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:3.1.3.5 (5'-nucleotidase)
3,167 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Myocardial tolerance against infarction is substantially increased by exposing myocytes to 3-10 min transient ischaemia. In this phenomenon, termed 'preconditioning', the adenosine receptor is one of the redundant triggers and the best characterized factor in the cardioprotective mechanism. 2. An increase in interstitial adenosine during preconditioning is thought to be derived primarily from hydrolysis of 5'-AMP in the myocyte by cytosolic 5'-nucleotidase, although a contribution of ectosolic 5'-nucleotidase remains controversial. Adenosine production during ischaemia is substantially suppressed in the preconditioned myocardium, probably due to a decrease in ATP utilization. 3. The adenosine receptor needs to be activated not only at the time of preconditioning ischemia, but also during ischaemic insult for the preconditioning to be cardioprotective. However, the extent of cardioprotection afforded by preconditioning is primarily determined by the interstitial adenosine level achieved during preconditioning ischaemia, not by the level during sustained ischaemia. These data suggest that a post-receptor mechanism downstream of the adenosine receptor may be up-regulated after preconditioning. 4. Studies in vitro suggest that the subtypes of adenosine receptor relevant to preconditioning against infarction are A1 and A3, the activation of which appears to provide additive protection. The functional interrelationship between these subtypes in vivo remains unknown. 5. An important step downstream of adenosine receptor activation is protein kinase C (PKC), which facilitates opening of ATP-sensitive potassium (KATP) channels, probably leading to enhancement of myocardial tolerance. However, activation of other protein kinases, such as tyrosine kinase, may also be important in preconditioning, depending on the animal species and preconditioning protocols. The PKC isoform and location of KATP channels (i.e. sarcolemmal vs mitochondrial KATP) that induce anti-infarct tolerance in myocytes remain to be identified.
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PMID:Adenosine and preconditioning revisited. 1006 27

Adenosine increases blood flow and decreases excitatory nerve firing. In the heart, it reduces rate and force of contraction and preconditions the heart against injury by prolonged ischemia. Based on indirect kinetic arguments, an AMP-selective cytosolic 5'-nucleotidase designated cN-I has been implicated in adenosine formation during ATP breakdown. The molecular identity of cN-I is unknown, although an IMP/GMP-selective cytosolic 5'-nucleotidase (cN-II) and an ecto-5'-nucleotidase (e-N) have been cloned. We utilized the high abundance of cN-I in pigeon heart to purify a 40-kDa subunit for partial protein sequencing and subsequent cDNA cloning. We obtained a full-length clone encoding a novel 40-kDa peptide, unrelated to cN-II or e-N, that was most abundant in heart, brain, and breast muscle. Immunolocalization in heart showed a striated cytoplasmic location, suggesting association with contractile elements. Transient expression in COS-7 cells, generated a 5'-nucleotidase that catalyzed adenosine formation from AMP, which was increased during ATP catabolism. In conclusion, the cloning and expression of cN-I provides definitive evidence of its ability to produce adenosine during ATP breakdown.
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PMID:The mechanism of adenosine formation in cells. Cloning of cytosolic 5'-nucleotidase-I. 1036 22

Adenosine, derived from hydrolysis of 5'-AMP by 5'-nucleotidase activity, may be involved in coupling coronary blood flow to cardiac function and metabolism; it has been postulated as a cardioprotective substance in ischemic myocardium. The stimulation of beta-adrenergic receptors produces an increase in adenosine by 5'-AMP hydrolysis. In addition, it has been demonstrated that in Chagas' disease there is decreased cardiac perfusion. We show in this paper by histochemical and densitometric procedures that ecto-5'-nucleotidase activity increases in ventricles of acutely Trypanosoma cruzi-infected mice and that the density of beta-adrenergic receptors is significantly diminished with affinity similar to controls, showing that a compensatory mechanism was absent. The increase of ecto-5'-nucleotidase in heart myocytes from infected mice may produce cardioprotective adenosine that may be independent of beta-adrenergic function, based on the hypoperfusion conditions of acute chagasic cardiomyopathy.
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PMID:Trypanosoma cruzi: increased 5'-nucleotidase activity associated with dysfunction of adrenergic receptors in acutely infected albino Swiss mice. 1057 39

Adenosine has been implicated as an important endogenous regulator of various tissue functions. In diabetes, the responsiveness of several tissues to adenosine is altered. The aim of this study was to investigate the activities of enzymes metabolizing adenosine in tissues of diabetic rats. The cytosolic activity (V(max)) of adenosine kinase (AK) was decreased by 50% in the kidney and by 40% in the heart and liver of diabetic rats. A decrease in the V(max) of AK in diabetic tissues was not associated with a change in the K(m) for adenosine. Evaluation of AK gene transcript status showed significantly lower levels of AK mRNA in diabetic tissues as compared to normal tissues. In diabetic kidneys, the level of AK gene transcript was lowered by 50% on first day after streptozotocin administration, and these reduced levels were sustained declined during the next 10 days. Smaller changes in AK gene transcript levels were observed in the heart and liver than in the kidney. The cytosolic activities of 5'-nucleotidase, AMP deaminase, and adenosine deaminase were unchanged in kidney, heart, and liver of diabetic rats. These results suggest that the turnover of the AMP-adenosine metabolic cycle might be impaired in diabetic tissues due to the reduced activity of adenosine kinase.
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PMID:Decreased expression of adenosine kinase in streptozotocin-induced diabetes mellitus rats. 1068 43

