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Originally published In Press as doi:10.1074/jbc.M203134200 on July 5, 2002

J. Biol. Chem., Vol. 277, Issue 38, 35760-35765, September 20, 2002
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Phospholipase C-gamma Modulates Epithelial Tight Junction Permeability through Hyperphosphorylation of Tight Junction Proteins*

Peter D. WardDagger , Ryan R. Klein§, Matthew D. Troutman§, Shaleish Desai||, and Dhiren R. ThakkerDagger §**

From the Dagger  Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, § Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599,  GlaxoSmithKline, Research Triangle Park, North Carolina 27709, and || Quality Chemical Laboratories, Wilmington, North Carolina 28405

Phospholipase C-gamma (PLC-gamma ) is stimulated by epidermal growth factor via activation of the epidermal growth factor receptors. The PLC inhibitor, 3-nitrocoumarin (3-NC), selectively inhibited PLC-gamma in Madin-Darby canine kidney cells without affecting the activity of PLC-beta . In contrast, inhibitors of PLC-beta , hexadecylphosphocholine and U73122, had no effect on the activity of PLC-gamma . Inhibition of PLC-gamma by 3-NC was associated with an increase in tight junction permeability across Madin-Darby canine kidney cell monolayers, as evidenced by 3-NC-induced decrease in transepithelial electrical resistance and increase in mannitol flux over a concentration range that was inhibitory to PLC-gamma . An analog of 3-NC, 7-hydroxy-3-NC (7-OH-3-NC), which was inactive as an inhibitor of PLC-gamma , also had no effect on tight junction permeability. Treatment with 3-NC caused punctate disruption in the cortical actin filaments. The PLC-gamma inhibitor, 3-NC, but not the inactive analog, 7-OH-3-NC, caused hyperphosphorylation of the tight junction proteins, occludin, ZO-1, and ZO-2. The serine/threonine kinase inhibitor, staurosporine (50-200 nM), significantly attenuated 3-NC-induced hyperphosphorylation of ZO-2. This corresponded with attenuation by staurosporine of 3-NC-induced increase in tight junction permeability, suggesting a relationship between ZO-2 phosphorylation and tight junction permeability.

* This work was supported by PhRMA Foundation in the form of a Predoctoral Fellowship (to P. W.) and by GlaxoWellcome (unrestricted gift).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: School of Pharmacy, CB#7360, Beard Hall, University of North Carolina, Chapel Hill, NC 27599-7360. Tel.: 919-962-0092; Fax: 919-966-0197; E-mail: dhiren_thakker@unc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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