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:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In calcium-free media, neurones in the rat hippocampal slice develop bursts of population potentials and lose their sensitivity to adenosine. The present paper reports the unexpected and paradoxical finding that the xanthines theophylline and cyclopentyltheophylline, the latter of which is selective for A1 purine receptors, depressed the excitability of hippocampal pyramidal neurones in calcium-free media. Chelating residual calcium with EGTA reduced excitability which was additive with the xanthine effect, while 100 microM calcium depressed the response to theophylline. The inhibition by xanthines was prevented by adenosine, which had no effect by itself, but was not reproduced or modified by adenosine deaminase. The xanthine effects were also prevented by baclofen and carbamazepine. A common feature of adenosine, baclofen and carbamazepine which may account for their antagonism of the xanthines is the blockade of calcium fluxes. It is proposed that in the presence of low external concentrations of calcium xanthines can reduce excitability by promoting the mobilisation and trans-membrane movement of residual calcium in the medium or neuronal membranes.
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PMID:A paradoxical inhibitory effect of xanthines on hippocampal excitability in calcium-free media. 782 Jun 31

Conventional inhibitors of cyclic AMP-dependent protein kinase lack membrane-permeability or selectivity, or both. The Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate, Rp-cAMPS, is a novel membrane-permeable antagonist of cyclic AMP. We have assessed the ability of this compound to distinguish between cyclic AMP-dependent and cyclic AMP-independent contractile responses elicited in ventricular cardiomyocytes isolated from the hearts of adult rats. Cardiomyocytes were stimulated to contract at 0.5 Hz in the presence of calcium ion (2 mM) and adenosine deaminase (5 units/ml). Contractile shortening was expressed as maximum shortening relative to prestimulus cell length (delta L%). In the presence of a maximally-effective concentration of isoprenaline (100 nM), which acts by a cyclic AMP-dependent mechanism, Rp-cAMPS inhibited the contractile response in a concentration-dependent and time-dependent manner. Following preincubation for 30 min with Rp-cAMPS (100 microM), the contractile response to isoprenaline (100 nM) was 14% of that elicited in the absence of this inhibitor. An incubation time of 30 min was chosen for all subsequent studies. Rp-cAMPS (< or = 200 microM) inhibited the contractile response to isoprenaline (100 nM) significantly and in a concentration-dependent manner, but failed to inhibit the contractile responses elicited by phenylephrine (2 microM) and calcium ion (7 mM) which act by cyclic AMP-independent mechanisms. In the presence of Rp-cAMPs (200 microM), the contractile response to isoprenaline (100 nM) was 24% of that in the absence of inhibitor. Rp-cAMPS was used subsequently to investigate the contractile-coupling mechanisms associated with some novel inotropic agents. Rp-cAMPS (< or = 200 microM) also inhibited the contractile responses to secretin (20 nM) and VIP (20 nM) significantly. In the presence of Rp-cAMPS (200 microM), the contractile response elicited by secretin (20 nM) was 19% of that in the absence of inhibitor, while that elicited by VIP (20 nM) was abolished completely. Rp-cAMPS (< or = 200 microM) failed to inhibit the contractile response elicited by CGRP (1 nM). In summary, Rp-cAMPS is a membrane-permeable, selective antagonist of cyclic AMP in ventricular cardiomyocytes and can be used, in conjunction with the bioassay of the intracellular accumulation of cyclic AMP, to distinguish between cyclic AMP-dependent and cyclic AMP-independent contractile coupling mechanisms in these cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Use of the cyclic AMP antagonist, Rp-cAMPS, to distinguish between cyclic AMP-dependent and cyclic AMP-independent contractile responses in rat ventricular cardiomyocytes. 789 68

