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)

Incubating 3T3-L1 adipocytes with forskolin, which increases intracellular cAMP by activating adenylate cyclase, mimicked rapamycin by attenuating the effect of insulin on stimulating the phosphorylation of four (S/T)P sites in PHAS-I, a downstream target of the mammalian target of rapamycin (mTOR) signaling pathway. To investigate the hypothesis that increasing cAMP inhibits mTOR, the protein kinase activity of mTOR was measured in an immune complex assay with recombinant PHAS-I as substrate. Both forskolin and 8-(4-chlorophenylthio)adenosine 3'-5'-monophosphate (CPT-cAMP) prevented the activation of mTOR by insulin in adipocytes, but neither agent affected mTOR activity when added directly to the immunopurified protein. In contrast, the cAMP phosphodiesterase inhibitor, theophylline, inhibited mTOR activity not only when added to intact adipocytes but also when added to immunopurified mTOR in vitro, demonstrating that certain methylxanthines are able to inhibit mTOR independently of increasing cAMP. Forskolin and CPT-cAMP blocked the effect of insulin on increasing mTOR phosphorylation, which was assessed using mTAb1, an antibody whose binding is inhibited by phosphorylation of mTOR. Although the mTAb1 epitope contains a consensus site for protein kinase B, neither agent inhibited the activation of protein kinase B produced by insulin. These findings support the interpretation that increasing cAMP attenuates the effects of insulin on PHAS-I, p70(S6K), and other downstream targets of the mTOR signaling pathway by inhibiting the phosphorylation and activation of mTOR.
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PMID:Attenuation of mammalian target of rapamycin activity by increased cAMP in 3T3-L1 adipocytes. 985 18

The circadian oscillator in Xenopus retinal photoreceptor layers can be reset in similar ways by light and agonists of D2-like dopamine receptors. Treatments that increase cyclic AMP levels act on this oscillator in an opposite fashion, mimicking darkness in the induction of phase shifts. Light and dopamine have each been reported to inhibit adenylate cyclase in photoreceptors. Together, these data suggest that the transduction pathways for entrainment by dopamine and/or light include suppression of cyclic AMP or a cyclic AMP-sensitive step. In these studies, we examined this hypothesis by measuring the effects of treatment with a cyclic AMP analogue on the phase shifts induced in photoreceptor melatonin rhythms by light or a D2 receptor agonist (quinpirole). When photoreceptor layers were treated simultaneously with 8-(4-chlorophenylthio)cyclic AMP (8-CPT-cAMP) and quinpirole at any of three different phases of the circadian cycle, the resulting phase shifts of the melatonin rhythm were always the same as those caused by 8-CPT-cAMP alone. This indicates that there is a cyclic AMP-sensitive step in the dopamine entrainment pathway. In contrast, light pulses did reset the oscillator in the presence of elevated cyclic AMP. This suggests a separate cyclic AMP-insensitive transduction pathway for entrainment by light. Quinpirole reduced basal levels of cyclic AMP in photoreceptors, but light did not. These data suggest that cyclic AMP plays a role in the entrainment pathway activated by dopamine but not in the entrainment pathway activated by light.
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PMID:A role for cyclic AMP in entrainment of the circadian oscillator in Xenopus retinal photoreceptors by dopamine but not by light. 1021 57

We examined the effects of activation of metabotropic glutamate receptors (mGluRs) on glutamatergic synaptic transmission at the neuromuscular junction of newly hatched Drosophila larvae. In nominally Ca(2+)-free solutions puff-application of low concentrations of glutamate evoked a transient frequency increase of miniature synaptic currents (mSCs). The mean amplitude of mSCs was unaffected, suggesting that this effect was presynaptic. Similar alterations of the mSC frequency were obtained using the mGluR agonists, (S)-4C3HPG, DCG-IV, or (1S,3S)-ACPD, but not when using agonists for ionotropic glutamate receptors, NMDA, AMPA or kainate. An mGluR antagonist, MCCG-I, blocked the effect of agonists on the mSC frequency. An adenylate cyclase activator, forskolin, and a cAMP analog, CPT-cAMP, mimicked the effects of mGluR activation. Meanwhile, an adenylate cyclase inhibitor, SQ22,536, blocked the mGluR agonist-induced effects, and in rutabaga, an adenylate-cyclase-defective mutant, the effect of the agonist was greatly reduced. In the presence of external Ca2+, (S)-4C3HPG decreased the failure rate and increased the mean amplitude of stimulus-evoked SCs, while MCCG-I decreased the amplitudes. We suggest that at the larval Drosophila neuromuscular junction endogenous glutamate released at the terminal potentiates synaptic transmission via a process involving cAMP.
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PMID:Activation of metabotropic glutamate receptors enhances synaptic transmission at the Drosophila neuromuscular junction. 1034 Mar 2

