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)

We have investigated the pharmacological profile of the opioid stimulation of adenylate cyclase activity in rat olfactory bulb, in order to identify the opioid receptor subtype(s) involved in this response. The synthetic delta-selective agonists (D-Ala2)deltorphin I, (2-D-penicillamine,5-D-penicillamine)-enkephalin, and (D-Ser-Leu5-enkephalyl)-threonine were effective stimulators of the enzyme activity, with EC50 values of 6.7, 420, and 63 nM, respectively. A significant increase was also observed with the mu-selective agonists (N-methyl-Phe3,D-Pro4)-morphiceptin, dermorphin, and (D-Ala2-N-methyl-Phe4-Gly-ol5)-enkephalin (DAGO). The latter two agonists displayed biphasic concentration-response curves, with high affinity components accounting for 75-80% of the maximal responses. The kappa-selective agonists U-50,488 and U-69,593 were ineffective, whereas (D-Ala2)dynorphin A-1-11, dynorphin A, dynorphin A-1-13, and dynorphin A-1-6 acted with a rank order of potency consistent with their affinity for delta receptors. The stimulatory responses of Leu-enkephalin, beta-endorphin, dynorphin A, and delta-selective agonists were counteracted by naltrindole with pA2 values of 9.39-8.93, whereas naloxone was less potent (pA2 = 8.17-7.59). The kappa-selective antagonist norbinaltorphimine was the least potent. The inhibition by naltrindole and naloxone of DAGO stimulation showed biphasic curves, with 90% of the response being antagonized more potently by naloxone than by naltrindole. These results demonstrate that delta- and mu- but not kappa-opioid receptor subtypes stimulate basal adenylate cyclase activity in rat olfactory bulb.
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PMID:Characterization of opioid receptors mediating stimulation of adenylate cyclase activity in rat olfactory bulb. 132 51

The preproenkephalin A gene is a neurotransmitter gene whose expression can be modulated "trans-synaptically" by changes in neuronal activity. DNA sequences lying within 200 base pairs of this gene's transcription start site resemble consensus binding sites for several transcription factor families. In nonneuronal cell cultures, this promoter region is sufficient to mediate gene responses to depolarization, phorbol esters, adenylate cyclase, and calcium fluxes. To assess the role that these cis-acting elements could play in preproenkephalin expression and regulation in vivo, the expression of a construct containing this 200-base-pair region fused to the chloramphenicol acetyltransferase gene was examined in transgenic mice. This promoter confers modest expression in brain, adrenal, and small intestine, with substantially higher levels in testis. These elements confer trans-synaptic regulation in two well-studied models of trans-synaptic preproenkephalin upregulation but not in a third system, underscoring the specificity of the regulatory sequence elements implicated in the synaptic regulation of neuronal genes.
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PMID:Preproenkephalin promoter "cassette" confers brain expression and synaptic regulation in transgenic mice. 137 43

In homogenate of rat olfactory bulb, the opioid receptor agonists beta-endorphin, Leu-enkephalin, and dynorphin A stimulated adenylate cyclase activity in a concentration-dependent manner, with half-maximal effects displayed at 22, 63, and 176 nM, respectively. The maximal stimulation of the enzyme activity corresponded to about a 40% increase of basal activity for all three peptides. Naloxone antagonized the stimulation of beta-endorphin, Leu-enkephalin, and dynorphin A, with pA2 values of 8.0, 7.7, and 8.1, respectively. Kinetic analysis performed with Leu-enkephalin showed that the opioid peptide increased the Vmax of the enzyme, without changing the Km for the substrate Mg-ATP. Moreover, the opioid stimulation was associated with a significant increase of the affinity of the enzyme for Mg2+ activation and occurred in membranes incubated in a Ca2(+)-free medium. Addition of exogenous GTP at micromolar concentrations was absolutely necessary for the detection of the opioid effect. Treatment of olfactory bulbs with cholera toxin did not alter the stimulation of adenylate cyclase by Leu-enkephalin. However, the opioid stimulation disappeared in membranes obtained from bulbs injected with pertussis toxin. These results demonstrate the presence in the brain of a new functional class of opiate receptors coupled to stimulation of adenylate cyclase via a transduction mechanism that is Ca2+ independent and seems to involve a pertussis toxin-sensitive GTP-binding protein.
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PMID:Naturally occurring opioid receptor agonists stimulate adenylate cyclase activity in rat olfactory bulb. 167 23

