Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effect of extracellular sodium concentration on histamine release (HR) from human basophils initiated by immunologic and nonimmunologic stimuli. We found that lowering extracellular sodium markedly enhances HR induced by an immunologic stimulus from these cells. In buffer in which sodium had been replaced with univalent ions of strong bases, enhancement of HR increased as extracellular sodium decreased. Enhancement was the result of increased duration of release. When sucrose was used for replacement of sodium, we also observed that enhancement of HR increased as extracellular sodium decreased, but there was some lessening of enhancement at [Na+]e between 5 and 10 mmol/L. Ouabain, which is an inhibitor of the Na+/K+ adenosine triphosphatase, and bumetanide and furosemide, which are inhibitors of Cl(-)-dependent Na(+)-K+ cotransport, caused small increases in enhancement of HR by sodium-deficient buffers; 4,4'-diisothiocyanostilbene-2-2'-disulfonic acid, an anion transport inhibitor, caused some inhibition of enhancement of HR. Analogues of amiloride, such as 5-(N-N-hexamethylene) amiloride (HMA) and 5-(N-4-chlorobenzyl)-2'-4'dimethylbenzamil (CBDMB), inhibit Na+/H+ exchange, Na+/Ca++ exchange, and Na+ channels. Interestingly, at higher doses, HMA and CBDMB caused marked enhancement of HR in both normal and sodium-deficient buffers. These results suggest that several cellular regulatory mechanisms potentially are important for normal basophil secretion. The most likely are pH regulatory mechanisms that include Na+/H+ exchange and anion exchangers that transport alkaline equivalents. Our findings enhancement of basophil HR by HMA and CBDMB is particularly noteworthy in light of the recent interest in use of amiloride by inhalation for therapy of lung disease in patients with cystic fibrosis.
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PMID:Role of sodium in mediator release from human basophils. 137 73

Cystic fibrosis (CF) airway epithelia are characterized by enhanced Na(+) absorption probably due to a lack of downregulation of epithelial Na(+) channels by mutant CF transmembrane conductance regulator. Extracellular nucleotides adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) have been shown to activate alternative Ca(2+)-dependent Cl(-) channels in normal and CF respiratory epithelia. Recent studies suggest additional modulation of Na(+) absorption by extracellular nucleotides. In this study we examined the role of mucosal ATP and UTP in regulating Na(+) transport in native human upper airway tissues from patients with 16 patients with CF and 32 non-CF control subjects. To that end, transepithelial voltage and equivalent short-circuit current (I(SC)) were assessed by means of a perfused micro-Ussing chamber. Mucosal ATP and UTP caused an initial increase in lumen-negative I(SC) that was followed by a sustained decrease of I(sc) in both non-CF and CF tissues. The amiloride-sensitive portion of I(SC) was inhibited significantly in normal and CF tissues in the presence of either ATP or UTP. Both basal Na(+) transport and nucleotide-dependent inhibition of amiloride-sensitive I(SC) were significantly enhanced in CF airways compared with non-CF. Nucleotide-mediated inhibition of Na(+) absorption was attenuated by pretreatment with the Ca(2+)-adenosine triphosphatase inhibitor cyclopiazonic acid but not by inhibition of protein kinase C with bisindolylmaleimide. These data demonstrate sustained inhibition of Na(+) transport in non-CF and CF airways by mucosal ATP and UTP and suggest that this effect is mediated by an increase of intracellular Ca(2+). Because ATP and UTP inhibit Na(+) absorption and stimulate Cl(-) secretion simultaneously, extracellular nucleotides could have a dual therapeutic effect, counteracting the ion transport defect in CF lung disease.
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PMID:Inhibition of amiloride-sensitive epithelial Na(+) absorption by extracellular nucleotides in human normal and cystic fibrosis airways. 1110 28