Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An adenosine antagonist, 8-(3-chlorostyryl)caffeine (CSC), was shown previously to be 520-fold selective for A2a-adenosine receptors in radioligand binding assays in the rat brain. In reversing agonist effects on adenylate cyclase, CSC was 22-fold selective for A2a receptors in rat phenochromocytoma cells (Kb 60 nM) vs. A1 receptors in rat adipocytes (Kb 1.3 microM). Administered i.p. in NIH mice at a dose of 1 mg/kg, CSC shifted the curve for locomotor depression elicited by the A2a-selective agonist APEC to the right (ED50 value for APEC shifted from 20 micrograms/kg i.p. to 190 micrograms/kg). CSC had no effect on locomotor depression elicited by an ED50 dose of the A1-selective agonist CHA. CSC alone at a dose of 5 mg/kg stimulated locomotor activity by 22% over control values. Coadministration of CSC and the A1-selective antagonist CPX, both at non-stimulatory doses, increased activity by 37% (P < 0.001) over CSC alone, suggesting a behavioral synergism of A1- and A2-antagonist effects in the CNS.
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PMID:8-(3-Chlorostyryl)caffeine (CSC) is a selective A2-adenosine antagonist in vitro and in vivo. 849 27

Binding of an intrinsic agonist (cyclic AMP) to specific receptors on the cell surface induces transmembrane signals for the activation of adenylate cyclase in the cellular slime mold Dictyostelium discoideum. We found that stimulation by CaCl2, MgSO4 or polyamines having two to four positive charges induced the activation of adenylate cyclase in cells treated with saponin. The activation was roughly identical to the stimulation of the intrinsic agonist both in amount and in time course. The intact cells (saponin-untreated cells) responded to neither divalent cations nor polyamines. While saponin is known to have a detergent-like effect and to make the plasma membrane permeable, low molecular weight dyes did not penetrate the plasma membrane under our conditions for the saponin-treatment. Caffeine is known to inhibit the cAMP-induced activation of adenylate cyclase by blocking signal transduction, but not by acting directly on the enzyme [Brenner, M. and Thoms, S.D. (1984) Dev. Biol. 101, 136-146]. We found that caffeine inhibited the cation-induced activation. These results suggest that these divalent and polyvalent cations do not act directly on adenylate cyclase but that they mimic or induce the transmembrane activation signal for adenylate cyclase in the saponin-treated cells.
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PMID:Activation of adenylate cyclase by divalent cations and polyamines in saponin-treated Dictyostelium discoideum cells. 853 99

Recent experiments indicate that the calcium store (e.g., endoplasmic reticulum) is involved in electrical bursting and [Ca2+]i oscillation in bursting neuronal cells. In this paper, we formulate a mathematical model for bursting neurons, which includes Ca2+ in the intracellular Ca2+ stores and a voltage-independent calcium channel (VICC). This VICC is activated by a depletion of Ca2+ concentration in the store, [Ca2+]cs. In this model, [Ca2+]cs oscillates slowly, and this slow dynamic in turn gives rise to electrical bursting. The newly formulated model thus is radically different from existing models of bursting excitable cells, whose mechanism owes its origin to the ion channels in the plasma membrane and the [Ca2+]i dynamics. In addition, this model is capable of providing answers to some puzzling phenomena, which the previous models could not (e.g., why cAMP, glucagon, and caffeine have ability to change the burst periodicity). Using mag-fura-2 fluorescent dyes, it would be interesting to verify the prediction of the model that (1) [Ca2+]cs oscillates in bursting neurons such as Aplysia neuron and (2) the neurotransmitters and hormones that affect the adenylate cyclase pathway can influence this oscillation.
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PMID:Modeling slowly bursting neurons via calcium store and voltage-independent calcium current. 869 30

