Publication Date

2008-12-19

Availability

Open access

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2008-11-20

First Committee Member

Vance Lemmon - Committee Chair

Second Committee Member

Robert Keane - Committee Member

Third Committee Member

Nirupa Chaudhari - Committee Member

Fourth Committee Member

John N. Barrett - Mentor

Abstract

The combination of bone morphogenetic protein 7 (BMP7) and neurotrophins (e.g. brain-derived neurotrophic factor, BDNF) protects septal neurons during hypoglycemic stress. I investigated the signaling mechanisms underlying this synergistic protection. BMP7 (5 nM) increased phosphorylation and nuclear translocation of BMP-responsive Smads 1/5/8 within 30 min in cultures of rat embryonic septal neurons. BDNF (100 ng/ml) enhanced the BMP7-induced increase in phospho-Smad levels in both nucleus and cytoplasm; this effect was more pronounced after a hypoglycemic stress. BDNF increased both Akt and Erk phosphorylation, but pharmacological blockade of these kinase pathways (with wortmannin and U0126, respectively) did not reduce the Smad phosphorylation produced by the BMP7+BDNF combination. Inhibitors of casein kinase II (CK2) activity reduced the (BMP7 + BDNF)-induced Smad phosphorylation, and this trophic factor combination increased CK2 activity in hypoglycemic cultures. These findings suggest that BDNF can increase BMP-dependent Smad phosphorylation via a mechanism requiring CK2. Preliminary results indicate that a cytoplasmic component robustly inhibits CK2. Protection of septal cholinergic neurons during a hypoglycemic stress is inhibited by a CK2 inhibitor and by a Phosphatidylinositol 3-kinase inhibitor, indicating that increases in CK2 activity and in Smad phosphorylation are only part on the protective mechanisms.

Keywords

Smad1; BMP7; Septal Neurons; Hypoglycemia; CK2; BDNF

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