Purified striatal synaptosomes were superfused continuously with L-[3,5-3H]tyrosine to measure simultaneously the synthesis ([3H]water formed during the conversion of [3H]tyrosine into [3H]DOPA) and the release of [3H]dopamine ([3H]DA). Glutamate (10(-3) M) and NMDA (10(-3) M, in the absence of Mg2+) stimulated the release of [3H]DA, but they reduced the efflux of [3H]water. This reduction of [3H]DA synthesis was blocked by 2-amino-5-phosphonovalerate indicating the involvement of NMDA receptors. Although D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) and kainate stimulated the release of [3H]DA, they did not affect its synthesis. The glutamate-evoked inhibition of [3H]DA synthesis was prevented when synaptosomes were superfused continuously with adenosine deaminase plus quinpirole, a treatment which markedly reduces the phosphorylation of tyrosine hydroxylase by cAMP dependent protein kinase. The opposite effects of glutamate on [3H]DA synthesis and release were mimicked by ionomycin (10(-6) M). It is proposed that both an activation of a cyclic nucleotide phosphodiesterase and a dephosphorylation of tyrosine hydroxylase linked to the influx of calcium through NMDA receptors is responsible for the inhibition of dopamine synthesis by glutamate and that calcineurin could play a critical role in these processes.
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PMID:Opposite presynaptic regulations by glutamate through NMDA receptors of dopamine synthesis and release in rat striatal synaptosomes. 791 26

As shown on cultured astrocytes from the mouse, in the presence of adenosine deaminase, 2-chloroadenosine by acting on A1-adenosine receptors potentiated the activation of phospholipase C induced by the alpha 1-adrenergic agonist, methoxamine. This potentiation required the presence of external calcium and was blocked by pertussis toxin. Moreover, this potentiation resulted from a cascade of events: activation (by calcium and protein kinase C) of a phospholipase A2 coupled to A1-adenosine receptors, release of arachidonic acid, which inhibited the reuptake of glutamate into astrocytes and finally additional activation of phospholipase C by externally accumulated glutamate through metabotropic receptors. The effects of 2-chloroadenosine and methoxamine were respectively mimicked by somatostatin and substance P while endothelins reproduced the combined effects of 2-chloroadenosine and methoxamine. Conditioned media from treated astrocytes enriched in glutamate stimulated phospholipase C in cultured striatal neurones. In addition, glutamate alone was also found to stimulate phospholipase A2 in astrocytes through receptors exhibiting a pharmacological profile distinct from metabotropic receptors coupled to phospholipase C and the glutamate response was potentiated by ATP. Moreover, the neuronal arachidonic acid production evoked by glutamate was potentiated by acetylcholine. Finally, the combined application of 2-chloroadenosine and methoxamine on striatal astrocytes reduced the permeability of gap junctions between astrocytes and this response was mimicked by arachidonic acid. Together, these results emphasized the contribution of astrocytes in the regulation of glutamatergic transmission.
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PMID:Glial receptors and their intervention in astrocyto-astrocytic and astrocyto-neuronal interactions. 792 48

Purified striatal synaptosomes were continuously superfused with L,3,5[3H]tyrosine in order to estimate the synthesis ([3H]water) and release of newly formed [3H]dopamine. In the presence of magnesium, L-glutamate, D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) and kainate, but not N-methyl-D-aspartate (NMDA) and 1-aminocyclopentane-1S,3R-dicarboxylate (t-ACPD), stimulated the release of [3H]dopamine, in a dose-dependent manner. When magnesium was omitted or in the presence of AMPA, NMDA also increased the release of [3H]dopamine. The effects of AMPA and kainate were competitively inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or 6,7-dinitro-quinoxaline-2,3-dione (DNQX), whereas those of NMDA were reduced by 2-amino-5-phosphonovalerate (APV) or (+)-5-methyl-10,11-dihydro-5-H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate (MK801). The stimulation of [3H]dopamine release by a high concentration of glutamate resulted from the concomitant activation of AMPA and NMDA receptors since this effect was potentiated by glycine and reduced by 2-amino-5-phosphonovalerate or MK801. This reduction was almost complete in the combined presence of DNQX and MK801. Surprisingly, glutamate and NMDA (in the absence of magnesium) reduced the efflux of [3H]water. The reduction of [3H]dopamine synthesis was blocked by 2-amino-5-phosphonovalerate indicating the involvement of NMDA receptors. Neither AMPA nor kainate affected dopamine synthesis. The inhibition of [3H]dopamine synthesis resulting from the stimulation of NMDA receptors was prevented when synaptosomes were continuously superfused with adenosine deaminase and quinpirole, a combined treatment known to markedly reduce the phosphorylation of tyrosine hydroxylase by cAMP-dependent protein kinase. The opposite effects of a high concentration of glutamate on [3H]dopamine synthesis and release were mimicked by ionomycin. As a working hypothesis, it is proposed that the NMDA-triggered calcium influx could lead to a reduction of tyrosine hydroxylase phosphorylation, possibly through an activation of calcineurin.
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PMID:Presynaptic control of dopamine synthesis and release by excitatory amino acids in rat striatal synaptosomes. 799 95

1. Previous work has suggested that presynaptic effects of adenosine may be dependent on divalent cations. The present study was undertaken to determine whether a similar requirement existed at postsynaptic sites. 2. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum or antidromic stimulation of the alveus. In antidromic stimulation experiments, CaCl2 was omitted (calcium-free medium) or reduced to 0.24 mM (low calcium medium) and in some experiments MgSO4 was increased to 2 mM. Kynurenic acid at concentrations of 1 and 5 mM in calcium-free medium and 1 mM in low calcium medium had no effect on secondary spike size. 3. Adenosine and baclofen induced a concentration-dependent reduction in the amplitude of orthodromic potentials with maximum effects at 20 and 5 microM respectively. 4. In nominally calcium-free medium, bursts of multiple population spikes were obtained in response to antidromic stimulation. Adenosine had little effect in reducing the secondary spike amplitude. At high concentration (2 mM) an initial depression was seen which declined within 3-5 min. 5. Sensitivity to adenosine was restored in low calcium medium or by raising magnesium. Although raising the divalent cation concentration increased the inhibitory effect of adenosine, desensitization was still seen. 6. 2-Chloroadenosine (100-500 microM) and R-PIA (50 microM), which are not substrates for either the nucleoside transporters or adenosine deaminase, were inactive in the absence of calcium. S-(2-hydroxy-5 nitrobenzyl)-6-thioinosine, an adenosine uptake blocker, at a concentration 100 MicroM had no effect on secondary potential size and did not restore adenosine sensitivity in calcium-free medium.7. Thapsigargin, which discharges intracellular calcium stores, had no significant effect at 1 MicroM on the bursts of action potentials and did not change the effect of 0.5 mM adenosine in calcium-free medium.8. Unlike adenosine, baclofen concentration-dependently reduced the secondary spike size in calcium free medium and no sign of recovery was observed during maintained superfusion for up to 45 min. No cross-desensitization was seen between baclofen and adenosine.9. Applications of adenosine locally by pressure to neuronal somata or dendrites still resulted in desensitized responses in calcium-free medium.10. It is concluded that the postsynaptic sensitivity to adenosine is dependent on the concentration of divalent cations in the extracellular space implying an effect of cations on adenosine receptor activation or transduction processes.
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PMID:The effect of calcium removal on the suppression by adenosine of epileptiform activity in the hippocampus: demonstration of desensitization. 803 57

We examined the effects of brief periods of hypoxia or application of cyanide on the discharge and membrane properties of medullary pacemaker neurones in slices of the rostral ventrolateral reticular nucleus (RVL) of the medulla oblongata of rats. Stable intracellular recordings were obtained from seventy-nine neurones within the RVL which exhibited spontaneous rhythmic discharge in the absence of excitatory postsynaptic potentials (EPSPs). The membrane potential cycles of these neurones could be reset with an evoked spike without eliciting EPSPs or inhibitory postsynaptic potentials and hence met criteria of RVL pacemaker neurones. Hypoxia, produced by reducing O2 from 95 to 20% for 40 s or exposure to cyanide (30-300 microM for 40 s), reversibly increased neuronal discharge 1.6-fold (20% O2) or 2.6-fold (300 microM cyanide), respectively, in association with membrane depolarization and a significant fall in membrane resistance. The membrane responses to hypoxia and cyanide were observed in the presence of tetrodotoxin (TTX) at a concentration (10 microM) which eliminated spontaneous spikes or spikes evoked by intracellular depolarization. When recorded at a holding potential of -70 mV by single-electrode voltage clamp, hypoxia or cyanide (300 microM) elicited inward currents of 0.44 +/- 0.06 and 0.58 +/- 0.08 nA, respectively, which are attenuated by reducing the concentration of extracellular Ca2+ ions, and abolished by 2 mM CoCl2 and 100 microM NiCl2, but not affected by 50 microM CdCl2, replacement of 83% extracellular Na+, or adenosine deaminase (2U ml-1). We conclude that hypoxia and cyanide directly excite RVL pacemaker neurones in vitro by a common mechanism: activation of Ca2+ channel conductance.
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PMID:Hypoxia-activated Ca2+ currents in pacemaker neurones of rat rostral ventrolateral medulla in vitro. 804 26

