Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with medically intractable temporal lobe epilepsy (TLE) undergo medial temporal lobectomy with hippocampectomy for one of two reasons. (1) A lesion (tumor or arteriovenous malformation) adjacent to, but not invasive of, the hippocampus, results in the removal of the lesion and adjacent hippocampus in order to ensure a tumor-free margin. This group will be referred to as tumor-related TLE (TTLE) patients. (2) The operation is performed when depth electrode recordings and other evaluative techniques point to the hippocampus as the focus of seizure initiation. This group will be referred to as cryptogenic TLE (CTLE) patients. Analysis of the hippocampi of these two groups of patients reveals that the TTLE hippocampus is quite similar to that of autopsy subjects in its chemical neuroanatomy. However, the dentate gyrus of the CTLE patients shows considerable morphological and cytochemical reorganization. This reorganization is characterized by a number of features. (1) There is a loss of granule cells which occurs either as a patchy loss and/or a thinning of the granule cell layer. (2) Remaining granule cells which contain dynorphin appear to produce recurrent collaterals into the inner molecular layer of the dentate gyrus. (3) In the subgranular region of the hilus (the polymorphic layer) there is a selective loss of interneurons immunoreactive for somatostatin, neuropeptide Y and substance P. (4) There appears to be an increase in fibers immunoreactive for somatostatin and neuropeptide Y which extend throughout the dentate molecular layer. Somatostatin fibers being less numerous than neuropeptide Y fibers (5). The distributions of a number of neurotransmitter receptors also show striking reorganization in the dentate gyrus of the CTLE hippocampus. (6) Second messenger systems protein kinase C and adenylate cyclase, and Na+, K(+)-ATPase activity, as determined by ouabain binding, is increased in the molecular layer of CTLE. This remodeling of the CTLE hippocampus may hold the key to the mechanisms of hyperexcitability of the granule cells in the hippocampus of this group, and consequently the generation of seizures. The removal of the hippocampus in CTLE patients results in good control of seizures, whereas removal of hippocampi that do not show such reorganization, in a group of patients classified as atypical CTLE patients, results in inadequate seizure control. These findings suggest a complex series of processes in converting the properly regulated granule cells into hyperexcitable ones.
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PMID:Neurotransmitters and their receptors in human temporal lobe epilepsy. 136 31

The effect of ouabain on exocytotic and nonexocytotic norepinephrine release was investigated in perfused rat and guinea pig hearts. The overflow of endogenous norepinephrine and its neuronal metabolite 3,4-dihydroxyphenylethyleneglycol (DOPEG) was determined by high-pressure liquid chromatography. DOPEG served as the indicator of free axoplasmic norepinephrine concentrations. The overflow of the norepinephrine cotransmitter neuropeptide Y (NPY) was determined by radioimmunoassay and NPY was used as marker for exocytotic release. Electrical stimulation of the left stellate ganglion resulted in exocytotic norepinephrine release in rat and guinea pig hearts. Ouabain caused an increase in stimulation-induced norepinephrine overflow from rat and guinea pig hearts by 40%. However, overflow of NPY was decreased by 40%, indicating a reduced exocytosis rate. Ouabain increased both norepinephrine and NPY overflow, suggesting enhancement of exocytosis, when neuronal catecholamine uptake (uptake1) was blocked by desipramine or when presynaptic alpha 2-adrenoceptors were inhibited by yohimbine. The results demonstrate an interaction of ouabain with both calcium-dependent exocytosis and uptake1 of norepinephrine. Under calcium-free conditions, ouabain or potassium-free perfusate resulted in norepinephrine release from hearts when the axoplasmic norepinephrine concentration was elevated by the reserpinelike agent Ro 4-1284. This release was independent from neural activity, not accompanied by NPY overflow, and suppressed by the uptake1 blocker desipramine. These findings are in keeping with carrier-mediated nonexocytotic norepinephrine release that is caused by reversal of the transport direction of the uptake1 carrier. During myocardial ischemia nonexocytotic norepinephrine release was accelerated and enhanced by inhibition of Na+,K(+)-ATPase before ischemia. This study demonstrates the potential of digitalis glycosides to interact both with transmitter exocytosis and with the neuronal catecholamine transport system by Na+,K(+)-ATPase inhibition. Interaction with the catecholamine transport system involves both inhibition of norepinephrine inward transport and induction of norepinephrine outward transport, resulting in nonexocytotic norepinephrine release.
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PMID:Effect of digitalis glycosides on norepinephrine release in the heart. Dual mechanism of action. 203 16

Isolated perfused rat hearts were used to compare the effects of the synthetic neuropeptide Y (NPY) and 4-norleucine-NPY on cardiac function. Each peptide exhibited both negative inotropic and chronotropic effects, and also caused coronary vasoconstriction leading to a reduction in coronary flow. A comparison of the IC50 values from dose-response curves using 10(-14) to 10(-7) M peptides (IC50 is the peptide concentration that produced a 50% decrease of the maximal effect) indicated that NPY was more potent as inhibitor of contractility and less potently inhibited coronary flow and heart rate, whereas 4-norleucine-NPY had more inhibitory influence on coronary flow and heart rate and less on cardiac contractility. This difference in potencies suggests that the inhibitory effects of NPY on contractility, coronary flow and heart rate may be independent of each other. Since NPY also decreased the contractile force of isolated left atrial and right ventricular strips of the rat heart, the coronary flow decrease cannot be the cause of the negative inotropy of isolated heart. Pretreatment of atrial and ventricular strips with NPY did not influence the positive inotropic effect produced by the cardiac glycoside ouabain indicating that sarcolemmal Na+, K+-ATPase was not involved in the inhibitory inotropic effect of NPY. Further studies towards elucidating the mechanism of the negative inotropy of cardiac muscles using isolated heart mitochondria revealed that NPY uncoupled oxidative phosphorylation and blocked mitochondrial calcium uptake; the former event fosters negative inotropy. Since these effects on mitochondria occurred at concentrations 100-fold higher than those required for negative inotropy, the two effects of NPY may not be related.
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PMID:Comparison of the effects of neuropeptide Y (NPY) and 4-norleucine-NPY on isolated perfused rat hearts; effects of NPY on atrial and ventricular strips of rat heart and on rabbit heart mitochondria. 341 95

The sympathetic renal nerves are of central importance for the regulation of sodium balance. Sodium excretion decreases following renal nerve activation and increases following denervation. These effects have been attributed to norepinephrine (NE) acting on alpha-adrenergic receptors. In the present study, using isolated permeabilized rat renal proximal convoluted tubule (PCT) cells, neuropeptide Y (NPY) was shown to stimulate Na+, K(+)-ATPase activity. This 36-amino acid peptide is a messenger molecule in the sympathetic nervous system which is co-stored with NE and dopamine-beta-hydroxylase (DBH), the NE synthesizing enzyme in the renal nerves. The effect is likely to be mediated via the NPY Y2 receptor, a pertussis toxin (PTX)-sensitive G-protein, and calcium. It is partially antagonized by alpha-adrenergic antagonists, and enhanced by the subthreshold doses of alpha-adrenergic agonists. Our results suggest an important role for this peptide in the regulation of the sodium balance in the kidney.
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PMID:Coexisting NPY and NE synergistically regulate renal tubular Na+, K(+)-ATPase activity. 752 51

The effect of neuropeptide Y on the number and affinity of catecholamine receptors in the ventricular myocardium was investigated. Receptor binding studies showed that incubation of cardiac membrane in the presence of neuropeptide Y (NPY, 10(-7) M) decreased the number of alpha/beta-adrenoceptor binding sites (Bmax) without affecting the affinity (KD) of these receptors. Although not able to modulate the contractility by itself, NPY was able to decrease the positive inotropic effects of phenylephrine and isoproterenol in the isolated, perfused myocardium. Ca2+/Mg(2+)-ATPase activity, measured from the sarcolemma, sarcoplasmic reticulum and myofibrils, was unaltered whereas the activity of sarcolemmal Na+/K(+)-ATPase was decreased when NPY was included in the media. On the other hand, NPY was shown to increase the phosphoinositide-phospholipase C associated with the sarcolemma. These findings support the hypothesis that NPY modulates postsynaptic adrenergic receptors in the myocardium and can affect the adrenergic-induced, inotropic response.
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PMID:Adrenoreceptor-mediated effect of neuropeptide Y decreases cardiac inotropic responses. 803 15

1. Desensitization of Gs-coupled receptors, the beta 2-adrenoceptor for example, involves rapid and slower components but little is known regarding the existence of rapid desensitization of Gi-coupled receptors and its possible mechanisms. In HEL-cells stimulation of alpha 2A-adrenoceptors by adrenaline or Y1-like neuropeptide Y receptors by neuropeptide Y, transiently mobilizes Ca2+ from intracellular stores via a Gi-protein. We have used this model to study the existence and possible mechanisms of rapid desensitization of a Gi-mediated cellular response. 2. Following stimulation by adrenaline or neuropeptide Y Ca2+ levels returned towards baseline a few minutes after agonist addition and were refractory to a second agonist exposure demonstrating rapid desensitization. Cross-desensitization experiments with neuropeptide Y, adrenaline and moxonidine demonstrated the presence of homologous (both receptors) and heterologous desensitization (neuropeptide Y receptors only), and that the alpha 2A-adrenoceptor desensitization was not specific for phenylethylamine (adrenaline) or imidazoline agonists (moxonidine). 3. The protein kinase C activator, phorbol ester, rapidly desensitized the hormonal Ca2+ responses and inhibitors of protein kinase C enhanced the hormonal responses inconsistently. The tyrosine kinase inhibitor, herbimycin, enhanced Ca2+ mobilization by adrenaline and neuropeptide Y, whereas the protein phosphatase inhibitor, okdadaic acid, did not affect Ca2+ mobilization or its desensitization. 4. In the absence of extracellular Ca2+ the endoplasmic reticulum Ca(2+)-ATPase inhibitor, thapsigargin, reduced hormone-stimulated Ca2+ elevations, demonstrating that mobilization occurs from a thapsigargin-sensitive pool in the endoplasmic reticulum. The inositol phosphate-independent Ca2+release modulator, ryanodine, significantly enhanced adrenaline- and neuropeptide Y-stimulated Ca2+elevations. Blockade of the endoplasmic reticulum Ca2+-ATPase by thapsigargin in the presence of extracellular Ca2+ enhanced hormone-stimulated Ca2+ increases, demonstrating the importance of this enzyme for the termination of the Ca2+ signal.5. It is concluded that adrenaline and neuropeptide Y-stimulated Ca2+ mobilization in HEL-cells occurs from a thapsigargin- and ryanodine-sensitive store in the endoplasmic reticulum and desensitizes rapidly;this appears to involve multiple mechanisms including protein kinases, possibly acting on receptors, and Ca2+ release and sequestration mechanisms.
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PMID:Rapid desensitization of adrenaline- and neuropeptide Y-stimulated Ca2+ mobilization in HEL-cells. 807 68

This study was performed in order to test the hypothesis that the connecting peptide of proinsulin, C-peptide, might in itself possess biological activity. Renal tubular Na+, K(+)-ATPase, which is a well-established target for many peptide hormones, was chosen as a model. Rat C-peptide (I) was found to stimulate Na+, K(+)-ATPase activity in single, proximal convoluted tubules dissected from rat kidneys. C-peptide increased the Na+ affinity of the enzyme and all subsequent studies were performed at non-saturating Na+ concentrations. C-peptide stimulation of Na+, K(+)-ATPase activity occurred in a concentration-dependent manner in the dose range 10(-8)-10(-6) mol/l. The presence of neuropeptide Y, 5 x 10(-9) mol/l, enhanced this effect and stimulation of Na+, K(+)-ATPase activity then occurred in the C-peptide dose range 10(-11)-10(-8) mol/l. C-peptide stimulation of Na+, K(+)-ATPase activity was abolished in tubules pretreated with pertussis toxin. It was also abolished in the presence of FK 506, a specific inhibitor of the Ca2(+)-calmodulin-dependent protein phosphatase 2B. These results indicate that C-peptide stimulates Na+, K(+)-ATPase activity, probably by activating a receptor coupled to a pertussis toxin-sensitive G-protein with subsequent activation of Ca2(+)-dependent intracellular signalling pathways.
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PMID:C-peptide stimulates rat renal tubular Na+, K(+)-ATPase activity in synergism with neuropeptide Y. 863 72

The molecular mechanisms underlying the regulation of sodium excretion are incompletely known. Here we propose a general model for a bi-directional control of tubular sodium transporters by natriuretic and antinatriuretic factors. The model is based on experimental data from studies on the regulation of the activity of Na+,K+-ATPase, the enzyme that provides the electrochemical gradient necessary for tubular reabsorption of electrolytes and solutes in all tubular segments. Regulation is carried out to a large extent by autocrine and paracrine factors. Of particular interest are the two catecholamines, dopamine and norepinephrine. Dopamine is produced in proximal tubular cells and inhibits Na+,K+-ATPase activity in several tubule segments. Renal dopamine availability is regulated by the degrading enzyme, catechol-O-methyl transferase. Renal sympathetic nerve endings contain norepinephrine and neuropeptide Y (NPY). Activation of alpha-adrenergic receptors increase and activation of beta-adrenergic receptors decrease Na+,K+-ATPase activity. alpha-Adrenergic stimulation increases the Na+ affinity of the enzyme and thereby the driving force for transcellular Na+ transport. NPY acts as a master hormone by synergizing the alpha- and antagonizing the beta-adrenergic effects. Dopamine and norepinephrine control Na+,K+-ATPase activity by exerting opposing forces on a common intracellular signaling system of second messengers, protein kinases and protein phosphatases, ultimately determining the phosphorylation state of Na+,K+-ATPase and thereby its activity. Important crossroads in this network are localized and functionally defined. Phosphorylation sites for protein kinase A and C have been identified and their functional significance has been verified.
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PMID:Cellular mechanisms for bi-directional regulation of tubular sodium reabsorption. 874 89

Na+,K+-ATPase in tubular cells plays a pivotal role for the regulation of renal sodium excretion. In adult rats the activity of this enzyme is inhibited by natriuretic hormones and stimulated by antinatriuretic hormones. Here we have examined the tubular response to alpha-adrenergic agonists and neuropeptide Y (NPY) in both infant and adult rats. In the adult kidney, alpha-adrenergic agonists and NPY stimulate Na+,K+-ATPase activity via Ca2+-dependent pathways. Oxymetazoline, a selective alpha-adrenergic agonist, and NPY failed to stimulate proximal tubular (PT) Na+,K+-ATPase activity in 10-d-old rats in doses of 10(-8) to 10(-5) M and 10(-8) to 10(-6) M, respectively, but when tubules were incubated simultaneously with both oxymetazoline 10(-8) M and NPY 5 x 10(-9) M, stimulation was observed in both 10- and 40-d-old rat PT. This effect was abolished by FK 506, an inhibitor of Ca2+ and calmodulin-dependent protein phosphatase 2B in both age groups. A23187, a calcium ionophore, stimulated Na+,K+-ATPase in both infant and adult PT, but 10-fold higher doses were required for the infant tubules. The effect of alpha-adrenergic agonists and NPY on free intracellular Ca2+ was studied in PT cells in primary culture. The Ca2+ response to each agent was less pronounced in infant than in adult cells. Preincubation with NPY, which increases Ca2+ influx into the cells, enhanced the response to the alpha-adrenergic agonist in both infant and adult cells. The results support the concept that the systems regulating renal tubular Na+, K+-ATPase and sodium metabolism undergo postnatal maturation.
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PMID:Maturation of rat renal tubular response to alpha-adrenergic agonists and neuropeptide Y: a study on the regulation of Na+,K+-ATPase. 892 77

The effects of selective cholinergic cell loss within the basal forebrain (BF) were determined using a task that requires shifting of attention between two visual stimuli. Discriminability between two stimuli and response bias were determined in young and old F-344 rats given BF injections of IgG-192 saporin (100 ng). The lesion reduced ChAT activity in the frontal and parietal cortices, hippocampus, and olfactory bulbs. The lesion did not significantly alter Na+/K(+)-ATPase activity in cortex, hippocampus, or olfactory bulbs, or endogenous levels of neuropeptide Y and neurokinin B within the BF. The BF lesions impaired both stimulus discriminability and response bias in young and old rats. The BF lesions had a significantly greater effect upon stimulus discriminability and response bias in aged rats, compared to young rats, only when the stimulus duration was very brief, i.e., when the task was most difficult to solve. At longer stimulus durations, aging and lesions showed no interaction. The results suggest that the selective loss of cholinergic cells in the BF, but not normal aging, impairs the ability to discriminate between independent sensory stimuli. The loss of these cells confers a response bias in simple operant tasks involving motor responses to reward-related visual stimuli.
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PMID:The effects of selective cholinergic basal forebrain lesions and aging upon expectancy in the rat. 915 60


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