The vasoactive substances adenosine and nitric oxide (NO) are credible candidates in the local regulation of skeletal muscle blood flow. Adenosine and NO have both been shown to increase in skeletal muscle cells and interstitial fluid during exercise and the enzymes responsible for their formation, AMP 5'-nucleotidase and NO synthase (NOS), have been shown to be activated upon muscle contraction. In vitro as well as in vivo evidence suggest that the contraction-induced increase in interstitial adenosine concentration largely stems from extracellular formation via the membrane-bound ecto-form of AMP 5'-nucleotidase. It remains unclear whether the exercise-induced NO formation in muscle originates from endothelial NOS in the microvascular endothelium, or from neuronal NOS (nNOS) in nerve cells and muscle fibres. Functional evidence for the role of adenosine in muscle blood flow control stems from studies using adenosine receptor agonists and antagonists, adenosine deaminase or adenosine uptake inhibitors. The majority of these studies have been performed on laboratory animals and, although the results show some discrepancy, the majority of studies indicate that adenosine does participate in the regulation of muscle blood flow. In humans, evidence is lacking. The role of NO in the regulation of skeletal muscle blood flow has mainly been studied using NOS inhibitors. Despite a large number of studies in this area, the role of NO for the contraction-induced increase in skeletal muscle blood flow is uncertain. The majority, but not all, human and animal studies show that, whereas blockade of NOS reduces muscle blood flow at rest and in recovery from exercise, there is no effect on the exercise-induced increase in muscle perfusion. Conclusive evidence for the mechanisms underlying the precise regulation of the multiphased increase in skeletal muscle blood flow during exercise and the role and potency of various vasoactive substances, remain missing.
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PMID:Adenosine and nitric oxide in exercise-induced human skeletal muscle vasodilatation. 1075 94

Adenosine has been proposed as an endogenous anticonvulsant which can play an important role in seizure initiation, propagation and arrest. Besides the release of adenosine per se, the ectonucleotidase pathway is an important metabolic source of extracellular adenosine. Here we evaluated ATP diphosphohydrolase and 5'-nucleotidase activities in synaptosomes from hippocampus and cerebral cortex at different periods after induction of status epilepticus (SE) by intraperitoneal administration of pilocarpine or kainate. Ectonucleotidase activities from synaptosomes of hippocampus and cerebral cortex of rats were significantly increased at 48-52 h, 7-9 days and 45-50 days after induction of SE by pilocarpine. In relation to kainate model, both hippocampal enzymes were enhanced at 7-9 days and 45-50 days, but only 5'-nucleotidase remained elevated at 100-110 days after the treatment. In cerebral cortex, an increase in ATP diphosphohydrolase was observed at 48-52 h, 7-9 days and 45-50 days after induction of SE by kainate. However, 5'-nucleotidase activity only presented significant changes at 45-50 and 100-110 days. Our results suggest that SE can induce late and prolonged changes in ectonucleotidases activities. The regulation of the ectonucleotidase pathway may play a modulatory role during the evolution of behavioral and pathophysiological changes related to temporal lobe epilepsy.
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PMID:Changes in synaptosomal ectonucleotidase activities in two rat models of temporal lobe epilepsy. 1077 Dec 49

Nephron function is stabilized by tubuloglomerular feedback (TGF). TGF operates within the juxtaglomerular apparatus, sensing changes in tubular flow and eliciting compensatory changes in single nephron GFR (SNGFR). The mediator(s) of TGF remains unconfirmed. One theory is that ATP consumed in active transport by the macula densa leads to formation of adenosine, which causes glomerular vasoconstriction. We performed micropuncture in rats to test this hypothesis. Adenosine activity was manipulated by microperfusing nephrons with adenosine A1 receptor blocker, A1-agonist, or 5'-nucleotidase inhibitor. Effects on TGF were characterized by changes in TGF efficiency (the compensation for small perturbations in tubular flow) and by changes in the maximum range over which TGF can cause SNGFR to change. These data were further applied to generate TGF profiles [SNGFR versus late proximal flow (V(LP))]. TGF efficiency was significantly reduced by blocking A1-receptors. TGF efficiency, TGF range, and the slope of the TGF profile (DeltaSNGFR/DeltaV(LP)) were all significantly reduced by blocking 5'-nucleotidase. When adenosine activity was clamped by combining 5'-nucleotidase inhibitor with A1-agonist to determine whether TGF requires adenosine to be present or to fluctuate, the TGF slope was reduced by 83%, indicating that adenosine activity must fluctuate for normal TGF to occur and that adenosine is a mediator of TGF.
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PMID:Adenosine formed by 5'-nucleotidase mediates tubuloglomerular feedback. 1090 45

