Pflügers Archiv - European Journal of Physiology

, Volume 457, Issue 3, pp 609–622 | Cite as

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

  • Jai Moo Shin
  • Keith Munson
  • Olga Vagin
  • George Sachs
Ion Channels, Receptors and Transporters

Abstract

The gastric H,K-ATPase, a member of the P2-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 N-linked 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 E1 (ion site in) to an E2 (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 E2P 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 E2P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E1 configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases.

Keywords

The gastric H,K-ATPase ATPase structure–function Proton pump inhibitors Acid pump antagonists Gastric acid secretion 

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Jai Moo Shin
    • 1
  • Keith Munson
    • 1
  • Olga Vagin
    • 1
  • George Sachs
    • 1
    • 2
  1. 1.Department of Physiology, David Geffen School of MedicineUniversity of California at Los Angeles and VA Greater Los Angeles Healthcare SystemLos AngelesUSA
  2. 2.George SachsMembrane BiologyLos AngelesUSA

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