Abstract
Repeated electroconvulsive seizure (ECS), a model for electroconvulsive therapy (ECT), exerts neuroprotective and proliferative effects in the brain. This trophic action of ECS requires inhibition of apoptotic activity, in addition to activation of survival signals. c-Myc plays an important role in apoptosis of neurons, in cooperation with the Bcl-2 family proteins, and its activity and stability are regulated by phosphorylation and ubiquitination. We examined c-Myc and related proteins responsible for apoptosis after repeated ECS. In the rat frontal cortex, repeated ECS for 10 days reduced the total amount of c-Myc, while increasing phosphorylation of c-Myc at Thr58, which reportedly induces degradation of c-Myc. As expected, ubiquitination of both phosphorylated and total c-Myc increased after 10 days ECS, suggesting that ECS may reduce c-Myc protein level via ubiquitination-proteasomal degradation. Bcl-2 family proteins, caspase, and poly(ADP-ribose) polymerase (PARP) were investigated to determine the consequence of down-regulating c-Myc. Protein levels of Bcl-2, Bcl-X(L), Bax, and Bad showed no change, and cleavage of caspase-3 and PARP were not induced. However, phosphorylation of Bad at Ser-155 and binding of Bad to 14-3-3 increased without binding to Bcl-X(L) after repeated ECS, implying that repeated ECS sequesters apoptotic Bad and frees pro-survival Bcl-XL. Taken together, c-Myc down-regulation via ubiquitination-proteasomal degradation and Bad inactivation by binding to 14-3-3 may be anti-apoptotic mechanisms elicited by repeated ECS in the rat frontal cortex. This finding further supports the trophic effect of ECS blocking apoptosis as a possible therapeutic effect of ECT.
Highlights
Electroconvulsive therapy (ECT) is effective for treating mood disorder and schizophrenia, but the molecular basis for its beneficial effects remains unknown
Our most important finding is that repeated electroconvulsive seizure (ECS) induced the down-regulation of c-Myc via ubiquitination, and the inactivation of Bad by increasing binding with 14-3-3 protein in the rat frontal cortex
Increased phosphorylation at the Thr58 residue and ubiquitination of c-Myc with a reduction in the total amount of c-Myc in response to repeated ECS suggests that ECS may reduce c-Myc protein levels via the ubiquitination-proteasomal degradation process
Summary
Electroconvulsive therapy (ECT) is effective for treating mood disorder and schizophrenia, but the molecular basis for its beneficial effects remains unknown. Madsen et al (2005) demonstrated glial cell proliferation in the rat frontal cortex after repeated ECS, and we reported that repeated ECS activates proliferative signals in the rat frontal cortex, such as the Cdk2-pRB-E2F1 cell cycle pathway and ERK pathway (Kim et al, 2005; Kang et al, 2006). This trophic action of ECS is associated with the activation of intracellular survival signal pathways.
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