title: An inhibitor of Ca2+/calmodulin-dependent protein kinase II, KN-62, inhibits cholinergic-stimulated parietal cell secretion.
abstract: Cholinergic stimulation of parietal cell secretion is mediated by an increase in intracellular calcium. KN-62, a selective inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMK II), has recently been synthesized (Tokomitsu et al. J. Biol. Chem. 265: 4315-4320, 1990). To define the role of CaMK II in parietal cell secretion, we determined the effects of KN-62 on secretagogue-stimulated acid secretion in isolated rabbit parietal cells. Pretreatment of parietal cells with KN-62 resulted in the inhibition of carbachol-stimulated [14C]aminopyrine uptake over a concentration range of 3 to 60 microM (IC50 of 20 microM). KN-62 (60 microM) reduced carbachol-stimulated aminopyrine uptake to unstimulated levels. KN-62 did not alter carbachol-stimulated increases in cytoplasmic free Ca2+ concentration. High concentrations of KN-62 (60 microM) elicited a small decrease in aminopyrine uptake stimulated by forskolin, but did not significantly inhibit histamine stimulation. A potent CaMK II activity was identified in total membrane from parietal cells. These results suggest that CaMK II may mediate cholinergic-stimulated parietal cell secretion.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Y
authors.initials: Y
authors.lastname: Tsunoda
authors.forename: M
authors.initials: M
authors.lastname: Funasaka
authors.forename: I M
authors.initials: IM
authors.lastname: Modlin
authors.forename: H
authors.initials: H
authors.lastname: Hidaka
authors.forename: L M
authors.initials: LM
authors.lastname: Fox
authors.forename: J R
authors.initials: JR
authors.lastname: Goldenring
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002217:Carbachol / Q000494:pharmacology; D002469:Cell Separation; D005576:Colforsin / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000494:pharmacology*; D010295:Parietal Cells, Gastric / Q000201:enzymology / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D007546:Isoquinolines; D010277:Parasympathomimetics; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D005576:Colforsin; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002217:Carbachol; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases