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σ-1 Receptors (σ1 Binding Sites) Form Raft-Like Microdomains and Target Lipid Droplets on the Endoplasmic Reticulum: Roles in Endoplasmic Reticulum Lipid Compartmentalization and Export
Abstract
The brain sigma-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 sigma-1 receptors specifically target lipid storage sites (lipid droplets) on the endoplasmic reticulum by forming a distinct class of lipid microdomains. Both endogenously expressing sigma-1 receptors and transfected C-terminally enhanced yellow fluorescent protein (EYFP)-tagged sigma-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). sigma-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 sigma-1 receptors is truncated, sigma-1 receptors no longer exist on ER-LDs, but predominantly target c-LDs, which contain ADRP. sigma-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 sigma-1 receptors to disappear from the microdomains. N-Terminally EYFP-tagged sigma-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, sigma-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.
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“Interestingly, SIGMAR1 appears to promote the compartmentalization of cholesterol in ER membranes (158), although depletion of cholesterol promoted mitochondrial–ER association in in vitro membrane association assays and cell models (159).”
From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [158]
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Metadata
- Authors
- Hayashi, T., & Su, T.-P.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Su, Tsung-Ping
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 306
- Issue
- 2
- Pages
- 718-725
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2156975935
- Cited by
- 262
- References
- 41
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 6 · 2023: 14 · 2022: 5 · 2021: 25 · 2020: 13 · 2019: 9 · 2018: 6 · 2017: 13 · 2016: 12 · 2015: 12 · 2014: 18 · 2013: 11 · 2012: 12
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
- Keywords
- sigma-1 receptor, lipid rafts, lipid droplets, endoplasmic reticulum, caveolin-2, ADRP, pentazocine, neutral lipids, cholesterol, neurosteroids, NG108-15 cells
- MeSH terms
- Sigma-1 Receptor, Animals, Bacterial Proteins, Binding Sites, Endoplasmic Reticulum, Guinea Pigs, Hybridomas, Intracellular Membranes, Luminescent Proteins, Tumor Cells, Cultured, Protein Structure, Tertiary, Receptors, sigma, Mice, Rats
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