Turnover of the gastric H+,K+-Adenosine triphosphatase α subunit and its effect on inhibition of rat gastric acid secretion

Gedda, Karin; Scott, David; Besancon, Marie; Lorentzon, Pia; Sachs, George

doi:10.1016/0016-5085(95)90571-5

Cited by 79 publications

(38 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It takes about 3 days to reach steadystate inhibition of acid secretion, as a balance is struck between covalent inhibition of active pumps, subsequent stimulation of inactive pumps after the drug has been eliminated from the blood, and de novo synthesis of new pumps. The pump protein has a half-life of about 54 h in the rat [15] (and probably in man); thus, about 20% new pumps are synthesized over a 24-h period, and it may be that there is greater pump synthesis at night than during the day. In addition, bedtime administration will not add to inhibition of nocturnal acid breakthrough, as the drug will have disappeared by the time nighttime acid secretion is evident.…”

Section: Biology Of Proton Pump Inhibitorsmentioning

confidence: 99%

“…A prelude to this analysis was evident in measurement of the halftime of pump protein biosynthesis in rats treated for 7 days with omeprazole (54 h in untreated and treated rats) and the halftime of restoration of ATPase activity (15 h), suggesting a more rapid recovery of ATPase activity and acid secretion than if only de novo biosynthesis was responsible for restoration of ATPase activity [15]. In other experiments, the halftime of restoration of acid secretion in omeprazole-treated rats was 20 h [19,70].…”

Section: Biology Of Proton Pump Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

The gastric HK-ATPase: structure, function, and inhibition

Shin

Munson

Vagin

et al. 2008

Pflugers Arch - Eur J Physiol

Self Cite

220

181

View full text Add to dashboard Cite

The gastric H,K-ATPase, a member of the P 2 -type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an α,β-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8. Comparison to the known structure of the SERCA pump, mutagenesis, and molecular modeling has identified these as constituents of the ion binding domain. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the β subunit contains six or seven Nlinked glycosylation sites. N-glycosylation is important for the enzyme assembly, maturation, and sorting. The enzyme pumps acid by a series of conformational changes from an E 1 (ion site in) to an E 2 (ion site out) configuration following binding of MgATP and phosphorylation. Several experimental observations support the hypothesis that expulsion of the proton at 160 mM (pH 0.8) results from movement of lysine 791 into the ion binding site in the E 2 P configuration. Potassium access from the lumen depends on activation of a K and Cl conductance via a KCNQ1/KCNE2 complex and Clic6. K movement through the luminal channel in E 2 P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E 1 configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases.

show abstract

Section: Biology Of Proton Pump Inhibitorsmentioning

confidence: 99%

Section: Biology Of Proton Pump Inhibitorsmentioning

confidence: 99%

The gastric HK-ATPase: structure, function, and inhibition

Shin

Munson

Vagin

et al. 2008

Pflugers Arch - Eur J Physiol

Self Cite

220

181

View full text Add to dashboard Cite

show abstract

“…A prelude to this analysis of reversibility was evident in measurement of the half-time of pump protein biosynthesis in rats treated for 7 days with omeprazole (54 h in untreated and treated rats) and the half-time of restoration of ATPase activity (15 h) suggesting a more rapid recovery of ATPase activity and acid secretion than if only de novo biosynthesis was responsible for restoration of ATPase activity [57]. In other experiments, the halftime of restoration of acid secretion in omeprazole-treated rats was 20 h [58,59].…”

Section: Restoration Of Acid Secretion After Ppi Inhibitionmentioning

confidence: 99%

Molecular mechanisms in therapy of acid-related diseases

Shin

Vagin

Munson

et al. 2007

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogenpotassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists.

show abstract

“…Measurement of protein turnover in the rat showed that the alpha subunit of the pump had a half-life of 54 hr and that this was unaffected by proton pump inhibition [59].…”

Section: Reversal Of Acid Secretory Inhibitionmentioning

confidence: 99%