Chronic treatment with the adenosine receptor antagonist caffeine evokes an up-regulation of A1 adenosine receptors and increased coupling of the receptor to G proteins in rat brain membranes. However, chronic agonist exposure has not been explored. Primary cultures of cerebellar granule cells were exposed chronically to A1 adenosine receptor agonists and antagonists. Exposure to the A1 adenosine receptor agonist N6-cyclopentyladenosine resulted in (1) a time- and concentration-dependent reduction in the density of receptors labeled by 1,3-[3H]dipropyl-8-cyclopentylxanthine, (2) an enhanced ability of guanyl nucleotides to decrease the fraction of A1 adenosine receptor sites displaying high affinity for 2-chloroadenosine, and (3) a functional uncoupling of receptors from adenylyl cyclase (EC 4.6.1.1). The adenosine antagonists caffeine and 8-p-sulfophenyltheophylline produced alterations in A1 adenosine receptor homeostasis that were antipodal to those associated with agonist treatment. Antagonist exposure (1) increased the density of A1 adenosine receptors in cerebellar granule cell membranes, (2) blunted the effect of guanyl nucleotides on receptor coupling to G proteins, and (3) increased the functional coupling of receptors to adenylyl cyclase inhibition. Forskolin treatment of cerebellar granule cells did not affect receptor density, suggesting that cyclic AMP is not involved in the regulation of A1 adenosine receptor expression.
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PMID:Chronic exposure to adenosine receptor agonists and antagonists reciprocally regulates the A1 adenosine receptor-adenylyl cyclase system in cerebellar granule cells. 886 96

The effect of adenosine on Na+/H+ exchange activity was examined in cultured A6 renal epithelial cells. Adenosine and its analogue N6-cyclopentyladenosine (CPA) had different effects on Na+/H+ exchange activity depending on the side of addition. Basolateral CPA induced a stimulation of Na+/H+ exchange activity that was completely prevented by preincubation with an A2A-selective antagonist, 8-(3-chlorostyryl)caffeine, whereas apical CPA induced a slight but significant inhibition of Na+/H+ exchange activity that was significantly reduced by the A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine. Protein kinase C activation may be involved in mediating the apical CPA inhibition of Na+/H+ exchange activity; this inhibition was prevented by the protein kinase C inhibitor calphostin C. Treatment with either forskolin or 8-bromo-cAMP significantly stimulated Na+/H+ exchange activity; only basolateral CPA addition induced an increase in cAMP level. These observations together with the finding that the CPA-dependent stimulation of exchange activity was prevented by the protein kinase A inhibitor H-89 support the hypothesis that basolateral CPA stimulates Na+/H+ exchange via adenylate cyclase/protein kinase A activation. Basolateral CPA also increased transepithelial Na+ transport, and this stimulation was prevented by the Na+/H+ exchange inhibitor HOE-694, suggesting that changes in pHi during hormone action can act as an intermediate in the second-messenger cascade.
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PMID:Polarization of adenosine effects on intracellular pH in A6 renal epithelial cells. 905 8

Rat neuromuscular junction was used to study the characteristics of presynaptic A1 adenosine receptors. We investigated the ability of the 8-substituted caffeine, 8-cyclohexylcaffeine (CHC), as well as of 1,3,8-substituted xanthines, 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX) and 8-p-sulfophenyl-1-isoamyl-3-isobutylxanthine (SPIIBX) to antagonize the inhibitory effect of 2-chloroadenosine on the amplitude of nerve-evoked twitches of the rat phrenic-hemidiaphragm, and we compared the affinity of these xanthines with that of 1,3-dipropyl-8-cyclopenthylxanthine (DPCPX). CHC, DPSPX and SPIIBX in a near parallel manner shifted to the right the log concentration-response curve for the inhibitory effect of 2-chloroadenosine on nerve-evoked twitch amplitude. Linear Schild plots with slopes near to unity were obtained for all these xanthines. The order of potency of the xanthines was DPCPX (Ki = 0.53 nM) > DPSPX (38 nM) = CHC (41 nM) > SPIIBX (404 nM). The affinities of DPSPX and SPIIBX for the A1 receptor at the rat neuromuscular junction are in agreement with the affinities described for A1 receptors at brain membranes. The now reported affinity of CHC for the presynaptic A1 receptor is 683 times higher than that obtained in binding studies in rat brain membranes, and is only 49 times higher than that obtained in functional assays (adenylate cyclase activity) in non-neuronal preparations (rat fat cells).
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PMID:On the high affinity of 8-cyclohexylcaffeine for the presynaptic inhibitory adenosine receptor present in rat motor nerve terminals. 922 67

The involvement of cyclic AMP in the settlement of the cypris larva of Balanus amphitrite amphitrite Darwin has been examined through the use of compounds that affect intracellular cyclic AMP levels. The activation of adenylate cyclase with forskolin, and the inhibition of phosphodiesterase with 3-isobutyl-1-methylxanthine, caffeine and theophylline, significantly increased the settlement of cyprids. Although the analogue dibutyryl cyclic AMP appeared to increase settlement, the effect was not significant. No marked increase in settlement resulted from the incubation of cyprids with dibutyryl cyclic GMP, 8-(4-chlorophenylthio) (CPT) cyclic AMP or papaverine (a phosphodiesterase inhibitor). Miconazole nitrate, an adenylate cyclase inhibitor, prevented settlement, but this effect appeared to be physico-chemical rather than pharmacological. Radioimmunoassay did not clearly show whether cyclic AMP levels changed following exposure of cyprids to a pulse of crude barnacle extract. However, exposure to forskolin significantly increased the cyclic AMP titre of cyprids. We conclude that compounds that alter intracellular cyclic AMP levels alter normal patterns of cyprid settlement. Whether this is because of an alteration in signal transduction is unclear.
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PMID:Evidence for the involvement of cyclic AMP in the pheromonal modulation of barnacle settlement 931 89

Changes in acetylcholine secretion in the cholinergic synapses of the rat cerebral hemispheres and brain stem were studied in in vivo experiments against the background of modulation of the activity of the adenylate cyclase and phosphoinositide secondary messenger systems by injection of caffeine and lithium chloride. The level of mediator secretion was determined according to the content of bound acetylcholine fractions in the homogenate of the indicated parts of the animal's brain. It was established that secretion of the mediator in the rat hemispheres is regulated by postsynaptic N-cholinoceptors located on the body of cholinergic neurons which have a phosphoinositide system actiung as secondary mediators and, possibly are related to subtype M1. It is also possible that the secretion is also regulated by presynaptic autoreceptors connected with the adenylate cyclase system, which function according to the mechanism of negative feedback and is related to subtype M2. Acetylcholine secretion in the brain stem synapses is regulated according to the negative feedback mechanism by muscarine receptors linked with the adenylate cyclase system and probably related to subtype M4.
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PMID:[The role of adenylate cyclase and phosphoinositide second messenger systems in regulation of acetylcholine secretion in synapses of the cerebral hemispheres and brain stem in rats]. 946 May 86

Growth and development of a wild-type Sclerotinia sclerotiorum isolate were examined in the presence of various pharmacological compounds to investigate signal transduction pathways that influence the development of sclerotia. Compounds known to increase endogenous cyclic AMP (cAMP) levels in other organisms by inhibiting phosphodiesterase activity (caffeine and 3-isobutyl-1-methyl xanthine) or by activating adenylate cyclase (NaF) reduced or eliminated sclerotial development in S. sclerotiorum. Growth in the presence of 5 mM caffeine correlated with increased levels of endogenous cAMP in mycelia. In addition, incorporation of cAMP into the growth medium decreased or eliminated the production of sclerotia in a concentration-dependent manner and increased the accumulation of oxalic acid. Inhibition of sclerotial development was cAMP specific, as exogenous cyclic GMP, AMP, and ATP did not influence sclerotial development. Transfer of developing cultures to cAMP-containing medium at successive time points demonstrated that cAMP inhibits development prior to or during sclerotial initiation. Together, these results indicate that cAMP plays a role in the early transition between mycelial growth and sclerotial development.
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PMID:Increase in Endogenous and Exogenous Cyclic AMP Levels Inhibits Sclerotial Development in Sclerotinia sclerotiorum. 964 27

Whole-cell patch clamp experiments were carried out in rat striatal brain slices. In a subset of striatal neurons (70-80%), NMDA-induced inward currents were inhibited by the adenosine A2A receptor selective agonist CGS 21680. The non-selective adenosine receptor antagonist 8-(p-sulphophenyl)-theophylline and the A2A receptor selective antagonist 8-(3-chlorostyryl)caffeine abolished the inhibitory action of CGS 21680. Intracellular GDP-beta-S, which is known to prevent G protein-mediated reactions, also eliminated the effect of CGS 21680. Extracellular dibutyryl cAMP, a membrane permeable analogue of cAMP, and intracellular Sp-cAMPS, an activator of cAMP-dependent protein kinases (PKA), both abolished the CGS 21680-induced inhibition. By contrast, Rp-cAMPS and PKI 14-24 amide, two inhibitors of PKA had no effect. Intracellular U-73122 (a phospholipase C inhibitor) and heparin (an inositoltriphosphate antagonist) prevented the effect of CGS 21680. Finally, a more efficient buffering of intracellular Ca2+ by a substitution of EGTA (11 mM) by BAPTA (5.5 mM) acted like U-73122 or heparin. Hence, A2A receptors appear to negatively modulate NMDA receptor channel conductance via the phospholipase C/inositoltriphosphate/Ca2+ pathway rather than the adenylate cyclase/PKA pathway.
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PMID:Adenosine A2A receptors inhibit the conductance of NMDA receptor channels in rat neostriatal neurons. 987 38


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