Premium
Sigma‐1 receptors regulate hippocampal dendritic spine formation via a free radical‐sensitive mechanism involving Rac1·GTP pathway
Author(s) -
TSAI SHANGYI ANNE,
HAYASHI TERUO,
HARVEY BRANDON K,
WANG YUN,
WU WELL W,
SHEN RONGFENG,
ZHANG YONGQING,
BECKER KEVIN G,
HOFFER BARRY J,
SU TSUNGPING
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb139
Subject(s) - microbiology and biotechnology , dendritic spine , chemistry , rac1 , sigma 1 receptor , gene knockdown , endoplasmic reticulum , signal transduction , hippocampal formation , biology , receptor , apoptosis , biochemistry , neuroscience , agonist
Sigma‐1 receptors (Sig‐1Rs) are endoplasmic reticulum (ER)‐resident proteins known to involve in learning and memory. This study tested if 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 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. Microarray analyses indicate Sig‐1R knockdown highly correlate to oxidative stress response pathways. The application of a hydroxyl free radical scavenger N‐acetyl cysteine (NAC) to the Sig‐1R‐knockdown neurons rescues dendritic spines and mitochondria from deficits caused by the 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, and constitutively active Rac1·GTP also rescues the siRNA‐caused dendritic spine deficits, respectively. These results implicate Sig‐1Rs as endogenous key regulators in hippopcampal synaptic plasticity and suggest a free radical‐sensitive ER‐mitochondrion‐Rac1·GTP pathway in the regulations of dendritic spine formation in the hippocampus.