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σ‐1 Receptors potentiate epidermal growth factor signaling towards neuritogenesis in PC12 cells: Potential relation to lipid raft reconstitution
Author(s) -
Takebayashi Minoru,
Hayashi Teruo,
Su TsungPing
Publication year - 2004
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20041
Subject(s) - lipid raft , neurite , epidermal growth factor , microbiology and biotechnology , phosphorylation , raft , epidermal growth factor receptor , chemistry , signal transduction , receptor , nerve growth factor , biology , biochemistry , in vitro , organic chemistry , copolymer , polymer
We previously demonstrated that overexpression of σ‐1 receptors (σ‐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 σ‐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 σ‐1 receptor‐overexpressing PC12 cells (σ‐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 σ‐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‐β‐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 σ‐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 σ‐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. σ‐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. Synapse 53:90–103, 2004. Published 2004 Wiley‐Liss, Inc.