Title | Activation of brain protein phosphatase-1(I) following cardiac arrest and resuscitation involving an interaction with 14-3-3 gamma. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Platholi J, Heerdt PM, Tung HYLim, Hemmings HC |
Journal | J Neurochem |
Volume | 105 |
Issue | 5 |
Pagination | 2029-38 |
Date Published | 2008 Jun |
ISSN | 1471-4159 |
Keywords | 14-3-3 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. |
DOI | 10.1111/j.1471-4159.2008.05300.x |
Alternate Journal | J Neurochem |
PubMed ID | 18284617 |
PubMed Central ID | PMC3872065 |
Grant List | R01 NS056315 / NS / NINDS NIH HHS / United States |