Cultured peritubular cells prepared from the testes of 20-day-old rats contained both preproenkephalin (A) mRNA (1.5 kb) and amyloid beta-protein precursor mRNA (3.6 and 2.8 kb). The phorbol ester TPA and forskolin (an adenylate cyclase activator) increased the preproenkephalin mRNA abundance to 9.0 and 5.8 times the control, respectively. TPA alone had no effect on the intracellular cAMP level. A combination of TPA and forskolin elicited a synergistic increase in the ppEnk mRNA abundance over 30-fold. Dexamethasone potentiated the effect of forskolin but not of TPA. These results suggest that TPA regulates the preproenkephalin mRNA abundance through a cAMP-independent pathway. In contrast, TPA, forskolin, and dexamethasone showed little or no effect on the abundance of amyloid beta-protein precursor mRNA.
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PMID:Phorbol ester regulates the abundance of enkephalin precursor mRNA but not of amyloid beta-protein precursor mRNA in rat testicular peritubular cells. 254 64

The effects of mu- and delta-preferring agonists on adenylate cyclase activity have been investigated in vitro in homogenates of guinea pig cochleas. Morphine, Leu-enkephalin, D-Ala2, N-methyl-Phe4, Gly-ol5-enkephalin (DAGO) and D-Ser2-Leu-enkephalin-Thr (DSLET) each inhibited the synthesis of cyclic AMP. This effect was reversed by naloxone which had a greater affinity in blocking the effect of the mu-preferring agonists (morphine, DAGO) than in blocking the effect of the delta-preferring agonists (Leu-enkephalin, DSLET). Finally, no additive effects were observed when various combinations of two agonists were used. These results indicate that opioid receptors exist in the guinea pig cochlea and that they are negatively linked to adenylate cyclase. The different affinities shown by naloxone to reverse the inhibition induced by the mu- and delta-preferring agonists suggest that morphine and DAGO act through mu-receptors, whereas Leu-enkephalin and DSLET act through delta-receptors. Since no additive effects have been found when combining two different agonists, it can be hypothesized that the mu- and delta-receptors are coupled to the same pool of adenylate cyclase. It may be proposed from these findings that in vivo enkephalins inhibit the synthesis of cyclic AMP via mu- and delta-receptors. However, whether this effect occurs at a presynaptic level (within opioid-containing olivocochlear varicosities) or at the postsynaptic level (within dendrites of the primary auditory neurons) remains to be determined.
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PMID:Opioid receptors inhibit the adenylate cyclase in guinea pig cochleas. 282 9

The presence of vasoactive intestinal peptide (VIP) binding sites and the adenylate cyclase activity in response to VIP were examined in the human term placenta. Slices were used in order to preserve the physicochemical environment and the structural integrity of this heterogeneous organ. 125I-VIP binding to placental slices was saturable. The steady state was reached after 90 min at 37 degrees C and was maintained up to 3 h. Unlabeled VIP was able to compete in a dose-dependent manner with an IC50 value of 5.2 +/- 1.3 x 10(-10) M. Autoradiography and histological analysis showed that VIP binding sites were essentially located on fetal vascularization, especially arteries of stem villi. VIP produced a stimulatory effect on cAMP synthesis at a concentration as low as 10(-10) M. The dose-response curve was monophasic with an ED50 value of 2.9 +/- 1.6 x 10(-9) M. The specificity of the VIP effect was tested with peptides structurally related to VIP such as glucagon, secretin, gastric inhibitory polypeptide and human growth-hormone releasing factor. Only secretin at high concentrations (greater than 10(-6) M) increased cAMP production. Leu-enkephalin or insulin were ineffective. The presence of both VIP binding sites on fetal vascularization and VIP-induced adenylate cyclase activation would seem to suggest a regulatory role of the peptide on fetoplacental blood flow.
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PMID:Autoradiographic localization of vasoactive intestinal peptide (VIP) binding sites in the human term placenta. Relationship with activation of adenylate cyclase. 282 91

Primary cultures of pure populations of neuronal or glial cells from the striatum, the cerebral cortex, and the mesencephalon of the mouse embryo were used to look for the presence of opiate receptors coupled to adenylate cyclase. Leu-enkephalin inhibited cAMP production in membranes of embryonic striatal neurons but not in those of other cell types examined. Mu and delta opiate receptors seemed to be coupled negatively to adenylate cyclase in embryonic striatal neurons. It was found that DTLET (a selective delta agonist), as well as DAGO (a selective mu agonist), inhibited cAMP production on these cells. DTLET but not, however, DAGO produced a similar effect on homogenates from the adult rat striatum and on membranes from the neuroblastoma x glioma hybrid cell line NG 108-15, two preparations known to possess only delta receptors negatively coupled to adenylate cyclase. The selective kappa agonist U 50.488 was ineffective on all types of membrane preparations used. The inhibitory effects of both DTLET and DAGO on basal adenylate cyclase activity in striatal neurons were reversed by naloxone with a similar efficacy. Two other selective mu agonists, trimu 5 and morphiceptin, inhibited cAMP production in membranes of striatal neurons as well. The nonadditivity of the inhibitory effects of DTLET and DAGO on basal or forskolin-induced activation of adenylate cyclase suggested that mu and delta receptors were colocalized on a similar subpopulation of striatal cells in primary culture. These cells possess dopaminergic receptors of the D1 subtype as well since the amplitude of the inhibitory effects of DTLET and DAGO on cAMP production was increased in the presence of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mu and delta opiate receptors coupled negatively to adenylate cyclase on embryonic neurons from the mouse striatum in primary cultures. 284 21

