Submitted on June 14, 2007
Accepted on January 5, 2008
Superoxide-induced Potentiation in the Hippocampus Requires Activation of Ryanodine Receptor Type 3 and ERK
A. Tara Huddleston1, Wei Tang2, Hiroshi Takeshima3, Susan L. Hamilton2, and Eric Klann4*
1 Neuroscience, Baylor College of Medicine, Houston, Texas, United States
2 Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, Texas, United States
3 Biological Chemistry, Kyoto University, Kyoto, Japan
4 Center for Neural Science, New York University, New York, New York, United States
* To whom correspondence should be addressed. E-mail: eklann{at}cns.nyu.edu.
Reactive oxygen species (ROS) are required for the induction of long-term potentiation (LTP) and behave as signaling molecules, via redox modifications of target proteins. In particular, superoxide, is necessary for induction of LTP and application of superoxide-to hippocampal slices is sufficient to induce long-lasting potentiation in area CA1. Although a rise in postsynaptic intracellular calcium is necessary for LTP induction, superoxide-induced potentiation does not require calcium flux through N-methyl-D-aspartate (NMDA) receptors. Ryanodine receptors (RyRs) mediate calcium-induced calcium release (CICR) from intracellular stores and have been shown to modulate LTP. In this study we investigated the highly redox-sensitive RyRs as a calcium source that might mediate superoxide-induced potentiation. In agreement with previous studies of skeletal and cardiac muscle we found that superoxide enhances activation of RyRs in the mouse hippocampus. We identified RyR3, a subtype enriched in area CA1, as the specific isoform required for superoxide-induced potentiation. Superoxide also enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) phosphorylation in area CA1 and ERK was necessary for superoxide-induced potentiation. Thus, superoxide-induced potentiation requires the redox targeting of RyR3 and the subsequent activation of ERK.
