Superoxide-Induced Potentiation in the Hippocampus Requires Activation of Ryanodine Receptor Type 3 and ERK

Abstract

Huddleston AT, Tang W, Takeshima H, Hamilton SL, Klann E. Superoxide-induced potentiation in the hippocampus requires activation of tyanodine receptor type 3 and ERK. J Neurophysiol 99: 1565-1571, 2008. First published January 16, 2008 doi:10.1152/jn.00659.2007. Reactive oxygen species (ROS) are required for the induction of longterm 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 LTP 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 from intracellular stores and have been shown to modulate LTP. In this study, we investigated the highly redox-sensitive RyRs and L-type calcium channels as calcium sources 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 a functional coupling between L-type voltage-gated calcium channels and RyRs and 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) 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.

NADPH Oxidase-Dependent Regulation of T-Type Ca2+Channels and Ryanodine Receptors Mediate the Augmented Exocytosis of Catecholamines from Intermittent Hypoxia-Treated Neonatal Rat Chromaffin Cells

“…Blockade of RyRs restored basal [Ca 2ϩ ] i levels in IH cells to levels seen in control cells, implying that constitutive activation of RyRs mediates the elevated basal [Ca 2ϩ ] i levels in IH cells. We further demonstrate that IH leads to NOX/ROSdependent S-glutathionylation of RyR2, which is known to constitutively activate RyRs (Murayama et al, 1999;Zissimopoulos and Lai, 2006;Bull et al, 2008;Huddleston et al, 2008;Belevych et al, 2009). These observations taken together demonstrate that NOX/ROS signaling activates RyRs by transcriptional upregulation as well as by posttranslational modifications involving S-glutathionylation in IH-treated neonatal chromaffin cells resulting in constitutive activation of RyRs.…”

“…Previous studies have shown that posttranslational redox modulation involving S-glutathionylation of cysteine residues activate RyRs under basal conditions (Murayama et al, 1999;Bull et al, 2008;Huddleston et al, 2008;Terentyev et al, 2008). To examine whether IH induces similar posttranslational modification of RyRs, adrenal chromaffin cell lystes were probed with anti-glutathionylated antibody and analyzed by immunoblot assay.…”

“…However, the source(s) of intracellular Ca 2ϩ stores and the mechanism by which IH mobilizes Ca 2ϩ stores has not been explored. Ryanodine receptors (RyRs) are one of the major regulators of mobilization of intracellular Ca 2ϩ stores (Simpson et al, 1995;Alonso et al, 1999), and ROS are potent activators of RyRs (Murayama et al, 1999;Zissimopoulos and Lai, 2006;Bull et al, 2008;Huddleston et al, 2008;Belevych et al, 2009). Therefore, in the present study, we examined the impact of neonatal IH on T-type Ca 2ϩ channels and RyRs expression in adrenal chromaffin cells and determined their roles in neurotransmitter release.…”

Glutathionylation of the Aquaporin-2 Water Channel

“…Mitochondria are also deeply involved in calcium homeostasis because they promote ER depletion by calcium buffering. Importantly, mitochondria calcium uptake stimulates ROS production, which plays a role in modulating ER and cytosolic calcium concentration (26) by affecting the activity of pivotal calcium signaling proteins via S-glutathionylation (20). We found that expression hCaSR-wt, hCaSR-R990G, and hCaSR-N124K not only reduced intracellular calcium level (13) but is also accompanied by a significant decrease of AQP2 S-glutathionylation secondary to a decrease of ROS content, which is associated to a relevant decrease of NADPH oxidase activity.…”

Oxidative Stress and Neurodegenerative Disorders

“…Incubation of hippocampal slices with exogenous superoxide dismutase (SOD) attenuates LTP [47]. ROS can induce LTP by modulating the activity of a number of protein kinases such as PKA, PKC, CaMKII and ERK [48][49][50]. In addition, ROS can also induce LTP through suppression of the activity of a number of protein phosphatases, such as protein tyrosine phosphatase, protein phosphatase 2A and calcineurin [48].…”