Sorting of P-type ATPases in polarized epithelial cells

L. A. Dunbar, N. Courtois-Coutry, D. L. Roush, T. R. Muth, C. J. Gottardi, V. Rajendran, J. Geibel, M. Kashgarian, M. J. Caplan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The Na,K-ATPase and the H,K-ATPase are highly homologous members of the P-type family of ion transporting ATPases. Despite their structural similarity, these two pumps are sorted to different destinations in polarized epithelial cells. While the Na,K-ATPase is restricted to the basolateral surfaces of most epithelial cells types, the H,K-ATPase is concentrated at the apical plasmalemma and in a pre-apical vesicular storage compartment in the parietal cells of the stomach. We have generated molecular chimeras composed of complementary portions of these two pumps' α-subunits. By expressing these pump constructs in polarized epithelial cells in culture, we have been able to identify sequence domains which participate in the targetting of the holoenzyme. We find that information embedded within the sequence of the fourth transmembrane domain of the H,K-ATPase is sufficient to account for this protein's apical localization. Stimulation of gastric acid secretion results in insertion of the intracellular H,K-ATPase pool into the apical plasma membrane and inactivation of acid secretion is accompanied by the re-internalization of these pumps. We have identified a tyrosine- based signal in the cytoplasmic tail of the H,K-ATPase β-subunit which appears to be required for this endocytosis. We have mutated the critical tyrosine residue to alanine and expressed the altered protein in transgenic mice. The H,K-ATPase remains continuously at the apical cell surface in parietal cells from these animals, and they constitutively hypersecrete gastric acid. These results demonstrate that the β-subunit sequence mediates the internalization of the H,K-ATPase and is required for the cessation of gastric acid secretion. Thus, at least two sorting signals are required to ensure the proper targetting and regulation of the gastric H,K pump.

Original languageEnglish (US)
Pages (from-to)289-295
Number of pages7
JournalActa Physiologica Scandinavica, Supplement
Volume163
Issue number643
StatePublished - 1998

Keywords

  • Acid secretion
  • Endocytosis
  • Epithelia
  • Ion pumps
  • Polarity
  • Sorting

ASJC Scopus subject areas

  • Physiology

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