title: Sigma-1 receptors potentiate epidermal growth factor signaling towards neuritogenesis in PC12 cells: potential relation to lipid raft reconstitution.
abstract: We previously demonstrated that overexpression of sigma-1 receptors (sigma-1R) potentiated neurite sprouting caused by nerve growth factor in PC12 cells (Takebayashi et al. 2002 J Pharmacol Exp Ther 202:1227-1237). In this study we examined if sigma-1R may be involved in the action of epidermal growth factor (EGF). EGF is conventionally recognized as a mitogenic factor that stimulates only the proliferation of various types of cells, including PC12 cells. We found here that in sigma-1 receptor-overexpressing PC12 cells (sigma-1R OE cells), EGF markedly stimulates neuritogenesis without affecting cellular proliferation. EGF receptors (EGFR) are largely reduced in lipid rafts and are enriched in non-raft regions in sigma-1R OE cells. The enrichment of EGFR in the non-raft region is correlated with enhanced downstream signaling of EGFR including the phosphorylation of both EGFR and extracellular signal-regulated kinases (ERKs). Destruction of cholesterol-containing rafts by treating cells with methyl-beta-cyclodextrin also causes a reduction of EGFR in lipid rafts, a concomitant increase in the phosphorylation of both EGFR and ERK, and an increase in the EGF-induced neurite sprouting in wildtype cells. Furthermore, while overexpression of sigma-1R increases the level of lipid raft-associated cholesterol, the overexpression alters the levels of gangliosides in lipid rafts: GM1 and GM2 are decreased, whereas GD1a is increased. We conclude that sigma-1R cause the remodeling of lipid rafts, at least by increasing the level of lipid raft-associated cholesterol and by altering the levels of certain critical lipid raft-forming gangliosides. sigma-1R may thus play an important role in directing EGF signaling towards neuritogenesis, perhaps by shifting EGFR from the lipid raft into non-raft regions.
authors.affiliation: Cellular Pathobiology Unit, Development and Plasticity Section, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health/DHHS, Baltimore, Maryland, USA.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takebayashi
authors.forename: Teruo
authors.initials: T
authors.lastname: Hayashi
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
mesh_terms: D000818:Animals; D004815:Epidermal Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D021962:Membrane Microdomains / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016501:Neurites / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D017480:Receptors, sigma / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000097605:Sigma-1 Receptor
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor