Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1·GTP pathway
Open Access
- 29 December 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (52), 22468-22473
- https://doi.org/10.1073/pnas.0909089106
Abstract
Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER)-resident proteins known to be involved in learning and memory. Dendritic spines in hippocampal neurons play important roles in neuroplasticity and learning and memory. This study tested the hypothesis that Sig-1Rs might regulate denritic spine formation in hippocampal neurons and examined potential mechanisms therein. In rat hippocampal primary neurons, the knockdown of Sig-1Rs by siRNAs causes a deficit in the formation of dendritic spines that is unrelated to ER Ca2+ signaling or apoptosis, but correlates with the mitochondrial permeability transition and cytochrome c release, followed by caspase-3 activation, Tiam1 cleavage, and a reduction in Rac1·GTP. Sig-1R-knockdown neurons contain higher levels of free radicals when compared to control neurons. The activation of superoxide dismutase or the application of the hydroxyl-free radical scavenger N-acetyl cysteine (NAC) to the Sig-1R-knockdown neurons rescues dendritic spines and mitochondria from the deficits caused by Sig-1R siRNA. Further, the caspase-3-resistant TIAM1 construct C1199DN, a stable guanine exchange factor able to constitutively activate Rac1 in the form of Rac1·GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1·GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radical-sensitive ER-mitochondrion-Rac1·GTP pathway in the regulation of dendritic spine formation in the hippocampus.This publication has 47 references indexed in Scilit:
- The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor RegulatorScience, 2009
- Convergent CaMK and RacGEF signals control dendritic structure and functionTrends in Cell Biology, 2008
- Probing the Steroid Binding Domain-like I (SBDLI) of the Sigma-1 Receptor Binding Site Using N-Substituted Photoaffinity LabelsBiochemistry, 2008
- The role of the endoplasmic reticulum Ca2+ store in the plasticity of central neuronsTrends in Pharmacological Sciences, 2006
- Neuroprotective effect of N-acetyl cysteine on hypoxia-induced oxidative stress in primary hippocampal cultureBrain Research, 2005
- Lateral Diffusion of Inositol 1,4,5-Trisphosphate Receptor Type 1 Is Regulated by Actin Filaments and 4.1N in Neuronal DendritesOnline Journal of Public Health Informatics, 2004
- Calcium and mitochondriaFEBS Letters, 2004
- The anti-amnesic effects of sigma1 (σ1) receptor agonists confirmed by in vivo antisense strategy in the mouseBrain Research, 2001
- Actin cleavage by CPP-32/apopain during the development of apoptosisOncogene, 1997
- Structural-Functional Correlates of Neuroprotection in the Aging Rabbit by a Calcium Channel Blocker. Nimodipine Reverses Neocortical Dendritic Atrophy and Improves Memory RetentionAnnals of the New York Academy of Sciences, 1995