Alpha1-adrenoceptor agonists may potentiate relaxation to beta-adrenoceptor agonists, although the mechanisms are unclear. We compared relaxations induced by beta-adrenoceptor agonists and cyclic AMP-dependent vasodilators in rat pulmonary arteries constricted with prostaglandin F2alpha (PGF2alpha) or the alpha1-adrenoceptor agonist phenylephrine (PE). In addition, we examined whether differences were related to cyclic AMP- or nitric oxide (NO) and cyclic GMP-dependent pathways. Isoprenaline-induced relaxation was substantially potentiated in arteries constricted with PE compared with PGF2alpha. Methoxamine was similar to PE, whereas there was no difference between PGF2alpha and 30 mM KCl. The potentiation was primarily due to a marked increase in the NO-independent component of relaxation, from 9.1+/-1.7% for PGF2alpha to 55.1+/-4.4% for PE. NO-dependent relaxation was also enhanced, but to a lesser extent (50%). Relaxation to salbutamol was almost entirely NO-dependent in both groups, and was potentiated approximately 50% by PE. Relaxation to forskolin (activator of adenylate cyclase) was also enhanced in PE constricted arteries. Part of this relaxation was NO-dependent, but the major effect of PE was to increase the NO-independent component. Propranolol diminished but did not abolish the potentiation. There was no difference in response to CPT cyclic AMP (membrane permeant analogue) between PE and PGF2alpha, suggesting that mechanisms distal to the production of cyclic AMP were unchanged. Relaxation to sodium nitroprusside (SNP) was the same for PE and PGF2alpha, although relaxation to acetylcholine (ACh) was slightly depressed. This implies that potentiation by PE does not involve the cyclic GMP pathway directly. Mesenteric arteries constricted with PE did not show potentiation of isoprenaline-induced relaxation compared to those constricted with PGF2alpha, suggesting that this effect may be specific to the pulmonary circulation. These results clearly show that PE potentiates both the NO-independent and -dependent components of cyclic AMP-mediated relaxation in pulmonary arteries of the rat, although the effect on the former is more profound. We suggest that potentiation of both components is largely due to direct activation of adenylate cyclase via alpha1-adrenoceptors, within the smooth muscle and endothelial cells respectively.
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PMID:Potentiation of cyclic AMP-mediated vasorelaxation by phenylephrine in pulmonary arteries of the rat. 1036 85

The vasodilator effects of pituitary adenylate cyclase activating polypeptide (PACAP-27) are subject to tachyphylaxis in rats treated with the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). This study examined whether this tachyphylaxis is due to the loss of vasodilator potency of cAMP generated by activation of the G(s) protein-coupled PACAP receptors. Five successive treatments with PACAP-27 (2 nmol/kg iv) produced pronounced vasodilator responses in saline-treated rats that were not subject to tachyphylaxis. The first injection of PACAP-27 (2 nmol/kg iv) in L-NAME (50 micromol/kg iv)-treated rats produced vasodilator responses of similar magnitude to those in saline-treated rats, whereas four subsequent injections produced progressively and markedly smaller responses. The hemodynamic effects of the membrane-permeable cAMP analog 8-(4-chlorophenylthiol)-cAMP (8-CPT-cAMP; 5-15 micromol/kg iv) were similar in L-NAME-treated rats and in L-NAME-treated rats that had received the five injections of PACAP-27. In addition, five injections of 8-CPT-cAMP (10 micromol/kg iv) produced pronounced vasodilator responses in saline- and L-NAME-treated rats that were not subject to the development of tachyphylaxis. These results suggest that a loss of biological potency of cAMP is not responsible for tachyphylaxis to PACAP-27 in L-NAME-treated rats. This tachyphylaxis may be due to the inability of the G(s) protein-coupled PACAP receptor to activate adenylate cyclase.
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PMID:Tachyphylaxis to PACAP-27 after inhibition of NO synthesis: a loss of adenylate cyclase activation. 1056 19

