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NEUROPHARMACOLOGY

Intracellular Dynamics of -1 Receptors (₁ Binding Sites) in NG108-15 Cells

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 -1 receptors bind diverse kinds of psychoactive compounds, including cocaine, and translocate upon stimulation by these compounds. However, the exact intracellular localization and dynamics of -1 receptors have been unclear. We recently found that -1 receptors specifically localize on cholesterol-enriched loci on the endoplasmic reticulum (ER) membrane that function as neutral lipid storage sites (i.e., ER lipid droplets or ER-LDs) from which neutral lipids bud out to form cytosolic lipid droplets. By combining immunocytochemistry and real-time monitoring of enhanced yellow fluorescent protein (EYFP)-tagged -1 receptors (Sig-1R-EYFP) in living cells, we characterized the -1 receptor translocation in this study. (+)-Pentazocine, a selective -1 receptor agonist, causes a significant decrease of -1 receptors in ER-LDs and a diffused distribution of -1 receptors over the entire endoplasmic reticulum reticular network in NG108-15 cells. In the presence of -1 receptor agonists, Sig-1R-EYFP move out from ER-LDs and slide along the endoplasmic reticulum network toward nuclear envelope and the tip of neurites. Fluorescence recovery after photobleaching analysis demonstrates that Sig-1R-EYFP on endoplasmic reticulum reticular network are highly mobile compared with those in ER-LDs. A sucrose gradient fractionation study shows that (+)-pentazocine shifts -1 receptors from ER-LD membranes to higher density membranes. These results indicate that -1 receptors localize on ER-LDs and upon stimulation translocate on continuous endoplasmic reticulum reticular network toward peripheries of cells. Because -1 receptors specifically target ER lipid storage sites and compartmentalize neutral lipids therein, these results suggest that -1 receptors' dynamic translocation might affect lipid transport and distribution in neuronal cells.

Address correspondence to: Dr. Tsung-Ping Su, Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, TRIAD Bldg., 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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