Preconditioning is a powerful form of (myocardial) protection that follows brief sublethal ischemia. G-protein-coupled receptors constitute the trigger for entrance to the preconditioned state. In conjunction with other receptors, various membrane adenosine receptors play an important role in the transduction of extracellular signals, leading to protection by preconditioning, lasting 1-3 hr. Adenosine A(1)- and A(3)-receptors mediate inhibition of adenylate cyclase via a guanine nucleotide binding inhibitory protein (G(i/o)). A(2)-receptors couple to a comparable stimulatory protein (G(s)). Adenosine receptors are especially abundant in the central nervous system; in lesser numbers, they are found in many tissues, including the heart. A(1)-receptors are located on cardiomyocytes and vascular smooth muscle cells, A(2)-receptors on endothelial and vascular smooth muscle cells, and A(3)-receptors on ventricular myocytes. Ischemic preconditioning by endogenous adenosine takes place through A(1)- and A(3)-receptors. A(2A/B)-receptor activation results in vasodilation. The relevance of cellular mediators, such as 5'-nucleotidase, to generate adenosine for preconditioning is controversial. In contrast, the role of protein kinase C (PKC) is clearly established. Signals from different receptors converge at PKC, reaching a threshold activation of the kinase necessary to induce protection. Tyrosine and mitogen-activated protein kinases may play a role in addition to PKC. The exact products downstream responsible for the memory of preconditioning are elusive. A prime candidate for the end-effector of preconditioning is the K(ATP) channel. Preconditioning with adenosine-receptor agonists offers the possibility for treatment of coronary artery disease, but research in this field is still in its infancy.
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PMID:The role of adenosine in preconditioning. 1100 96

The mechanism underlying beta,gamma-methylene ATP (beta,gamma-MeATP)-induced cAMP elevation was investigated in rat glioma C6Bu-1 cells. Beta,gamma-MeATP increased forskolin-stimulated cAMP formation in a manner sensitive to both the P1 antagonist xanthine amine congener (XAC) and the P2 antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). Adenosine deaminase (ADA; 1 U/mL), which abolished the adenosine-induced response, did not eliminate the beta,gamma-MeATP-induced response. However, combination of ADA with alpha,beta-methylene ADP (alpha,beta-MeADP), an ecto-5'-nucleotidase inhibitor, blocked the beta,gamma-MeATP-induced response. AMP, the substrate for ecto-5'-nucleotidase, also induced cAMP formation in a manner sensitive to XAC and alpha,beta-MeADP inhibition. However, the AMP-induced response was not blocked by PPADS. HPLC analyses revealed that adenosine was generated from beta,gamma-MeATP and AMP. In addition, alpha,beta-MeADP inhibited the conversion of beta,gamma-MeATP and AMP to adenosine, whereas PPADS blocked adenosine formation from beta,gamma-MeATP but not from AMP. [3H]Adenosine generated from [3H]AMP was preserved on the cell surface environment even in the presence of ADA. The mRNAs for ecto-phosphodiesterase/pyrophosphatase 1 (EC 3.1.4.1), ecto-5'-nucleotidase (EC 3.1.3.5) and adenosine A2B receptor were detected by RT-PCR. These results suggest that C6Bu-1 cells possess ecto-enzymes converting beta,gamma-MeATP to adenosine, and the locally accumulated adenosine in this mechanism efficiently stimulates A2B receptors in a manner resistant to exogenous ADA.
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PMID:Beta,gamma-methylene ATP-induced cAMP formation in C6Bu-1 cells: involvement of local metabolism and subsequent stimulation of adenosine A2B receptor. 1115 59

Adenosine production catalysed by cytosolic 5'-nucleotidase (cN-I) regulates diverse physiological processes. We report here a mouse cN-I (mcN-I) cloned from heart and testis. The open reading frame contains several potential translation initiation sites, which yield similarly active 5'-nucleotidases. Using overexpression in COS-7 cells we showed that mcN-I, like the previously cloned pigeon cN-I, is activated by ADP and catalyses adenosine formation during ATP breakdown. The N- and C-termini of mcN-I and pcN-I are divergent. Deletion of the 12 C-terminal amino acids or the first 19 N-terminal amino acids of pcN-I does not diminish activity, although deletion of the first 31 N-terminal amino acids reduces activity by 70%. Overall mcN-I is only 66% identical to pcN-I or the recently cloned human cN-I (hcN-I), while hcN-I and pcN-I are 85% identical. We report here a partial hcN-I sequence that is only 70% identical with the published hcN-I amino acid sequence but is 87% identical with mcN-I. Both hcN-I sequences have perfect matches to distinct human genome sequences. Our data imply the existence of at least two genes for cN-I, cN-I(A), previously cloned from pigeon and human, and cN-I(B) that we report here from mouse and partially from human.
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PMID:Cloning of a mouse cytosolic 5'-nucleotidase-I identifies a new gene related to human autoimmune infertility-related protein. 1169 Jun 31


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