Whole cell perforated patch-clamp methods were used to investigate ionic mechanisms underlying histamine-evoked excitatory responses in small intestinal AH-type myenteric neurons. When physiological concentrations of Na(+), Ca(2+), and Cl(-) were in the bathing medium, application of histamine significantly increased total conductance as determined by stepping to 50 mV from a holding potential of -30 mV. The current reversed at a membrane potential of -30 +/- 5 (SE) mV and current-voltage relations exhibited outward rectification. The reversal potential for the histamine-activated current was unchanged by removal of Na(+) and Ca(2+) from the bathing medium. Reduction of Cl(-) from 155 mM to 55 mM suppressed the current when the neurons were in solutions with depleted Na(+) and Ca(2+). Current-voltage curves in solutions with reduced Cl(-) were linear and the reversal potential was changed from -30 +/- 5 mV to 7 +/- 4 mV. Niflumic acid, but not anthracene-9-carboxylic acid (9-AC) nor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), suppressed the histamine-activated current. A membrane permeable analogue of cAMP evoked currents similar to those activated by histamine. A selective histamine H(2) receptor agonist (dimaprit) mimicked the action of histamine and a selective histamine H(2) receptor antagonist (cimetidine) blocked the conductance increase evoked by histamine. A selective adenosine A(1) receptor agonist (CCPA) reduced the histamine-activated current and a selective adenosine A(1) receptor antagonist (CPT) reversed the inhibitory action. The results suggest that histamine acts at histamine H(2) receptors to increase Cl(-) conductance in AH-type enteric neurons. Cyclic AMP appears to be a second messenger in the signal transduction process. Results with a selective adenosine A(1) receptor agonist and antagonist add to existing evidence for co-coupling of inhibitory adenosine A(1) receptors and histamine H(2) receptors to adenylate cyclase in AH-type enteric neurons.
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PMID:Histamine H(2) receptor activated chloride conductance in myenteric neurons from guinea pig small intestine. 1075 93

A perforated patch recording method was used to determine how plating cells on laminin (20 microg ml(-1); >2 h) alters cholinergic regulation of L-type Ca(2+) current (I(Ca,L)) in atrial myocytes. Acetylcholine (ACh; 1 microm)-induced inhibition of basal I(Ca,L) was not different between cells on glass and laminin. However, stimulation of I(Ca,L) elicited by ACh withdrawal was significantly smaller in cells on laminin (10 +/- 2 %) than on glass (48 +/- 5 %) (P < 0.001). Stimulation of I(Ca,L) induced by either spermine-NO (200 microm), milrinone (10 microm), IBMX (100 microm) or forskolin (1 microm) was significantly smaller in cells plated on laminin than on glass. However, stimulation of I(Ca,L) by 100 microm 8-CPT-cAMP or intracellular dialysis with 50 microM cAMP was not different between cells plated on laminin or glass. Basal, forskolin- and IBMX-stimulated cAMP content was significantly smaller in cells plated on laminin than on glass. Stimulation of I(Ca,L) by ACh withdrawal was significantly smaller in cells plated on an alpha beta 1-integrin antibody (10 +/- 4 %) than on glass (3 +/- 6 %; P < 0.001). In cells on laminin, prior exposure to 100 microg ml-1 YIGSR, a laminin receptor-binding peptide, restored ACh-induced stimulation of I(Ca,L) (58 +/- 14 %)laminin alone (7 +/- 2 %; P < 0. 05). Addition of 20 microm cytochalasin D or 1 microM latrunculin A, agents that prevent actin polymerization, to cells on laminin restored ACh-induced stimulation of I(Ca,L). We conclude that laminin binding to beta 1 integrins acts in association with the actin-based cytoskeleton to attenuate adenylate cyclase activity. As a result, laminin inhibits NO-mediated stimulation of I(Ca,L) elicited by ACh withdrawal. Laminin-integrin signalling may be relevant to changes in autonomic regulation that occur during cardiac development and/or disease.
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PMID:Laminin acts via beta 1 integrin signalling to alter cholinergic regulation of L-type Ca(2+) current in cat atrial myocytes. 1087 99

