and iNOS transcription. The effects of DA were not due to homovanillic acid/3,4-dihydroxyphenylacetic acid, the autoxidative products superoxide (O(2)(-))/hydrogen peroxide (H(2)O(2)) or direct reactions with NO(2)(-). Forskolin, adenylate cyclase activator, dose-dependently reduced NO(2)(-). Meanwhile, (+/-) SKF-38393 D(1) receptor agonist attenuated iNOS in a similar fashion to DA. In addition, the results indicated that DA attenuation of iNOS was significantly impeded by the adenylate cyclase inhibitor MDL-12,330A, the D(1) antagonist SCH-23390, the beta2 adrenergic receptor antagonist ICI-118,551 and the beta1 adrenergic receptor antagonist atenolol. In conclusion, it appears that DA attenuates iNOS through a D(1), beta1 and beta2 adrenergic receptor-linked adenylate cyclase-mediated cAMP cascade.
...
PMID:Characterization of neurotransmitters and dopamine attenuation of inducible nitric oxide synthase in glioma cells. 1245 38

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuroprotective peptide which exerts its effects mainly through the cAMP-protein kinase A (PKA) pathway. Here, we show that in cortical neurons, PACAP-induced PKA signaling exerts a major part of its neuroprotective effects indirectly, by triggering action potential (AP) firing. Treatment of cortical neurons with PACAP induces a rapid and sustained PKA-dependent increase in AP firing and associated intracellular Ca(2+) transients, which are essential for the anti-apoptotic actions of PACAP. Transient exposure to PACAP induces long-lasting neuroprotection in the face of apoptotic insults which is reliant on AP firing and the activation of cAMP response element (CRE) binding protein (CREB)-mediated gene expression. Although direct, activity-independent PKA signaling is sufficient to trigger phosphorylation on CREB's activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression. Full activation is dependent on CREB-regulated transcription co-activator 1 (CRTC1), whose PACAP-induced nuclear import is dependent on firing activity-dependent calcineurin signaling. Over-expression of CRTC1 is sufficient to rescue PACAP-induced CRE-mediated gene expression in the face of activity-blockade, while dominant negative CRTC1 interferes with PACAP-induced, CREB-mediated neuroprotection. Thus, the enhancement of AP firing may play a significant role in the neuroprotective actions of PACAP and other adenylate cyclase-coupled ligands.
...
PMID:Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1. 2162 92


<< Previous 1 2 3 4 5 6

---