1. The hypothesis that ATP released by presynaptic stimulation is hydrolysed to adenosine and mediates prejunctional neuromuscular depression was tested at vertebrate neuromuscular junctions. Electrophysiological recordings of evoked acetylcholine (ACh) release and perineural ionic currents at motor nerve endings were made using the frog cutaneous pectoris nerve-muscle preparation. Either tubocurarine or alpha-bungarotoxin was used to block muscle contractions. 2. Either alpha,beta-methylene ADP (which inhibits ecto-5'nucleotidases and thus prevents the degradation of ATP to adenosine) or selective adenosine receptor antagonists (8-cyclo-pentyl alkyl xanthines) prevented the inhibitory effects of exogenous ATP on ACh release in response to low-frequency nerve stimulation. These results confirm earlier findings that ATP must be hydrolysed to adenosine to inhibit ACh release. 3. The presence of alpha,beta-methylene ADP completely prevented neuromuscular depression in response to repetitive high-frequency nerve stimulation (0.5-1 Hz). alpha,beta-Methylene ADP had no effect on ACh secretion under conditions where ACh release is well maintained (low-frequency stimulation, 0.05 Hz). 4. Selective adenosine receptor antagonists completely eliminated neuromuscular depression produced by repetitive high-frequency nerve stimulation (1.0 Hz) but had no effect on ACh release at low frequencies of stimulation (0.05 Hz). 5. Exogenous adenosine deaminase (5 i.u. ml-1), which degrades adenosine to its inactive nucleoside inosine, also eliminated neuromuscular depression but had no significant effect on ACh release at frequencies of nerve stimulation too low to produce prejunctional depression. 6. During maximal neuromuscular depression, the effects of exogenous adenosine or 2-chloroadenosine, an adenosine agonist, were occluded. 7. The calcium-sensitive component of perineurial recordings of motor nerve terminal currents did not change during depression or during application of adenosine receptor antagonists and adenosine deaminase, suggesting that neuromuscular depression in this species was not associated with changes in presynaptic Ca2+ currents. 8. These results suggest that, under the conditions of these experiments, endogenous ATP, after hydrolysis to adenosine, causes prejunctional neuromuscular depression. This inhibitory effect of endogenous adenosine occurs at a site distal to the locus of Ca2+ entry in the frog.
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PMID:ATP released together with acetylcholine as the mediator of neuromuscular depression at frog motor nerve endings. 807 78

The adenosine modulation of glutamate exocytosis from guinea pig cerebrocortical synaptosomes is investigated. Endogenously leaked adenosine is sufficient to cause a partial tonic inhibition of 4-aminopyridine-evoked glutamate release, which can be relieved by adenosine deaminase. The adenosine A1 receptor is equally effective in mediating inhibition of glutamate exocytosis evoked by 4-aminopyridine (where K(+)-channel activation would inhibit release) and by elevated KCl (where K(+)-channel activation would have no effect), arguing for a central role of Ca(2+)-channel modulation. In support of this, the plateau phase of depolarization-evoked free Ca2+ elevation is decreased by adenosine with both depolarization protocols. No effect of adenosine agonists is seen on membrane potential in polarized or KCl- or 4-aminopyridine-stimulated synaptosomes. The interaction of protein kinase C with the A1 receptor-mediated inhibition is examined. Activation of protein kinase C by 4 beta-phorbol dibutyrate has been shown previously by this laboratory to modulate glutamate release via K(+)-channel inhibition, and is shown here to have an additional action of decoupling the adenosine inhibition of glutamate exocytosis.
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PMID:Adenosine A1 receptor inhibition of glutamate exocytosis and protein kinase C-mediated decoupling. 809 42

This study examined the effects of adenosine- and adenosine deaminase-loaded liposomes upon the contractile activity of the vascular smooth muscle, using the isolated, de-endothelised rat aorta ring as in vitro model. While control liposomes had no effect, intraliposomal adenosine (5 x 10(-3) M) induced contraction of the preparation. Intraliposomal adenosine deaminase induced partial relaxation of high K(+)-precontracted rings. The adenosine-induced contraction seems to involve Ca2+ influx through L-type channels as an essential component, but protein kinase C may also have a modulatory role.
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PMID:Effects of liposome-entrapped adenosine in the isolated rat aorta. 811 11


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