QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.051284v1 306/2/718    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hayashi, T. Articles by Su, T.-P. Search for Related Content PubMed PubMed Citation Articles by Hayashi, T. Articles by Su, T.-P.

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

This article has been cited by other articles:

				A. Pal, U. B. Chu, S. Ramachandran, D. Grawoig, L.-W. Guo, A. R. Hajipour, and A. E. Ruoho Juxtaposition of the Steroid Binding Domain-like I and II Regions Constitutes a Ligand Binding Site in the {sigma}-1 Receptor J. Biol. Chem., July 11, 2008; 283(28): 19646 - 19656. [Abstract] [Full Text] [PDF]

				K. T. Tchedre and T. Yorio {sigma}-1 Receptors Protect RGC-5 Cells from Apoptosis by Regulating Intracellular Calcium, Bax Levels, and Caspase-3 Activation Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2577 - 2588. [Abstract] [Full Text] [PDF]

				C. P. Palmer, R. Mahen, E. Schnell, M. B.A. Djamgoz, and E. Aydar Sigma-1 Receptors Bind Cholesterol and Remodel Lipid Rafts in Breast Cancer Cell Lines Cancer Res., December 1, 2007; 67(23): 11166 - 11175. [Abstract] [Full Text] [PDF]

				A. Pal, A. R. Hajipour, D. Fontanilla, S. Ramachandran, U. B. Chu, T. Mavlyutov, and A. E. Ruoho Identification of Regions of the {sigma}-1 Receptor Ligand Binding Site Using a Novel Photoprobe Mol. Pharmacol., October 1, 2007; 72(4): 921 - 933. [Abstract] [Full Text] [PDF]

				G. Cormaci, T. Mori, T. Hayashi, and T.-P. Su Protein Kinase A Activation Down-Regulates, Whereas Extracellular Signal-Regulated Kinase Activation Up-Regulates {sigma}-1 Receptors in B-104 Cells: Implication for Neuroplasticity J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 202 - 210. [Abstract] [Full Text] [PDF]

				D. T. Browman, M. E. Resek, L. D. Zajchowski, and S. M. Robbins Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER J. Cell Sci., August 1, 2006; 119(15): 3149 - 3160. [Abstract] [Full Text] [PDF]

				A. Azzariti, N. A. Colabufo, F. Berardi, L. Porcelli, M. Niso, G. M. Simone, R. Perrone, and A. Paradiso Cyclohexylpiperazine derivative PB28, a {sigma}2 agonist and {sigma}1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer. Mol. Cancer Ther., July 1, 2006; 5(7): 1807 - 1816. [Abstract] [Full Text] [PDF]

				Y. Yagasaki, T. Numakawa, E. Kumamaru, T. Hayashi, T.-P. Su, and H. Kunugi Chronic Antidepressants Potentiate via Sigma-1 Receptors the Brain-derived Neurotrophic Factor-induced Signaling for Glutamate Release J. Biol. Chem., May 5, 2006; 281(18): 12941 - 12949. [Abstract] [Full Text] [PDF]

				W. E. Ackerman IV, J. M. Robinson, and D. A. Kniss Despite Transcriptional and Functional Coordination, Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Largely Reside in Distinct Lipid Microdomains in WISH Epithelial Cells J. Histochem. Cytochem., November 1, 2005; 53(11): 1391 - 1401. [Abstract] [Full Text] [PDF]

				S. Ozeki, J. Cheng, K. Tauchi-Sato, N. Hatano, H. Taniguchi, and T. Fujimoto Rab18 localizes to lipid droplets and induces their close apposition to the endoplasmic reticulum-derived membrane J. Cell Sci., June 15, 2005; 118(12): 2601 - 2611. [Abstract] [Full Text] [PDF]

				T. Hayashi and T.-P. Su Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation PNAS, October 12, 2004; 101(41): 14949 - 14954. [Abstract] [Full Text] [PDF]

				E. Aydar, C. P. Palmer, and M. B. A. Djamgoz Sigma Receptors and Cancer: Possible Involvement of Ion Channels Cancer Res., August 1, 2004; 64(15): 5029 - 5035. [Abstract] [Full Text] [PDF]

				T. Hayashi and T.-P. Su Intracellular Dynamics of {sigma}-1 Receptors ({sigma}1 Binding Sites) in NG108-15 Cells J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 726 - 733. [Abstract] [Full Text] [PDF]