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J. Biol. Chem. 276 (22): 18673-18680

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of a Human Chloride Channel
A PARADIGM FOR INTEGRATING INPUT FROM CALCIUM, TYPE II CALMODULIN-DEPENDENT PROTEIN KINASE, AND INOSITOL 3,4,5,6-TETRAKISPHOSPHATE*

Melisa W. Y. HoDagger §, Marcia A. Kaetzel, David L. Armstrong||, and Stephen B. ShearsDagger

From the Dagger  Inositide Signaling and || Membrane Signaling Groups, Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709 and the  Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0576

We have studied the regulation of Ca2+-dependent chloride (ClCa) channels in a human pancreatoma epithelial cell line (CFPAC-1), which does not express functional cAMP-dependent cystic fibrosis transmembrane conductance regulator chloride channels. In cell-free patches from these cells, physiological Ca2+ concentrations activated a single class of 1-picosiemens Cl--selective channels. The same channels were also stimulated by a purified type II calmodulin-dependent protein kinase (CaMKII), and in cell-attached patches by purinergic agonists. In whole-cell recordings, both Ca2+- and CaMKII-dependent mechanisms contributed to chloride channel stimulation by Ca2+, but the CaMKII-dependent pathway was selectively inhibited by inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4). This inhibitory effect of Ins(3,4,5,6)P4 on ClCa channel stimulation by CaMKII was reduced by raising [Ca2+] and prevented by inhibition of protein phosphatase activity with 100 nM okadaic acid. These data provide a new context for understanding the physiological relevance of Ins(3,4,5,6)P4 in the longer term regulation of Ca2+-dependent Cl- fluxes in epithelial cells.

* This work was supported in part by National Institutes of Health Grant DK 46433 and a grant from the Caroline Spahn Halfter Trust Genetic Research Fund.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed. Tel.: 919-541-2630; Fax: 919-541-0559; E-mail: ho1@niehs.nih.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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