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NEUROPHARMACOLOGY
-1 Receptors (1 Binding Sites) Form Raft-Like Microdomains and Target Lipid Droplets on the Endoplasmic Reticulum: Roles in Endoplasmic Reticulum Lipid Compartmentalization and Export
Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health. Department of Health and Human Services, Baltimore, Maryland
The brain 
-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 -1
receptors specifically target lipid storage sites (lipid droplets) on the
endoplasmic reticulum by forming a distinct class of lipid microdomains. Both
endogenously expressing -1 receptors and transfected C-terminally
enhanced yellow fluorescent protein (EYFP)-tagged -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). -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 -1 receptors is truncated, -1 receptors no longer
exist on ER-LDs, but predominantly target c-LDs, which contain ADRP. -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 -1 receptors to disappear from the microdomains.
N-Terminally EYFP-tagged -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, -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.
Address correspondence to: Dr. Tsung-Ping Su, Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Dr., Baltimore, MD 21224. E-mail: tsu{at}intra.nida.nih.gov
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