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Protein Kinase C Signaling in Neurodegeneration

Kumar, Varun
http://orcid.org/0000-0001-6867-494X
http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051

Abstract Details

2016, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Global cerebral ischemia occurs due to cardiac arrest, which results in delayed neurodegeneration. Pharmacological agents such as Protein Kinase C epsilon (PKC epsilon) peptide activators when applied before ischemia are known to confer neuroprotection against ischemia-induced cell death. However, the occurrence of cardiac arrest or cerebral ischemia is unpredictable. Thus, therapeutic targets that can be applied after ischemia have to be unraveled. Moreover, the effect of PKC epsilon deletion after global cerebral ischemia has not been studied yet. Therefore, we have studied the effect of PKC epsilon deletion after global cerebral ischemia. Using mouse model of global cerebral ischemia, we found that hippocampal neurodegeneration was significantly reduced in knock-out (KO) mice compared with PKC epsilon wild-type (WT) mice three days after ischemia. To determine the mechanisms underlying the role of PKC epsilon in ischemia-induced neurodegeneration, we have investigated the role of activating transcription factor 2 (ATF2) and found that PKC epsilon regulates the subcellular localization of ATF2 via Threonine 52 (Thr52) phosphorylation and mediates apoptosis in hippocampal neurons. This study will give insight into the role of PKC epsilon-ATF2 signaling and other PKC isozymes in hippocampal neurons after global cerebral ischemia. PKC delta, another member of novel PKC family, has been implicated in stroke-reperfusion injury. To better study the role of PKC delta in normal function and disease, we have developed an ATP analog-specific PKC delta (AS-PKC delta) that is sensitive to specific kinase inhibitors and can be used to identify PKC delta substrates. To understand the mechanisms for specificity and affinity of these analogs, we have created in silico WT and AS-PKC delta homology models based on the crystal structure of Protein Kinase C iota (PKC iota). N6-(benzyl)-ATP and ATP showed similar positioning within the purine binding pocket of AS-PKC delta, while N6-(benzyl)-ATP was displaced from the pocket of WT-PKC delta and was unable to interact with the glycine-rich loop that is required for phosphoryl-transfer. The adenine ring of 1NA-PP1 and 2MB-PP1 matched the adenine ring of ATP when docked in AS-PKC delta and this interaction prevented the potential binding of ATP with Lys-378, Glu-428, and Leu-430 residues. 1NA-PP1 failed to effectively dock within WT-PKC delta. Moreover, other PP1 analogs failed effectively to interact with either AS-PKC delta or WT-PKC delta. These results provide a structural basis for the ability of AS-PKC delta to efficiently and specifically utilize N6-(benzyl)-ATP as a phosphate donor, and for its selective inhibition by 1NA-PP1 and 2MB-PP1. Such homology modeling could prove useful in designing molecules to target PKC delta and other kinases to understand their function in cell signaling and to identify unique substrates.
Wen-Hai Chou, PhD (Advisor)
Srinivasan Vijayaraghavan, PhD (Committee Member)
Alexander L. Mdzinarishvili, PhD (Committee Member)
Werner J. Geldenhuys, PhD (Committee Member)
Gail C. Fraizer , PhD (Committee Member)
105 p.
Neurobiology
PKC, Neurodegeneration, ATF2

Recommended Citations

Citations

  • Kumar, V. (2016). Protein Kinase C Signaling in Neurodegeneration [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051

    APA Style (7th edition)

  • Kumar, Varun. Protein Kinase C Signaling in Neurodegeneration. 2016. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051.

    MLA Style (8th edition)

  • Kumar, Varun. "Protein Kinase C Signaling in Neurodegeneration." Doctoral dissertation, Kent State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051

    Chicago Manual of Style (17th edition)

kent1455721051
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© 2016, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.