Cultured C6 rat glioma cells contain mRNA coding for preproenkephalin (A), the precursor of methionine- and leucine-enkephalin. The abundance in untreated cells was determined by blot hybridization methods to be 3-6 pg per micrograms total RNA. Treatment of confluent cells for 12 h with 10 microM (-)-norepinephrine, which activates C6 adenylate cyclase, transiently elevated preproenkephalin mRNA to 3.3 and 7.7 times the control in the absence and presence of the glucocorticoid dexamethasone, respectively. Hydrocortisone and corticosterone also potentiated the effect of norepinephrine. However, glucocorticoids alone did not alter the preproenkephalin mRNA abundance. The effect of norepinephrine + dexamethasone was blocked by the beta-adrenergic antagonist propranolol but not by the alpha-adrenergic antagonist phentolamine. Forskolin, which directly activates adenylate cyclase, similarly elevated the preproenkephalin mRNA abundance; its effect was also potentiated by dexamethasone. C6 cells contain Met-enkephalin-containing protein resembling proenkephalin (apparent Mr 30,000) but little Met-enkephalin, suggesting a low level of proper precursor processing. Treatment with norepinephrine + dexamethasone raised the content of proenkephalin-like protein 11-fold. Thus, preproenkephalin mRNA levels in C6 cells are regulated synergistically by adenosine 3':5'-cyclic monophosphate and glucocorticoids. These results suggest modes of regulation of proenkephalin biosynthesis in normal rat enkephalinergic cells.
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PMID:Expression of the enkephalin precursor gene in C6 rat glioma cells: regulation by beta-adrenergic agonists and glucocorticoids. 287 71

Regulation of preproenkephalin gene expression was studied in NG108-15 neuroblastoma-glioma hybrid cells. Untreated cells contain 20-120 fg preproenkephalin mRNA per microgram cellular RNA. Treatment of cells with a glucocorticoid (e.g. dexamethasone) for 24 hr or 8 days elevated the abundance of this mRNA to 3 or 9 times the control, respectively. Treatment with 8-bromo-cyclic AMP or an adenylate cyclase activator such as prostaglandin E1 or forskolin elevated preproenkephalin mRNA to twice the control or less. Treatment with both glucocorticoid and forskolin for 24 hr or 8 days markedly increased preproenkephalin mRNA to 5-8 and 30 times the control, respectively. Intracellular Met-enkephalin immunoreactivity was increased in parallel with the mRNA abundance. The results demonstrate that preproenkephalin gene expression is synergistically regulated by glucocorticoids and cAMP.
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PMID:Glucocorticoids and cyclic AMP synergistically regulate the abundance of preproenkephalin messenger RNA in neuroblastoma-glioma hybrid cells. 302 Nov 19

4 beta-Phorbol 12-myristate 13-acetate (PMA), added to a lysed mitochondrial fraction of rat striatum, stimulates adenylate cyclase activity with an apparent time lag of approximately 30 s. Half-maximal and maximal enzyme stimulations are obtained with 8 and 200 nM PMA, respectively. The PMA stimulation is GTP dependent, reaching a maximum of approximately 60% at 50 microM GTP, and is associated with disappearance of the enzyme inhibition induced by micromolar concentrations of GTP. Enhancement of enzyme activity by cholera toxin and 3,4-dihydroxyphenylethylamine is amplified by PMA only at micromolar concentrations of GTP. PMA does not affect the enzyme stimulation by forskolin but reverses the inhibition of forskolin-stimulated enzyme by GTP. When guanyl-5'-yl-imidodiphosphate is substituted for GTP, PMA does not modify adenylate cyclase activity. Enzyme inhibition by acetylcholine, Leu-enkephalin, and R(-)N6-(2-phenylisopropyl)adenosine is magnified by PMA. Stimulation of adenylate cyclase by PMA is markedly reduced following EGTA treatment, is not observed when adenyl-5'-yl-imidodiphosphate is substituted for ATP as substrate for adenylate cyclase, and is enhanced by L-alpha-phosphatidyl-L-serine. Like PMA, 4 beta-phorbol 12,13-dibutyrate and 1-oleoyl-2-acetylglycerol stimulate striatal adenylate cyclase, whereas 4 beta-phorbol and 4 beta-phorbol 13-acetate are ineffective. The results indicate that phorbol esters increase striatal adenylate cyclase activity by reducing the GTP-induced inhibition of the enzyme, presumably as a result of protein kinase C activation.
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PMID:Phorbol esters increase GTP-dependent adenylate cyclase activity in rat brain striatal membranes. 373 3


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