Effect of topiramate and dBcAMP on expression of the glutamate transporters GLAST and GLT-1 in astrocytes cultured separately, or together with neurons.
The mechanism of the antiepileptic drug topiramate is not fully understood, but interaction with the excitatory neurotransmission, e.g. glutamate receptors, is believed to be part of its anticonvulsant effect. The glutamate transporters GLAST and GLT-1 are responsible for the inactivation of glutamate as a neurotransmitter and it was therefore investigated if topiramate might affect the expression of GLAST and GLT-1 in astrocytes cultured separately or together with neurons. Since expression and membrane trafficking of glutamate transporters are affected by the protein kinase C system as well as by dBcAMP it was also investigated if these signalling pathways might play a role. In astrocyte cultures expressing mainly GLAST treatment with dBcAMP (0.25 mM) led to an increased expression of the total amount of GLAST as well as of its membrane association. The enhanced expression in the membrane was particularly pronounced for the oligomeric form of GLAST. No detectable effect on the expression of GLAST in astrocytes treated with topiramate in the presence and absence of protein kinase C activators or inhibitors was observed. Astrocytes co-cultured with neurons expressed both GLAST and GLT-1. In these cultures prolonged exposure to 30 muM topiramate (10 days) led to a statistically significant increase (P<0.025) in the membrane expression of GLAST. In case of GLT-1, culture in the presence of 30 microM topiramate for 1 and 10 days led to alterations in the total, cytoplamic and membrane expression of the oligomeric form of the transporter.
Poulsen
C F
CF
Department of Pharmacology and Pharmacotherapy, Danish University of Pharmaceutical Sciences, Copenhagen, DK, Denmark.
Schousboe
I
I
Sarup
A
A
White
H S
HS
Schousboe
A
A
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004622:Embryo, Mammalian / Q000166:cytology; D020536:Enzyme Activators / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000096:biosynthesis*; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D007211:Indoles; D008301:Maleimides; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000077236:Topiramate
C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D000927:Anticonvulsants; D002227:Carbazoles; D020536:Enzyme Activators; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D007211:Indoles; D008301:Maleimides; C493393:Slc1a3 protein, mouse; D000077236:Topiramate; D005632:Fructose; D003994:Bucladesine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate