title: Inhibition of acid secretion in gastric parietal cells by the Ca2+/calmodulin-dependent protein kinase II inhibitor KN-93.
abstract: 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.
authors.affiliation: Department of Pharmacology, Nagoya University School of Medicine, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Mamiya
authors.forename: J R
authors.initials: JR
authors.lastname: Goldenring
authors.forename: Y
authors.initials: Y
authors.lastname: Tsunoda
authors.forename: I M
authors.initials: IM
authors.lastname: Modlin
authors.forename: K
authors.initials: K
authors.lastname: Yasui
authors.forename: N
authors.initials: N
authors.lastname: Usuda
authors.forename: T
authors.initials: T
authors.lastname: Ishikawa
authors.forename: A
authors.initials: A
authors.lastname: Natsume
authors.forename: H
authors.initials: H
authors.lastname: Hidaka
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002217:Carbachol / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism*; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007700:Kinetics; D008854:Microscopy, Electron; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D047428:Protein Kinase Inhibitors; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D015056:1-Methyl-3-isobutylxanthine; D001596:Benzylamines; D002118:Calcium; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002217:Carbachol; D002927:Cimetidine; D005576:Colforsin; D000242:Cyclic AMP; D017506:H(+)-K(+)-Exchanging ATPase; D006632:Histamine; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides