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)

We investigated the role of adenosine A1-receptor in the regulation of basolateral Na(+)-3HCO3- cotransporter in the rabbit proximal convoluted tubule (PCT) microperfused in vitro by monitoring basolateral membrane potential and intracellular pH. FK-453, a highly specific A1 antagonist, inhibited basolateral HCO3- conductance in a concentration-dependent manner (10(-10)-10(-5) M). Other A1 antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) at 10(-5) M and theophylline at 10(-3) M, also had similar effects. N6-cyclohexyladenosine (CHA) at 10(-7) M attenuated the effect of low concentration (10(-8) M) of FK-453. Either enhancement of the degradation of adenosine by 0.1 U/ml adenosine deaminase (ADA) or inhibition of adenosine release from the cells by 10(-6) M S-(4-nitrobenzyl)-6-thioinosine (NBTI) mimicked the effects of A1 antagonists. These observations suggest that endogenous adenosine is released from PCT cells and stimulates Na(+)-3HCO3- cotransporter. Both 10(-4) M 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT-cAMP) and 10(-6) M forskolin also inhibited basolateral HCO3- conductance. Both 10(-6) M FK-453 and 10(-4) M CPT-cAMP decreased the initial rate as well as the magnitude of intracellular acidification induced by reduction of peritubular HCO3- concentration from 25 to 0 mM. Neither 10(-6) M FK-453 nor 10(-7) M CHA changed intracellular Ca2+ concentration as measured by fura-2 fluorescence. These results indicate that adenosine might stimulate HCO3- exit across the basolateral membrane through Na(+)-3HCO3- cotransporter by decreasing intracellular cAMP via A1-receptor activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of Na(+)-3HCO3- cotransport in rabbit proximal convoluted tubule via adenosine A1 receptor. 823 80

Intracellular recordings were performed on hippocampal CA3 neurons in vitro to investigate the inhibitory tonus generated by endogenously produced adenosine in this brain region. Bath application of the highly selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine at concentrations up to 100 nM induced both spontaneous and stimulus-evoked epileptiform burst discharges. Once induced, the 1,3-dipropyl-8-cyclopentylxanthine-evoked epileptiform activity was apparently irreversible even after prolonged superfusion with drug-free solution. The blockade of glutamatergic excitatory synaptic transmission by preincubation of the slices with the amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM), but not with the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid (50 microM), prevented the induction of epileptiform activity by 1,3-dipropyl-8-cyclopentylxanthine. The generation of the burst discharges was independent of the membrane potential, and the amplitude of the slow component of the paroxysmal depolarization shift increased with hyperpolarization, indicating that the 1,3-dipropyl-8-cyclopentylxanthine-induced bursts were synaptically mediated events. Recordings from tetrodotoxin-treated CA3 neurons revealed a strong postsynaptic component of endogenous adenosinergic inhibition. Both 1,3-dipropyl-8-cyclopentylxanthine and the adenosine-degrading enzyme adenosine deaminase produced an apparently irreversible depolarization of the membrane potential by about 20 mV. Sometimes, this depolarization attained the threshold for the generation of putative calcium spikes, but no potential changes resembling paroxysmal depolarization shift-like events were observed. At the concentrations used in electrophysiological experiments (30-100 nM), 1,3-dipropyl-8-cyclopentylxanthine displayed only a negligible inhibitory action on total cyclic nucleotide phosphodiesterase activity measured by means of a radiochemical assay in a homogenate of the rat cerebral cortex. Furthermore, even high concentrations of the selective phosphodiesterase inhibitor rolipram (10 microM), which displays no affinity to adenosine receptors, did not mimic the electrophysiological actions of 1,3-dipropyl-8-cyclopentylxanthine, thus excluding the possibility that the effects of the A1 receptor antagonist on neuronal discharge behavior can be ascribed to an inhibition of phosphodiesterases. The present data demonstrate that endogenously released adenosine exerts a vigorous control on the excitability of hippocampal CA3 neurons on both the pre- and postsynaptic sites. The long-lasting disinhibition following a transient suppression of adenosinergic inhibition strongly suggests that, besides its well-known short-term effects on neuronal activity, adenosine might also contribute to the long-term control of hippocampal excitability.
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PMID:Disinhibition of hippocampal CA3 neurons induced by suppression of an adenosine A1 receptor-mediated inhibitory tonus: pre- and postsynaptic components. 830 25

