The σ1 receptor regulates accumulation of GM1 ganglioside-enriched autophagosomes in astrocytes.
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.
Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.
Rika
R
Kasahara
Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan; Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa 920-1181, Japan. Electronic address: na-yamam@hokuriku-u.ac.jp.
Naoki
N
Yamamoto
Laboratory of Molecular Medicinal Science, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan.
Kenji
K
Suzuki
Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8622, Japan.
Kazuya
K
Sobue
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005029:Ethylenediamines / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D014150:Antipsychotic Agents; D005029:Ethylenediamines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; D050638:Receptors, Dopamine D4; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D005677:G(M1) Ganglioside; D006220:Haloperidol
GM1 ganglioside; astrocyte; autophagosome; sigma (σ)-1 receptor