title: Agonist-induced down-regulation of AMPA receptors in oligodendrocyte progenitors.
abstract: Prolonged exposure of oligodendrocyte progenitor cultures to non-toxic concentrations of glutamate receptor agonists for 24 h decreased cellular proliferation mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Since prolonged agonist stimulation can regulate the expression of various families of receptors, we examined this possibility. Pretreatment of progenitor cultures with 100 μM kainic acid (KA) for 1-24 h caused a time-dependent decrease in AMPA receptor activity, determined by agonist-induced (45)Ca(2+) uptake. The maximum effect (70-80% decrease), observed in the 24 h-pretreated cells, was accompanied by a significant reduction in AMPA receptor subunits, as determined by Western blotting. GluR2/3 and GluR4 subunits were the most affected. Receptor down-regulation and (45)Ca(2+) uptake were only partially reversible upon KA removal. Furthermore, 24 h co-treatment of cultures with CNQX blocked the KA-induced decreases in calcium uptake. To address whether calpain, a calcium-activated protease, was implicated in the regulation of the AMPA receptor subunits, cultures were treated with the specific inhibitor PD150606 alone or in combination with KA for 24 h. Calpain inhibition significantly increased GluR1 in both conditions and partly reversed downregulation of GluR4 by KA. Collectively, these results indicate that calpain is not involved in the agonist-induced down-regulation of AMPA receptors subunits 2/3 in oligodendrocyte progenitors, while it downregulates GluR1 and GluR4.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Shireen
authors.initials: S
authors.lastname: Hossain
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Hsueh-Ning
authors.initials: HN
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Fragoso
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada. Electronic address: guillermina.almazan@mcgill.ca.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Almazan
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000179:Acrylates / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000179:Acrylates; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C100442:PD 150606; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D002154:Calpain; D007608:Kainic Acid; D002118:Calcium; C108823:metabotropic glutamate receptor 4
keywords: AMPA receptors; Calpain; Extracellular calcium; Glutamate; Kainate; Oligodendrocytes; Receptor downregulation