Angiotensin Type-2 (At2) Receptor Modulation of Nmda-Mediated Current, Signaling and Apoptosis
Andres, Robert Douglas
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https://hdl.handle.net/2142/86311
Description
Title
Angiotensin Type-2 (At2) Receptor Modulation of Nmda-Mediated Current, Signaling and Apoptosis
Author(s)
Andres, Robert Douglas
Issue Date
2008
Doctoral Committee Chair(s)
Cameron, Jo Ann
Department of Study
Cell and Developmental Biology
Discipline
Cell and Developmental Biology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Cell
Language
eng
Abstract
In the current study, we examined whether treatment with Ang II regulates NMDA-mediated current, signaling and apoptosis. Western blot analysis revealed that Ang II, acting primarily through AT2 receptor activation of the protein phosphatase 2A (PP2A), attenuated NMDA-mediated increases in extracellular regulated kinase-2 (ERK-2) activity. We have identified that AT2 receptor activation inhibits cleavage of the DNA repair enzyme poly-(ADP-ribose) polymerase (PARP) following treatment with NMDA. Inhibition of ERK with MEK inhibitors (PD98059 and U0126) significantly decreased PARP cleavage (cPARP), while inhibition of PP2A with 10 nM okadaic acid, significantly increased NMDA-mediated cPARP expression. Further, we demonstrate that the AT2 receptor attenuates NMDA-mediated subunit phosphorylation and current to decrease intracellular Ca2+ levels and subsequent downstream signaling. Taken together these results characterize a novel mechanism for describing the AT2 receptor's neuroprotective functions.
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