Adenosine is recognised as an important regulator of myocardial function and coronary vascular tone in the ischaemic myocardium. It is produced by the enzymatic dephosphorylation of 5'-AMP by 5'-nucleotidase and the hydrolysis of SAH by SAH-hydrolase. 5'-Nucleotidase is thought to contribute to adenosine production aside from the accumulation of 5'-AMP in the ischaemic myocardium, while the hydrolysis of SAH plays a major role in adenosine production in the normoxic myocardium. 5'-Nucleotidase activity is reported to increase adenosine production through accumulation of ATP, ADP, H+, Mg2+ and inorganic phosphate during ischaemia. In addition, we have found that alpha 1 adrenergic receptors, activated in ischaemic hearts, increase both 5'-nucleotidase activity and adenosine production. Inactivation of adenosine deaminase and adenosine kinase may also contribute to adenosine production. On the other hand, the major role of endogenous adenosine is to increase coronary blood flow. This adenosine induced coronary vasodilatation is amplified by alpha 2 adrenoceptor stimulation. Adenosine induced vasodilatation is also enhanced by increasing H+ and opening ATP sensitive K+ channels, which occurs in the ischaemic myocardium. However, coronary vasodilatation is not the only effect of adenosine in the ischaemic myocardium. Stimulation of adenosine A2 receptors coupled to Gs proteins attenuates both free radical generation by activated leucocytes and aggregation of platelets. Adenosine A1 receptor activation coupled to G(i) proteins attenuates beta adrenoceptor mediated increases in myocardial contractility, Ca2+ influx into myocytes, and noradrenaline release from the presynaptic nerves. Any or all of these effects may attenuate ischaemic and reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of adenosine and its interaction with alpha adrenoceptor activity in ischaemic and reperfusion injury of the myocardium. 838 27

Non-adrenergic, non-cholinergic (NANC) nerve stimulation results in excitation (e.j.p., rebound depolarization, contractions) or inhibition (i.j.p., afterhyperpolarization, relaxations) of the gut. NANC neuronal mechanisms participate in the maintenance of the basal tone and spontaneous activity of the gut. There are however species differences, i.e. both NANC excitation and inhibition are present in the guinea pig and only NANC inhibition in the rat intestine. Substance P-like neuropeptide/s are suggested to be mediators released from excitatory NANC and sensory nerves. The latter are activated by histamine and degenerated by capsaicin. There is evidence in favor of a nitric oxide-like substance rather than ATP, dopamine, GABA and neuropeptides (e.g. VIP, PHI/PHM) as the inhibitory NANC mediator in the gut. TTX, high Mg(2+)-low Ca2+ media, 3,4-diaminopyridine, dipyridamol and adenosine deaminase modulate NANC excitation and inhibition. The NANC excitation is more sensitive than the NANC inhibition to the action of catecholamines, reserpine, 6-hydroxydopamine, chymotrypsin, prednisolon, bacitracin, opioids, free oxygen species and low concentration of local anesthetics.
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PMID:NANC transmission in intestines and its pharmacological modulation. 839 Nov 98

Human fibroblast lysosomes, purified on Percoll density gradients, contain an adenosine deaminase (ADA) activity that accounts for approximately 10% of the total ADA activity in GM0010A human fibroblasts. In assays of lysosomal ADA, the conversion of [3H]adenosine into [3H]inosine was proportional to incubation time and the amount of lysosomal material added to reaction mixtures. Maximal activity was observed between pH 7 and 8, and lysosomal ADA displayed a Km of 37 microM for adenosine at 25 degrees C and pH 5.5. Lysosomal ADA was completely inhibited by 2.5 mM Cu2+ or Hg2+ salts, but not by other bivalent cations (Ba2+, Cd2+, Ca2+, Fe2+, Mg2+, Mn2+ and Zn2+). Coformycin (2.5 mM), deoxycoformycin (0.02 mM), 2'-deoxyadenosine (2.5 mM), 6-methylaminopurine riboside (2.5 mM), 2'-3'-isopropylidene-adenosine (2.5 mM) and erythro-9-(2-hydroxy-3-nonyl)adenine (0.2 mM) inhibited lysosomal ADA by > 97%. In contrast, 2.5 mM S-adenosyl-L-homocysteine and cytosine were poor inhibitors. Nearly all lysosomal ADA activity is eluted as a high-molecular-mass protein (> 200 kDa) just after the void volume on a Sephacryl S-200 column, and is very heat-stable, retaining 70% of its activity after incubation at 65 degrees C for 80 min. We speculate that compartmentalization of ADA within lysosomes would allow deamination of adenosine to occur without competition by adenosine kinase, which could assist in maintaining cellular energy requirements under conditions of nutritional deprivation.
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PMID:Demonstration of adenosine deaminase activity in human fibroblast lysosomes. 845 34

