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)

Parameters of ligand binding, stimulation of low-Km GTPase, and inhibition of adenylate cyclase were determined in intact human neuroblastoma SH-SY5Y cells and in their isolated membranes, both suspended in identical physiological buffer medium. In cells, the mu-selective opioid agonist [3H]Tyr-D-Ala-Gly(Me)Phe-Gly-ol ([3H]DAMGO) bound to two populations of sites with KD values of 3.9 and 160 nM, with less than 10% of the sites in the high-affinity state. Both sites were also detected at 4 degrees C and were displaced by various opioids, including quaternary naltrexone. The opioid antagonist [3H]naltrexone bound to a single population of sites, and in cells treated with pertussis toxin the biphasic displacement of [3H]naltrexone by DAMGO became monophasic with only low-affinity binding present. The toxin specifically reduced high-affinity agonist binding but had no effect on the binding of [3H]naltrexone. In isolated membranes, both agonist and antagonist bound to a single population of receptor sites with affinities similar to that of the high-affinity binding component in cells. Addition of GTP to membranes reduced the Bmax for [3H]DAMGO by 87% and induced a linear ligand binding component; a low-affinity binding site, however, could not be saturated. Compared with results obtained with membranes suspended in Tris buffer, agonist binding, including both receptor density and affinity, in the physiological medium was attenuated. The results suggest that high-affinity opioid agonist binding represents the ligand-receptor-guanine nucleotide binding protein (G protein) complex present in cells at low density due to modulation by endogenous GTP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Opioid signal transduction in intact and fragmented SH-SY5Y neural cells. 156 Feb 22

Chronic treatment of neuroblastoma x glioma NG108-15 hybrid cells with the opioid agonist D-Ala,2 D-Leu5-enkephalin (DADLE) induces a homologous desensitization of the delta opioid receptors present in these cells. Since the Kd value of the delta opioid receptor's high-affinity state reflects the potency of the agonist, we examined the effect of receptor desensitization in NG108-15 cells on the percentage of receptor in the high-affinity state. When NG108-15 hybrid cells were treated with 10 or 100 nM DADLE for 4 hr at 24 degrees C, loss of DADLE's ability to inhibit adenylate cyclase was observed. However, when competition binding experiments were carried out with P2P3 membranes isolated from the delta opioid-desensitized hybrid cells, it was determined that 41.7 +/- 3.4% of the total binding sites remained in the high-affinity state, with no apparent alteration in the Kd value of either high- or low-affinity states. Similarly, when NG108-15 cells were treated with 100 ng/ml of pertussis toxin for 3 hr at 37 degrees C, 39.9 +/- 3.6% of the binding sites remained in the high-affinity state. This reduction in the percentage of receptor in high-affinity state was agonist specific, for chronic treatment of hybrid cells with levorphanol, a partial agonist, or the antagonist naloxone did not alter the percentage of opioid receptors in the high-affinity state. Furthermore, the delta opioid receptors remaining in the high-affinity state after chronic DADLE treatment were still sensitive to both Na+ and guanyldylimidodiphosphate, indicating that opioid ligand binding remained coupled to the G-proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of chronic D-Ala,2 D-Leu5-enkephalin or pertussis toxin treatment on the high-affinity state of delta opioid receptor in neuroblastoma x glioma NG108-15 hybrid cells. 184 9

The effects of mu, delta, and kappa receptor-agonists on forskolin stimulated cyclic adenosine-3',5'-monophosphate (cAMP) formation were examined in astroglial enriched primary cultures from the cerebral cortex of newborn rats. Intracellular cAMP accumulation was quantified by radioimmunoassay. Morphine was used as a mu-receptor agonist, D-Ala-D-Leu-Enkephalin (DADLE) as a delta-receptor agonist and dynorphin 1-13 (Dyn) as a kappa-receptor agonist. Basal cAMP levels were unaffected by either the opiate agonists or the antagonists used. In the presence of the cAMP stimulator forskolin, morphine had no significant effect on the cytoplasmic cAMP levels. DADLE caused a dose related inhibition of the forskolin stimulated cAMP accumulation. The effects of this delta receptor stimulation was blocked with the selective antagonist ICI 174.864. In the presence of Dyn, the forskolin stimulated cAMP accumulation was inhibited in a dose related manner. This kappa receptor stimulation was blocked with the selective antagonist MR 2266. Co-administration of DADLE and Dyn resulted in a non additive inhibition of the forskolin stimulated accumulation of cAMP. These findings indicate that astroglial enriched cultures from the cerebral cortex of rats express delta and kappa-receptors co-localized on the same population of cells, and that these receptors are inhibitory coupled to adenylate cyclase.
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PMID:Delta and kappa opiate receptors in primary astroglial cultures from rat cerebral cortex. 198 60

The putative regulatory effect of opioids on adenylate cyclase was investigated in two different preparations containing, respectively, two different populations of opioid receptors: the rabbit cerebellum (greater than 75% mu-opioid receptors) and the guinea pig cerebellum (greater than 80% kappa-opioid receptors). In the mu-preparation, but not in the kappa-preparation, opioids inhibited the basal and the forskolin-stimulated adenylate cyclase activity in a dose-dependent manner and stereospecifically. The inhibition was in the 20-30% range, required the presence in the assay medium of Mg2+ and of GTP, but was independent of the presence of Na+. Pharmacological characterization of the inhibitory response in the rabbit cerebellum clearly showed that it was under the control of a mu-opioid binding site, with the effect being elicited by non-selective (etorphine and morphine) and mu-selective (Tyr-D-Ala-Gly-Me-Phe-Gly-ol) agonists, whereas delta- and kappa-selective agonists were almost totally ineffective. ADP ribosylation of inhibitory GTP-binding protein by pertussis toxin failed to block the inhibitory effect of opioids, and data presented suggest that this failure is likely to be the consequence of a limited access of the toxin to its substrate in rabbit cerebellum membranes.
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PMID:mu-Opioid receptors and not kappa-opioid receptors are coupled to the adenylate cyclase in the cerebellum. 215 54

It has been suggested that the HIV virus binds to VIP recognition sites which can be blocked by the octapeptide, peptide T. Stimulation of VIP receptors on pinealocytes activates adenylate cyclase and increases the activity of the enzyme serotonin N-acetyltransferase (NAT). We examined whether peptide T or D-Ala peptide T amide affected this induction. We found no evidence for peptide T interference with NAT induction and conclude that if peptide T inhibits attachment of HIV virus to VIP receptors, it does so at regions other than that occupied by VIP in stimulating adenylate cyclase and NAT.
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PMID:Peptide T does not affect induction of pineal N-acetyltransferase by vasoactive intestinal peptide. 271 84

In purified rat pancreatic plasma membranes, (D-Phe4)PHI interacts as a selective VIP agonist for rat pancreatic VIP-preferring receptors, based on binding selectivity and adenylate cyclase activation, therefore allowing us to discriminate between the participation of VIP-preferring and secretin-preferring receptors in VIP stimulation. VIP-preferring receptors also bind GRF. They rely on disulfide bridges for their functional integrity. Their coupling with adenylate cyclase, based on the intrinsic activity of VIP analogues, is poor when compared to that of hepatic VIP receptors. In fresh rat liver plasma membranes, high-affinity VIP receptors are specifically labeled with [125I]helodermin and [125I]His1, D-Ala NLeu27)GRF and are well coupled to adenylate cyclase while low-affinity VIP receptors are not. The first subtype of VIP receptors is highly responsive to guanyl nucleotides and is easily altered by dithiothreitol. Only after freezing and thawing are low-affinity hepatic VIP receptors coupled to adenylate cyclase. Concerning the chemical characterization of VIP receptors, 66- and 35-kDa peptides are detected after specific [125I]VIP cross-linking with double agents in rat pancreatic membranes. In contrast, in intact pancreatic acini, the main source of radioactivity has a molecular mass of 130-180 kDa (with no contribution of intramolecular disulfide bridges), and an 80-kDa peptide is also detectable. The 66-kDa species in membranes can conceivably derive from the 80-kDa species observed in intact cells. Its molecular mass is higher than that of the 56-kDa [125I]VIP cross-linked protein previously observed in rat liver membranes. Besides, species differences between rat and guinea pig pancreas are also evident.
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PMID:Vasoactive intestinal peptide receptors in pancreas and liver. Structure-function relationship. 283 79

