Direct and reversible inhibition of brain protein phosphatase 2A by the cellular oxidant glutathione disulfide

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Title	Direct and reversible inhibition of brain protein phosphatase 2A by the cellular oxidant glutathione disulfide
Abstract	Increases in protein phosphorylation may underlie cellular response and adaptation to oxidative stress. The key oxidant(s) which signal these changes and the mechanisms by which oxidants stimulate protein phosphorylation are poorly understood. The present study investigated the effects of the cellular oxidant glutathione disulfide (GSSG), which is produced during oxidative stress, on the activity of protein phosphatase 2A (PP2A) in soluble fractions from rat brain, immune complexes, and purified from rabbit muscle. GSSG inhibited the activity of all three forms of PP2A. Moreover, inhibition of the brain soluble PP2A and rabbit muscle PP2A activities by GSSG was reversed by addition of the thiol-reducing agent dithiothreitol (DTT). The reversal of inhibition by DTT provides strong support for the view that GSSG inhibited PP2A activity by a mechanism involving disulfide bond formation. Furthermore, the ability of GSSG to inhibit the activity of the immune complex PP2A and purified PP2A argues that inhibition resulted from a direct reaction of GSSG with PP2A. The possibility that PP2A contains neighboring cysteine thiols capable of undergoing cross-linking was examined by using the thiol reagent phenylarsine oxide (PAO), which has a high affinity for vicinal thiols. Very low, micromolar concentrations of PAO inhibited PP2A activity in the brain soluble fraction as well as the immune complex PP2A. The potency of the inhibition of PP2A activity by PAO is consistent with the presence of neighboring cysteine residues on PP2A, which, importantly, could undergo cross-linking to form an intraprotein disulfide bond following exposure to GSSG. The present study provides a possible link between increases in GSSG and increases in protein phosphorylation in the cell under conditions of oxidative stress.
Creator	Petro, Laura A.
Degree	Master of Arts in Biochemistry
Department	Chemistry
Advisory Committee	Foley, Timothy Rusak, David A. Baumann, Christopher A.
Geographic Location	Scranton Pennsylvania
Publisher	The University of Scranton
Place of Publication	Scranton Pennsylvania
Date Created	2004-07-19
Academic Year	2003-2004
Decade	2000-2009
Type	Text
Language	eng
Rights	The author of this work retains the copyright. The author has granted to The University of Scranton a non-exclusive license to preserve and make the thesis available in the Electronic Theses Archives, with access open to the public. The author's signed Electronic Thesis Approval Form is on file in the Weinberg Memorial Library Digital Services Department.
Subject Keywords	Thesis Masters Chemistry
LCSH	Phosphoprotein phosphatases Brain -- Physiological aspects
Source	University of Scranton Archives
Collection	University of Scranton Masters Theses
Format	application/pdf
Date Digitized	2009-05-15
Access Rights	Public
Host	The University of Scranton Weinberg Memorial Library

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Direct and reversible inhibition of brain protein phosphatase 2A by the cellular oxidant glutathione disulfide

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