Calcium tolerant rabbit cardiomyocytes, isolated by collagenase perfusion, were preincubated for varying periods of time followed by resuspension in fresh media and centrifugation into an ischaemic pellet with restricted extracellular fluid. Pellets were incubated for 240 min under oil at 37 degrees C to mimic severe ischaemia. Time to onset of ischaemic contracture (rod to square transformation) and trypan blue permeability following resuspension in 85 mOSM media were monitored at sequential times. The protocol of Series 1 was a 5-10 min pre-incubation, immediately followed by ischaemic pelleting. Preincubation with pinacidil (50 microM) protected cells from ischaemic insult, but pinacidil added only into the ischaemic pellet did not protect. Protection was abolished by the protein kinase (PKC) inhibitors chelerythrine (10 microM) added with pinacidil and calphostin C (200nM) added only into the ischaemic pellet. Neither PKC inhibitor had an effect on injury of untreated ischaemic myocytes (data not shown). Series 2-5 were preconditioning protocols with a 10 min intervention period, followed by a 30 min oxygenated drug-free period, prior to ischaemic pelleting. In series 2 pinacidil protected cells from ischaemic insult and this protection was abolished when glyburide (10 microM) was present during preincubation, or during post-incubation and ischaemia. Glyburide only partially inhibited the protection when glyburide was added only into the ischaemic pellet. In Series 3, 8-sulfophenyltheophyline (SPT)(100 microM) or adenosine deaminase during preincubation, or SPT only added into the ischaemic pellet abolished pinacidil's protection. In Series 4, cardiomyocytes were ischaemically preconditioned by pelleting for 10 min followed by 30 min reoxygenation. Glyburide during initial ischaemic blocked protection, but when added during post incubation and into the final pellet protection was not reduced. In Series 5 8-cyclopentyl-1,3,dipropylxanthine (DPCPX) (10 microM) added into the final pellet abolished protection by pinacidil, but not protection following ischaemic preconditioning. In contrast to pinacidil, ischaemically preconditioned cells maintain protection in the presence of glyburide, indicating that: (1) pinacidil does not exactly mimic preconditioning and (2) ischaemically preconditioned cells do not require opened K+ATP channels for protection, although they appear to be important during initiation of the preconditioned state. It is hypothesized that pinacidil opening of K+ channels may facilitate induction of preconditioning.
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PMID:Potassium channels and preconditioning of isolated rabbit cardiomyocytes: effects of glyburide and pinacidil. 852 37

Secretin, vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) each exert potent positive contractile responses directly in rat ventricular cardiomyocytes. However, the contractile-coupling mechanisms associated with these responses have not been determined. In the present study, the involvement of L-type calcium channels in the contractile responses elicited by each peptide has been investigated using the selective antagonists at L-type calcium channels, verapamil and diltiazem. Ventricular cardiomyocytes, isolated from the hearts of adult rats, were stimulated to contract at 0.5 Hz in the presence of CaCl2 (2 mM) and adenosine deaminase (5U/ml). Cardiomyocytes were pre-incubated for 3 min prior to stimulation, in the absence of L-type calcium channel antagonist, and in the presence of verapamil (< or = 1 microM) or diltiazem (< or = 1 microM). Verapamil (< or = 1 microM) and diltiazem (< or = 1 microM) inhibited the contractile responses elicited by isoprenaline (100 nM) and forskolin (40 microM), used as positive controls, significantly, and in a concentration-dependent manner, but did not inhibit significantly the contractile response elicited by phenylephrine (2 microM), which was employed as a negative control. Verapamil (< or = 1 microM) and diltiazem (< or = 1 microM) inhibited the contractile responses to secretin (20 nM) and VIP (20 nM) significantly, and in a concentration-dependent manner, but did not inhibit the contractile response to CGRP. These data indicate that the positive contractile responses to secretin and VIP in mammalian ventricular cardiomyocytes involve the influx of calcium ion via L-type calcium channels, while the positive contractile response to CGRP does not.
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PMID:Inhibition by verapamil and diltiazem of agonist-stimulated contractile responses in mammalian ventricular cardiomyocytes. 852 57

The effect of the adenosine A1 receptor activation on calcitonin secretion was studied in medullary thyroid carcinoma cells of the rat (rMTC 6-23). Calcitonin was determined by radioimmunoassay, intracellular cAMP by protein binding assay, intracellular calcium in fura-2 loaded single cells using microspectrofluorimetry, and calcium channel activity by patch clamp technique. The adenosine A1 receptor analogue N-6 phenylisopropyl-adenosine (PIA) (10(-10)-10(-6) M) inhibits dose-dependently glucagon (10(-7) M) and rGRH (10(-7) M) stimulated cAMP formation and calcitonin secretion. These effects were partly abolished by pretreatment with pertussis toxin (PT) (100 ng/ml). PIA (10(-10)-10(-6) M) also suppressed extracellular calcium-stimulated calcitonin secretion, rises in intracellular calcium, and calcium channel currents. PT (100 ng/ml) pretreatment again partly abolished this inhibitory effect. The addition to the medium of adenosine deaminase (0.4 U/ml) stimulated calcitonin secretion. Our results suggest that in calcitonin-secreting cells A1 receptors couple to adenylate cyclase and calcium channels via PT-sensitive G proteins and thus inhibit calcitonin secretion. Adenosine seems to act as an autocrine/paracrine factor in calcitonin-secreting cells.
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PMID:Adenosine A1-receptors inhibit cAMP and Ca2+ mediated calcitonin secretion in C-cells. 855 39

Double-stranded RNA (dsRNA)-specific adenosine deaminase (DRADA) has been implicated as an enzyme responsible for the editing of RNA transcripts encoding glutamate-gated ion channel subunits (GLuR) in brain. In one case, the editing alters the gene-encoded glutamine (Q) to an arginine (R) located within the channel-forming domain of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor subunit GLuR-B. The result of editing at this site, called the 'Q/R' site, is a profound alteration of the Ca2+ permeability of the GLuR channel. Using recombinantly expressed DRADA proteins, we now demonstrate in vitro that DRADA is indeed involved in editing of the GLuR-B RNA. In addition to the formation of an RNA duplex structure involving exon and intron sequences, Q/R site-selective editing by DRADA also requires a cofactor protein(s) commonly present even in non-neuronal cells. The accuracy and efficiency of this RNA editing system appear to be determined by the quantitative balance between DRADA, cofactor and substrate GLuR-B RNA.
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PMID:Editing of the GLuR-B ion channel RNA in vitro by recombinant double-stranded RNA adenosine deaminase. 859 4

The interaction of platelets with neutrophil granulocytes is considered to play an important role in the inflammatory process, and the present study was focused on platelet-induced modulation of Fcgamma receptor-mediated functions in neutrophils. We found that phagocytosis and the respiratory burst (measured as luminol-enhanced chemiluminescence), triggered in neutrophils by immunoglobulin G (IgG)-opsonized yeast particles, were potentiated by platelets and that maximal enhancement was achieved at a physiological neutrophil/platelet ratio of about 1:50 to 1:100. Platelets both increased the intra- and extracellular generation of oxygen radicals as well as the release of myeloperoxidase from stimulated neutrophils. The presence of platelets also induced a cortical actin polymerization in neutrophils, which might explain the increased phagocytic capacity. Platelets appear to affect neutrophil function in a contact-independent manner that most likely involves ATP, indicated by the following: (1) platelet supernatants, but not fixed platelets, affected neutrophil function in the same way as viable platelets; (2) platelets raised the extracellular ATP level four- to fivefold; (3) exogenous ATP mimicked the effects of platelets on actin polymerization, phagocytosis, and the respiratory burst in neutrophils; (4) hydrolysis of extracellular ATP with apyrase or blocking of ATP receptors with suramin reversed the platelet-induced enhancement of neutrophil function. An increased accumulation of extracellular adenosine, induced by inhibiting endogenous adenosine deaminase or adding exogenous adenosine, reversed the effects of platelets. The platelet-induced potentiation of the respiratory burst was inhibited by the tyrosine kinase inhibitor genistein, suggesting that tyrosine phosphorylation is involved. However, platelets did not significantly affect the Fcgamma receptor-triggered calcium response in neutrophils. In conclusion, we show that platelets, through an ATP-dependent mechanism, potentiate IgG-mediated ingestion and production of oxygen metabolites in neutrophils.
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PMID:Platelets enhance Fc(gamma) receptor-mediated phagocytosis and respiratory burst in neutrophils: the role of purinergic modulation and actin polymerization. 869 24


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