To ascertain the presence of adenosine receptors in the trout testis, cells isolated from testes at different spermatogenetic stages were cultured in the presence or absence of adenosine, adenosine receptor agonists, or antagonists and of cAMP analogs, for up to 20 min, or 20 hr, or 4.5 days. Cyclic AMP production was then assayed or 3H-thymidine incorporation was measured. Cellular content of cAMP was enhanced by adenosine, by the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), and by 2-p(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680), an adenosine A2A receptor-selective agonist. The increase in cAMP induced by the adenylate cyclase activator L-858051 was inhibited by the adenosine A1)receptor-selective agonists R-N6-(2-phenylisopropyl)adenosine (R-PIA) and N6-cyclopentyladenosine (CPA). These effects were antagonized by the two adenosine A2)receptor antagonists 3,7-dimethyl-1-propargylxanthine (DMPX) and 8-(3-chlorostyryl)caffeine (CSC), and by the adenosine A1)receptor-selective antagonist 8-cyclopentyl-1,3dipropylxanthine (CPX), respectively. Increase in the cAMP content induced by adenosine was inhibited by the cell permeable adenylate cyclase inhibitor 2',5'-dideoxyadenosine. These data suggest that A(1) and A(2) adenosine receptors which respectively inhibit and stimulate adenylate cyclase activity are present on trout testicular cells (unidentified), while the presence of A3 adenosine receptor subtype was not apparent. 3H-thymidine incorporation decreased in the presence of the adenylate cyclase activator L-858051 and of the cAMP analogs 8-CPT cAMP and Sp-5,6-DCI-cBiMPS, regardless of the presence or absence of the phosphodiesterase inhibitor RO 20-1724. This suggests that an increase in testicular cAMP may act as a negative growth regulator for the mitotic germ cells. In agreement with these data, the activation of A2 stimulatory receptors inhibited short-term (20 hr) DNA synthesis. However, the activation of A1 inhibitory receptors had the same effect. This suggests that events, cAMP-dependent or independent, induced by the activation of testicular adenosine receptors, may participate in the regulation of trout male germ cell proliferation.
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PMID:Adenosine receptor-adenylate cyclase system in the trout testis: involvement in the regulation of germ cell proliferation. 1117 Feb 72

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the glucagon/secretin peptide family and its molecular structure is highly conserved among vertebrates. In this study, the role of PACAP in regulating growth hormone (GH) secretion in fish was examined in vitro using common carp pituitary cells under column perifusion. A dose-dependent increase in GH release was observed after exposing pituitary cells to increasing doses of ovine PACAP38 (oPACAP38) and PACAP27 (oPACAP27), but not vasoactive intestinal polypeptide (VIP). A lack of GH response to VIP stimulation is consistent with the pharmacological properties of PAC-1 receptors, suggesting that this receptor subtype may be involved in PACAP-induced GH secretion in carp species. Although the maximal GH responses induced by oPACAP38 and oPACAP27 were similar, the minimal effective dose and ED50 value for oPACAP38 were significantly lower than that for oPACAP27. These results may indicate that common carp PAC-1 receptors are more sensitive to stimulation by oPACAP38 than by oPACAP27. In parallel studies, oPACAP38 and oPACAP27 were also effective in increasing cAMP release, cellular cAMP content, total cAMP production, and intracellular Ca(2+) ([Ca(2+)](i)) levels in common carp pituitary cells. Besides, the rise in [Ca(2+)](i) induced by oPACAP38 was blocked by removing extracellular Ca(2+) ([Ca(2+)](e)) or by treatment with nifedipine, an inhibitor of voltage-sensitive Ca(2+) channels (VSCC). The dose dependence of PACAP-stimulated GH release in common carp pituitary cells was mimicked by activating adenylate cyclase using forskolin, inhibiting cAMP degradation using IBMX, increasing functional levels of intracellular cAMP using CPT-cAMP, or inducing [Ca(2+)](e) entry using the Ca(2+) ionophore A23187. In contrast, the GH-releasing effect of oPACAP38 was suppressed by treatment with the adenylate cyclase inhibitor MDL12330A, protein kinase A inhibitor H89, and VSCC blocker nifedipine, or by perifusion with a Ca(2+)-free culture medium. These results, as a whole, suggest that PACAP functions as a GH-releasing factor in common carp by activating pituitary receptors resembling mammalian PAC-1 receptors. Apparently, the GH-releasing action of PACAP is mediated through the adenylate cyclase/cAMP/protein kinase A pathway and [Ca(2+)](e) influx through VSCC.
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PMID:Regulation of growth hormone release in common carp pituitary cells by pituitary adenylate cyclase-activating polypeptide: signal transduction involves cAMP- and calcium-dependent mechanisms. 1245 43

1. The mechanisms and receptors involved in the vasoactive intestinal peptide (VIP)- and pituitary adenylate cyclase-activating polypeptide (PACAP)-induced relaxations of the pig intravesical ureter were investigated. 2. VIP, PACAP 38 and PACAP 27 concentration-dependently relaxed U46619-contracted ureteral strips with a similar potency. [Ala(11,22,28)]-VIP, a VPAC(1) agonist, showed inconsistent relaxations. 3. The neuronal voltage-gated Ca(2+) channel inhibitor, omega-conotoxin GVIA (omega-CgTX, 1 microm), reduced the VIP relaxations. Urothelium removal or blockade of capsaicin-sensitive primary afferents, nitric oxide (NO) synthase and guanylate cyclase with capsaicin (10 microm), N(G)-nitro-l-arginine (l-NOARG, 100 microm) and 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 microm), respectively, did not change the VIP relaxations. However, the PACAP 38 relaxations were reduced by omega-CgTX, capsaicin, l-NOARG and ODQ. 4. The VIP and VIP/PACAP receptor antagonists, [Lys(1), Pro(2,5), Arg(3,4), Tyr(6)]-VIP (1 microm) and PACAP (6-38) (0.4 microm), inhibited VIP and VIP and PACAP 38, respectively, relaxations. 5. The nonselective and large-conductance Ca(2)-activated K(+) channel blockers, tetraethylammonium (3 mm) and charybdotoxin (0.1 microm), respectively, and neuropeptide Y (0.1 microm) did not modify the VIP relaxations. The small-conductance Ca(2)-activated K(+) channel blocker apamin (1 microm) did not change the PACAP 27 relaxations. 6. The cAMP-dependent protein kinase A (PKA) blocker, 8-(4-chlorophenylthio)adenosine-3',5'-cyclic monophosphorothioate (Rp-8-CPT-cAMPS, 100 microm), reduced VIP relaxations. The phosphodiesterase 4 inhibitor rolipram and the adenylate cyclase activator forskolin relaxed ureteral preparations. The rolipram relaxations were reduced by Rp-8-CPT-cAMPS. Forskolin (30 nm) evoked a potentiation of VIP relaxations. 7. These results suggest that VIP and PACAP relax the pig ureter through smooth muscle receptors, probably of the VPAC(2) subtype, linked to a cAMP-PKA pathway. Neuronal VPAC receptors localized at motor nerves and PAC(1) receptors placed at sensory nerves and coupled to NO release, seem also to be involved in the VIP and PACAP 38 relaxations.
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PMID:Heterogeneity of neuronal and smooth muscle receptors involved in the VIP- and PACAP-induced relaxations of the pig intravesical ureter. 1466 37


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