RT Journal Article
SR Electronic
T1 σ-1 Receptors (σ<sub>1</sub> Binding Sites) Form Raft-Like  Microdomains and Target Lipid Droplets on the Endoplasmic Reticulum: Roles in  Endoplasmic Reticulum Lipid Compartmentalization and Export
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 718
OP 725
DO 10.1124/jpet.103.051284
VO 306
IS 2
A1 Teruo Hayashi
A1 Tsung-Ping Su
YR 2003
UL http://jpet.aspetjournals.org/content/306/2/718.abstract
AB The brain σ-1 receptors can bind neurosteroids and psychotropic drugs, including neuroleptics and cocaine and are implicated in schizophrenia, depression, and drug dependence. In this study, we found that σ-1 receptors specifically target lipid storage sites (lipid droplets) on the endoplasmic reticulum by forming a distinct class of lipid microdomains. Both endogenously expressing σ-1 receptors and transfected C-terminally enhanced yellow fluorescent protein (EYFP)-tagged σ-1 receptors (Sig-1R-EYFP) target unique “ring-like” structures associated with endoplasmic reticulum reticular networks in NG108-15 cells. The ring-like structures contain neutral lipids and are enlarged by the oleate treatment, indicating that they are endoplasmic reticulum-associated lipid droplets (ER-LDs). σ-1 receptors colocalize with caveolin-2, a cholesterol-binding protein in lipid rafts on the ER-LDs, but not with adipocyte differentiation-related protein (ADRP), a cytosolic lipid droplet (c-LD)-specific protein. When the double-arginine ER retention signal on the N terminus of σ-1 receptors is truncated, σ-1 receptors no longer exist on ER-LDs, but predominantly target c-LDs, which contain ADRP. σ-1 receptors on ER-LDs form detergent-resistant raft-like lipid microdomains, the buoyancy of which is different from that of plasma membrane lipid rafts. (+)-Pentazocine causes σ-1 receptors to disappear from the microdomains. N-Terminally EYFP-tagged σ-1 receptors (EYFP-Sig-1R) failed to target ER-LDs. EYFP-Sig-1R-transfected cells showed an unrestricted distribution of neutral lipids all over the endoplasmic reticulum network, decreases in c-LDs and cholesterol in plasma membranes, and the bulbous aggregation of endoplasmic reticulum. Thus, σ-1 receptors are unique endoplasmic reticulum proteins that regulate the compartmentalization of lipids on the endoplasmic reticulum and their export from the endoplasmic reticulum to plasma membrane and c-LDs. The American Society for Pharmacology and Experimental Therapeutics