Inhibition of acid secretion in gastric parietal cells by the Ca2+/calmodulin-dependent protein kinase II inhibitor KN-93

Biochem Biophys Res Commun. 1993 Sep 15;195(2):608-15. doi: 10.1006/bbrc.1993.2089.


A novel Ca2+/calmodulin-dependent protein kinase II (CaM Kinase II) inhibitor, KN-93 potently inhibits gastric acid secretion from parietal cells. As previously reported (1), treatment of parietal cells with a selective inhibitor of CaM kinase II, KN-62 resulted in the inhibition of cholinergic-stimulated rabbit parietal cell secretion, whereas it failed to inhibit the histamine and forskolin response. In contrast effects of carbachol, histamine and forskolin were significantly inhibited by KN-93 with an IC50 of 0.15, 0.3 and 1 microM, respectively; these effects occurred without any changes in intracellular cyclic AMP and Ca2+ levels. In the present study we investigated the mechanism by which KN-93 acts upon the acid-secreting machinery of gastric parietal cells. Neither redistribution of the proton pump activity nor the morphological transformation were affected by KN-93. The drug only weakly inhibited the H+, K(+)-ATPase activity but strongly dissipated the proton gradient formed in the gastric membrane vesicles and reduced the volume of luminal space. Thus KN-93 acts at pH gradient formation whereas KN-62 acts only at CaM Kinase II.

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Animals
  • Benzylamines / pharmacology*
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Carbachol / pharmacology
  • Cimetidine / pharmacology
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Gastric Acid / metabolism*
  • H(+)-K(+)-Exchanging ATPase / metabolism
  • Histamine / pharmacology
  • Hydrogen-Ion Concentration
  • In Vitro Techniques
  • Kinetics
  • Microscopy, Electron
  • Parietal Cells, Gastric / drug effects
  • Parietal Cells, Gastric / metabolism*
  • Parietal Cells, Gastric / ultrastructure
  • Protein Kinase Inhibitors*
  • Rabbits
  • Sulfonamides / pharmacology*


  • Benzylamines
  • Protein Kinase Inhibitors
  • Sulfonamides
  • KN 93
  • Colforsin
  • Cimetidine
  • Histamine
  • Carbachol
  • Cyclic AMP
  • Calcium-Calmodulin-Dependent Protein Kinases
  • H(+)-K(+)-Exchanging ATPase
  • Calcium
  • 1-Methyl-3-isobutylxanthine