Department of Anesthesiology

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Activation of brain protein phosphatase-1(I) following cardiac arrest and resuscitation involving an interaction with 14-3-3 gamma.

TitleActivation of brain protein phosphatase-1(I) following cardiac arrest and resuscitation involving an interaction with 14-3-3 gamma.
Publication TypeJournal Article
Year of Publication2008
AuthorsPlatholi J, Heerdt PM, Tung HYLim, Hemmings HC
JournalJ Neurochem
Volume105
Issue5
Pagination2029-38
Date Published2008 Jun
ISSN1471-4159
Keywords14-3-3 Proteins, Amino Acid Sequence, Animals, Brain, Enzyme Activation, Female, Heart Arrest, Humans, Molecular Sequence Data, Protein Phosphatase 1, Resuscitation, Signal Transduction, Swine
Abstract

The intracellular signaling mechanisms that couple transient cerebral ischemia to cell death and neuroprotective mechanisms provide potential therapeutic targets for cardiac arrest. Protein phosphatase (PP)-1 is a major serine/threonine phosphatase that interacts with and dephosphorylates critical regulators of energy metabolism, ionic balance, and apoptosis. We report here that PP-1(I), a major regulated form of PP-1, is activated in brain by approximately twofold in vivo following cardiac arrest and resuscitation in a clinically relevant pig model of transient global cerebral ischemia and reperfusion. PP-1(I) purified to near homogeneity from either control or ischemic pig brain consisted of the PP-1 catalytic subunit, the inhibitor-2 regulatory subunit, as well as the novel constituents 14-3-3gamma, Rab GDP dissociation protein beta, PFTAIRE kinase, and C-TAK1 kinase. PP-1(I) purified from ischemic brain contained significantly less 14-3-3gamma than PP-1(I) purified from control brain, and purified 14-3-3gamma directly inhibited the catalytic subunit of PP-1 and reconstituted PP-1(I). These findings suggest that activation of brain PP-1(I) following global cerebral ischemia in vivo involves dissociation of 14-3-3gamma, a novel inhibitory modulator of PP-1(I). This identifies modulation of PP-1(I) by 14-3-3 in global cerebral ischemia as a potential signaling mechanism-based approach to neuroprotection.

DOI10.1111/j.1471-4159.2008.05300.x
Alternate JournalJ. Neurochem.
PubMed ID18284617
Grant ListR01 NS056315 / NS / NINDS NIH HHS / United States