In Ca2+-free EGTA (1 mmol/l)-containing medium veratrine (3 mumol/l) and ouabain (100 mumol/l) strongly enhanced the efflux of 3H-noradrenaline from superfused rat brain neocortical slices prelabelled with the radioactive amine. In both cases 3H-noradrenaline release was prevented by tetrodotoxin (1 mumol/l). These effects of veratrine and ouabain were virtually additive and independent of whether the noradrenaline uptake carrier was blocked with 1 mumol/l desipramine or not. The adenylate cyclase activator forskolin (10 nmol/l - 10 mumol/l) strongly enhanced veratrine- and ouabain-induced 3H-noradrenaline release, without affecting spontaneous tritium efflux. The release induced by both stimuli was profoundly inhibited by the selective mu-opioid receptor agonist [D-Ala, MePhe4, Gly-ol5]enkaphalin (DAGO, 3 nmol/l - 1 mumol/l) in a concentration-dependent manner. The inhibitory effects of 1 mumol/l DAGO were abolished by 1 mumol/l naloxone. On the other hand, preincubation of the slices for 1 h with the delta-opioid receptor-selective irreversible ligand fentanyl isothiocyanate (1 mumol/l) did not change the inhibitory effects of DAGO. These data show that veratrine- and ouabain-induced 3H-noradrenaline release from central noradrenergic nerve terminals is facilitated by increasing intracellular cyclic AMP levels and reduced by activation of presynaptic mu-opioid receptors, indicating the involvement of exocytotic neurotransmitter release. The results provide further evidence for the hypothesis that under these conditions neurotransmitter release from central noradrenergic neurons is triggerred by a Na+-induced efflux of Ca2+ ions from intracellular stores.
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PMID:Sodium dependent 3H-noradrenaline release from rat neocortical slices in the absence of extracellular calcium: presynaptic modulation by mu-opioid receptor and adenylate cyclase activation. 285 12

D-1 dopamine receptor-stimulated cyclic AMP efflux from rat neostriatal slices (induced by 30 microM dopamine + 10 microM (-)sulpiride) was concentration-dependently reduced by morphine, [D-Ala-D-Leu]-enkephalin (DADLE), [D-Pen-D-Pen]enkephalin (DPDPE) and bremazocine. Naloxone (0.1 microM) selectively antagonized the inhibitory effect of (a submaximally effective concentration of) morphine, whereas ICI 174864 (0.75 microM) completely blocked the inhibitory effects of DADLE, DPDPE and bremazocine without affecting that of morphine, indicating a role of mu- as well as delta-opioid receptors. Upon simultaneous activation of D-1 dopamine receptors and delta-opioid receptors the (mu-receptor-mediated) inhibitory effect of morphine was abolished, while it was not changed following simultaneous activation of D-1 and (inhibitory) D-2 dopamine receptors. Cyclic AMP efflux induced by isoprenaline or adenosine was not affected by the opioids and that induced by vasoactive intestinal peptide (VIP) was inhibited by morphine and DADLE only. In the latter case naloxone, but not ICI 174864, antagonized the inhibitory effects. These data show that D-1 dopamine receptor-stimulated adenylate cyclase activity in rat neostriatum, but not that stimulated through other receptors, is inhibited by two pharmacologically distinct opioid receptor subtypes. It is speculated that these mu- and delta-opioid receptors share a common inhibitory guanine nucleotide binding protein and may represent closely associated recognition sites of a functional opioid receptor complex.
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PMID:Inhibition of dopamine-sensitive adenylate cyclase by opioids: possible involvement of physically associated mu- and delta-opioid receptors. 303 83

Organotypic cultures of fetal mouse spinal cord-ganglion explants (2-4 weeks in vitro) contain forskolin-stimulated adenylate cyclase (AC) activity that is inhibited by levorphanol and other opioid agonists in a dose-dependent manner. Inhibition by levorphanol no longer occurs if sodium is omitted from the incubation and the levorphanol inhibition is blocked by the opioid antagonist, naloxone. These findings together with the ineffectiveness of dextrorphan indicate that the opioid inhibition of forskolin-stimulated AC is receptor mediated. Both the delta- and kappa-receptor subtypes appear to be involved since the selective delta-opioid agonist, [D-Pen2, D-Pen5]enkephalin, and the selective kappa-opioid agonist, t-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]-benzene acetamide (U-50,488H) are both effective at nanomolar concentrations. In contrast, the selective mu-opioid agonist, Tyr-D-Ala-Gly-N-MePhe-Gly-ol, has no significant effect even at micromolar concentrations. Both cord and ganglion components of the explants contain opioid-sensitive AC. Forskolin-stimulated AC of the explants is also inhibited by serotonin and carbachol. The serotonin effect appears to be mediated by 5-HT1A receptors, based on relative agonist and antagonist selectivity. Chronic exposure of cultures to morphine results in enhanced basal and forskolin-stimulated AC as well as attenuation of opioid-inhibition of AC assayed in the presence of forskolin; treatment of explants with pertussis toxin causes similar changes in the AC system. The inhibitory effect of serotonin is also attenuated by the pertussis toxin treatment. Basal AC activity of the explants (assayed without forskolin present) is stimulated to a small but significant extent by opioids and by serotonin. The opioid stimulatory effect is markedly enhanced following either morphine or pertussis toxin treatment of the explants. The attenuation of opioid- and serotonin-inhibition of AC produced by chronic exposure to pertussis toxin and the attenuation of opioid inhibition produced by exposure to morphine are consonant with the attenuation of opioid and monoaminergic depression of sensory evoked dorsal horn network responses after similar chronic treatments. It is proposed that the inhibitory effects of opioids and serotonin on these neurons are mediated by receptors that are negatively coupled via a pertussis toxin sensitive Gi protein to AC. Furthermore, alterations of AC with chronic morphine treatment may be involved in the development of physiologic tolerance to opioids.
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PMID:Modulation of adenylate cyclase activity of mouse spinal cord-ganglion explants by opioids, serotonin and pertussis toxin. 337 Apr 65

Guanine nucleotides couple receptors to stimulate or inhibit adenylate cyclase as well as regulate binding of neurotransmitters. To explore the relationship between these different functions of guanosine 5'-triphosphate (GTP), rat brain membranes were preincubated in 50 mM sodium acetate, pH 4.5, which increased GTP regulation of 3H-opiate agonist binding. Assay of adenylate cyclase in the low pH-pretreated membranes revealed no loss of basal activity but a dramatic loss in fluoride- and guanylyl-5'-imidodiphosphate-stimulated activity, thus suggesting a loss in stimulatory guanine nucleotide coupling function. Manganese stimulation, which presumably occurs on the catalytic subunit of adenylate cyclase directly, was not affected by low pH treatment. In striatum, dopamine-stimulated adenylate cyclase was eliminated, but inhibition of adenylate cyclase by D-Ala2-Met5-enkephalinamide (D-Ala enk) was increased by low pH treatment. The effect of low pH on sodium fluoride-stimulated and D-Ala enk-inhibited adenylate cyclase could be reversed by addition of either cis-vaccenic acid or phosphatidylcholine to treated membranes, but the effect on GTP regulation of binding was not reversed by lipid incorporation. These results suggest that fundamental differences exist between membrane components which couple receptors to adenylate cyclase and those that regulate neurotransmitter binding.
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PMID:Modification of guanine nucleotide-regulatory components in brain membranes. II. Relationship of guanosine 5'-triphosphate effects on opiate receptor binding and coupling receptors with adenylate cyclase. 609 42


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