Cocaine hijacks sigma-1 receptors from the ER to the nuclear membrane to interact with Nesprins/Sun2/lamina complex: Effect on MeCP2 gene expression

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NIDA	MOLBIO-2

* FARE Award Winner

Authors

• CY Chuang
• SY Tsai
• T Hayashi
• JJ Hung
• WC Chang
• TP Su

Abstract

The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER)-resident non-opioid receptor that is expressed in the nervous system and can regulate cellular differentiation, neuroplasticity, and neuroprotection. Nuclear lamins in the nucleus are essential for the nuclear envelope assembly, DNA synthesis, and gene transcription. We tested here the hypothesis that cocaine, via Sig-1Rs, may affect the gene expression of methyl CpG binding protein 2 (MeCP2) which relates to cocaine addiction. In glial and neuroblastoma, NG108-15, cells, cocaine increases the nuclear envelope invaginations (NEI) and grooving, suggesting that the nuclear-cytoplasmic exchange is enhanced by cocaine. Confocal microscopic data show that cocaine and another Sig-1R agonist dehydroepiandrosterone sulfate (DHEA-S) cause the translocation of Sig-1Rs from the ER into the nuclear membrane. After cocaine treatment, Sig-1Rs localize mainly in the envelope of the nucleus and could increase the chance to interact with Nesprin1/3, Sun2, and lamins. Cocaine is known to cause addictive behavior by upregulating (MeCP2) in the brain. In rat primary cortical neurons, cocaine causes an increase in MeCP2. This effect is antagonized by Sig-1R antagonist BD1063. Our results suggest that Sig-1Rs could play an important role to increase MeCP2 gene expression by its nuclear envelope translocation to facilitate the Sig-1R-Nesprins/Sun/lamina interaction.

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