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)

In a search for more selective A1 adenosine receptor agonists, N6-[(R)-(-)-1-methyl-2-phenethyl]-1-deazaadenosine (1-deaza-R-PIA, 3a), N6-cyclopentyl-1-deazaadenosine (1-deazaCPA, 3b), N6-cyclohexyl-1-deazaadenosine (1-deazaCHA, 3c), and the corresponding 2-chloro derivatives 2a-c were synthesized from 5,7-dichloro-3-beta-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine. On the other hand, N-ethyl-1'-deoxy-1'-(1-deaza-6-amino-9H-purin-9-yl)-beta-D-ribofuranu ronamide (1-deazaNECA, 10) was prepared from 7-nitro-3-beta-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine, in an attempt to find a more selective A2 agonist. The activity of all deaza analogues at adenosine receptors has been determined in adenylate cyclase and in radioligand binding studies. 1-DeazaNECA proved to be a nonselective agonist at both subtypes of the adenosine receptor. It is about 10-fold less active than NECA but clearly more active than the parent compound 1-deazaadenosine as an inhibitor of platelet aggregation and as a stimulator of cyclic AMP accumulation. The N6-substituted 1-deazaadenosines largely retain the A1 agonist activity of their parent compounds, but lose some of their A2 agonist activity. This results in A1-selective compounds, of which N6-cyclopentyl-2-chloro-1-deazaadenosine (1-deaza-2-Cl-CPA, 2b) was identified as the most selective agonist at A1 adenosine receptors so far known. The activity of all 1-deaza analogues confirms that the presence of the nitrogen atom at position 1 of the purine ring is not critical for A1 receptor mediated adenosine actions.
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PMID:Adenosine receptor agonists: synthesis and biological evaluation of 1-deaza analogues of adenosine derivatives. 337 86

The effects of exogeneous cyclopiazonic acid (CPA, 10 microM), a selective inhibitor of the sarcoplasmic reticulum (SR) Ca2+ adenosinetriphosphatase, on cyclic nucleotide-induced relaxations of canine airway smooth muscle were examined. Strips of tracheal muscle were precontracted with carbachol (50% median effective concentration, 0.1 microM) or with 60 mM KCl. The beta-agonist isoproterenol (ISO, 10 microM) relaxed the tissue by approximately 50%. The relaxation was reduced in the presence of CPA when L-type Ca2+ channels were available but not when these were blocked by 0.1 microM nifedipine. Forskolin (1.0 microM), an adenylate cyclase activator, was less effective at inhibiting the contraction than ISO, and addition of CPA did not block its inhibitory effect as effectively as when ISO was used. Radioimmunoassay indicated that both these agents raised adenosine 3',5'-cyclic monophosphate (cAMP) levels to the same degree. Very little relaxation of the precontracted smooth muscle was elicited by 3 mM 8-bromo-adenosine 3',5'-cyclic monophosphate (8-BrcAMP), and addition of CPA had no effect. Sodium nitroprusside (100 microM) and 8-bromo-guanosine 3',5'-cyclic monophosphate (10 mM) inhibited contraction to a greater degree than any agent that raised cAMP. These inhibitions were greatly reduced in the presence of CPA when L-type Ca2+ channels were available. We conclude that pumping of Ca2+ into SR plays a major role guanosine 3',5'-cyclic monophosphate-produced but not cAMP-induced relaxation; L-type Ca2+ channels must be available for the relaxant role of Ca2+ pumping into the SR to be expressed; and ISO-induced relaxation may not involve primarily elevation of the cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of cyclic nucleotide-induced relaxation in canine tracheal smooth muscle. 790 Aug 22

Two classes of extracellular receptors for adenosine, A1 and A2, have been demonstrated in the mammalian retina. Our laboratory has previously reported the pharmacological characteristics of the mammalian retinal A1 receptors. We now report our characterization of retinal A2 receptors based on data obtained from both adenylate cyclase assays and radioligand binding studies. [3H]-5'-N-ethylcarboxamidoadenosine (NECA) in the presence of 10 nM cyclopentyladenosine (CPA, which selectively binds to A1 receptors) or [3H]-CGS 21680 were used to label the A2 binding sites. Using [3H]-NECA (plus CPA), two populations of binding sites, having Kds of 106 nM and 9.4 microM, were determined. [3H]-CGS 21680, a derivative of NECA which has been demonstrated to be highly selective for A2 receptors in brain synaptic membrane preparations was more potent than NECA at the higher affinity population of A2 sites, and saturation analysis revealed the presence of both a high affinity site, Kd of 18 nM, and a lower affinity site having a Kd of 4.3 microM. The high affinity site labeled by [3H]-CGS 21680 corresponds to the A2a receptor. Using either radioligand, guanosine triphosphate-dependent shifts to a single population of binding sites were observed. Despite the differences in affinities revealed by the two radioligands for the high affinity A2 site, both [3H]-CGS 21680 and [3H]-NECA were competitively displaced by increasing concentrations of a variety of adenosine receptor agonists and antagonists, and exhibited an identical rank order of potency that is consistent with that reported for high affinity A2a receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of adenosine A2 receptors in bovine retinal membranes. 850 May 67

The aim of the present study was to gain insight into the signaling pathway used by leptin to stimulate lipolysis. The lipolytic rate of white adipocytes from sex- and age-matched lean (+/+) and fa/fa rats was determined in the absence or presence of leptin together with a number of agents acting at different levels of the signaling cascade. Leptin did not modify FSK-, dbcAMP-, and IBMX-stimulated lipolysis. Lipolysis can also be maximally stimulated by lowering media adenosine levels with adenosine deaminase (ADA), i.e., in the ligand-free state. Although ADA produced near maximal lipolysis in adipocytes of lean animals, only half of the maximal lipolytic rate (50.9+/-3.2%) was achieved in fat cells from fa/fa rats (P=0.0034). In adipocytes from lean animals preincubated with ADA, leptin caused a concentration-related stimulation of lipolysis (P=0.0001). However, leptin had no effect on the lipolytic activity of adipocytes in the ligand-free state from fa/fa rats. The adenosine A1 receptor agonist CPA effectively inhibited basal lipolysis in both lean and obese adipocytes (P=0.0001 and P=0.0090, respectively). Leptin had no effect on the lipolytic rate of adipocytes isolated from fa/fa rats and preincubated with CPA. When adipocytes were incubated with the A1 receptor antagonist DPCPX, a significant increase in glycerol release was observed in fa/fa fat cells (P=0.009), whereas cells isolated from lean rats showed no differences to ADA-stimulated lipolysis. After pretreatment with PTX, which inactivates receptor-mediated Gi function, adipocytes of obese rats became as responsive to the stimulatory actions of ISO as cells from lean rats (P=0.0090 vs. ISO in fa/fa rats; P=0.2416 vs. lean rats, respectively). PTX treatment of lean cells, however, did not alter their response to this lipolytic agent. It can be concluded that the lipolytic effect of leptin is located at the adenylate cyclase/Gi proteins level and that leptin-induced lipolysis opposes the tonic inhibition of endogenous adenosine in white adipocytes.
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PMID:Leptin-induced lipolysis opposes the tonic inhibition of endogenous adenosine in white adipocytes. 1115 49

This study was performed to determine whether intravitreal or intravenous adenosine can alter the microcirculation in the optic nerve head (ONH) of rabbits. Capillary blood flow in the ONH was measured serially with a laser speckle tissue analyser for 2 hr after the intravitreal (0.1, 1.0 and 10 nmol) or intravenous (0.2 and 0.6 mg kg(-1)min) injections of adenosine. In addition, the effect of specific adenosine A(1) and A(2a) antagonists and an adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel blockers on the adenosine-induced changes on the ONH blood flow was analysed. Intravitreal adenosine increased the capillary blood flow in the ONH in a dose-dependent manner, while intravenous adenosine had no effect. Co-administration of the specific adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 nmol) significantly suppressed (P=0.006, ANOVA) the increase in the ONH blood flow induced by adenosine (10 nmol). The specific A(2a) receptor antagonist, 8-(3-chlorostyryl) caffeine (CSC, 10 nmol), had a weak effect in inhibiting the increase but the change was not significant (P=0.08, ANOVA). Both specific A(1) and A(2a) receptor agonists, N(6)-cyclopentyladenosine (CPA, 10 nmol) and 2-p-(2-carboxyethyl) phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS-21680, 10 nmol), increased the ONH tissue blood flow (P<0.01, ANOVA). Glibenclamide (10 nmol), a selective K(ATP) channels antagonist, suppressed the increase of ONH blood flow induced by 10 nmol adenosine significantly (P<0.001, ANOVA). On the other hand, 10 nmol of 8-Br-cAMP, a cAMP analog, failed to enhance the capillary blood flow in the ONH. These results indicate that adenosine increases the capillary blood flow in the ONH of rabbits, and it acts through A(1) and A(2a) receptors from the ablumenal side where pericytes are located. Activation of K(ATP) channels is strongly related to the mechanism of adenosine-induced increase in ONH blood flow, while the participation of adenylate cyclase is less likely.
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PMID:Effects of adenosine on optic nerve head circulation in rabbits. 1550 Aug 31

