The σ1 receptor regulates accumulation of GM1 ganglioside-enriched autophagosomes in astrocytes

• Published in: Neuroscience Vol. 340; pp. 176 - 187
• Main Authors: Kasahara, Rika, Yamamoto, Naoki, Suzuki, Kenji, Sobue, Kazuya
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 06.01.2017
• Subjects: Animals; Antipsychotic Agents - pharmacology; astrocyte; Astrocytes - drug effects; Astrocytes - metabolism; autophagosome; Autophagosomes - drug effects; Autophagosomes - metabolism; Cells, Cultured; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Dose-Response Relationship, Drug; Ethylenediamines - pharmacology; G(M1) Ganglioside - metabolism; GM1 ganglioside; Haloperidol - pharmacology; Intracellular Space - drug effects; Intracellular Space - metabolism; Neurology; Rats, Sprague-Dawley; Receptors, Dopamine D1 - antagonists & inhibitors; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D4 - antagonists & inhibitors; Receptors, Dopamine D4 - metabolism; Receptors, sigma - agonists; Receptors, sigma - antagonists & inhibitors; Receptors, sigma - metabolism; sigma (σ)-1 receptor; APP; extracellular signal-regulated kinase; Dulbecco’s modified Eagle’s medium; stealth small interfering RNA; CTX-HRP; amyloid β-protein; GM1; PFA; σ1R; phosphate-buffered saline; sigma (σ)-1 receptor; DR; dopamine receptor; detergent-resistant membrane microdomains; Aβ; DMEM; Horseradish peroxidase-cholera toxin B subunit; amyloid precursor protein; FBS; (±)-threo-1-phenyl-2-decanoylamine-3-morpholino-1-propanol hydrochloride; paraformaldehyde; (+)-SK&F 10,047 hydrochloride; PBS; alzheimer disease; AD; SKF10,047; siRNA; Astrocyte; GM1 ganglioside; fetal bovine serum; PDMP; DRMs; Autophagosome; ERK; astrocyte; autophagosome
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2016.10.058

Abstract GM1 gangliosides (GM1) are acidic glycosphingolipids that are present in cell membranes and lipid raft domains, being particularly abundant in central nervous systems. GM1 participate in modulating cell membrane properties, intercellular recognition, cell regulation, and signaling. We previously demonstrated that GM1 are expressed inside astrocytes but not on the cell surface. We investigated whether the antipsychotic drug haloperidol induces GM1 expression in astrocytes, and found that the expression of GM1 was significantly upregulated by haloperidol in the intracellular vesicles of cultured astrocytes. The effects of haloperidol on GM1 expression acted through the σ1 receptor (σ1R), but not the dopamine-2 receptor. Inhibition of the ERK pathway blocked the induction of GM1 through the σ1R by haloperidol. Interestingly, this increase in GM1 expression induced the accumulation of autophagosomes in astrocytes. Moreover, the effect of haloperidol on the σ1R induced a decrease in GM1 in the cellular membrane of astrocytes. These findings suggested that the effects of haloperidol on the σ1R induced GM1 accumulation in the autophagosomes of astrocytes through activating the ERK pathway and a decrease in GM1 expression on the cell surface.