Previously we have described the properties of store-operated channel currents (SOCs) in freshly dispersed rabbit portal vein smooth muscle cells. In addition to Ca(2+) store depletion these SOCs could also be activated by alpha-adrenoceptor stimulation and diacylglycerol (DAG) via a protein kinase C (PKC)-dependent mechanism. In the present study we have investigated the effect of beta-adrenoceptor stimulation on SOCs in rabbit portal vein myocytes. With whole-cell recording the selective beta-adrenoceptor agonist isoprenaline reduced the current evoked by cyclopiazonic acid (CPA, sarcoplasmic/endoplasmic reticulum ATPase inhibitor) by over 85%. With cell-attached patch recording, bath application of isoprenaline produced a pronounced inhibition of SOC activity evoked by either CPA or the acetoxymethyl ester form of BAPTA (BAPTA-AM). SOC activity evoked by CPA, the DAG analogue, 1-oleoyl-acetyl-sn-glycerol (OAG) or the phorbol ester, phorbol-12,13-dibutyrate (PDBu) was also markedly inhibited by the adenylate cyclase activator, forskolin, and the cell-permeable non-hydrolysable analogue of cyclic adenosine monophosphate (cAMP), 8-Br-cAMP. With inside-out patches, bath application of PDBu evoked channel currents with similar properties to SOCs which were inhibited by over 90% by a catalytic subunit of protein kinase A (PKA) and by 8-Br-cAMP. Moreover bath application of PKA inhibitors, H-89, KT5720 and an inhibitory peptide to quiescent cell-attached or inside-out patches, activated channel currents with similar properties to SOCs. These data suggest that in rabbit portal vein myocytes, stimulation of beta-adrenoceptors inhibits SOC activity via a cAMP-dependent protein kinase signal transduction cascade. In addition it is concluded that constitutive PKA activity has a profound inhibitory effect on SOC activity in this vascular preparation.
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PMID:Stimulation of beta-adrenoceptors inhibits store-operated channel currents via a cAMP-dependent protein kinase mechanism in rabbit portal vein myocytes. 1552 35

The excitatory action of brain-derived neurotrophic factor (BDNF) on synaptic transmission is triggered by adenosine A2A receptor activation. Since high-frequency neuronal firing, such as that inducing long-term potentiation (LTP), favours both A2A receptor activation and BDNF effects on transmission, we now evaluated the influence of adenosine on the facilitatory action of BDNF upon CA1 hippocampal LTP. theta-Burst stimulation of the pyramidal inputs induced a significant and persistent increase in field EPSP slopes, and this potentiation was augmented in the presence of BDNF (20 ng/ml), an action prevented by the inhibitor of Trk receptor autophosphorylation, K252a (200 nM). Removal of endogenous extracellular adenosine with adenosine deaminase (ADA, 1 U/ml), as well as the antagonism of adenosine A2A receptors with SCH58261 (100 nM), prevented the excitatory action of BDNF upon LTP. In an adenosine depleted background (with ADA), activation of adenosine A2A receptors (with 10nM CGS21680) restored the facilitatory effect of BDNF on LTP; this was fully prevented by the protein kinase A inhibitor, H-89 (1 microM) and mimicked by the adenylate cyclase activator, forskolin (10 microM). In similar experiments, activation of adenosine inhibitory A1 receptors (with 5 nM CPA) did not affect the facilitatory effect of BDNF. In conclusion, the facilitatory action of BDNF upon hippocampal LTP is critically dependent on the presence of extracellular adenosine and A2A receptor activation through a cAMP/PKA-dependent mechanism. Since extracellular adenosine accumulates upon high-frequency neuronal firing, the present results reveal a key process to allow the influence of BDNF upon synaptic plasticity.
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PMID:Enhancement of long-term potentiation by brain-derived neurotrophic factor requires adenosine A2A receptor activation by endogenous adenosine. 1838 19