Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line.
Marked reduction of RNA editing at the glutamine (Q)/arginine (R) site of the glutamate receptor subunit type 2 (GluR2) in motor neurons may be a contributory cause of neuronal death specifically in sporadic ALS. It has been shown that deregulation of RNA editing of several mRNAs plays a causative role in diseases of the central nervous system such as depression. We analyzed the effects of eight antidepressants on GluR2 Q/R site-RNA editing in a modified HeLa cell line that stably expresses half-edited GluR2 pre-mRNA. We also measured changes in RNA expression levels of adenosine deaminase acting on RNA type 2 (ADAR2), the specific RNA editing enzyme of the GluR2 Q/R site, and GluR2, in order to assess the molecular mechanism causing alteration of this site-editing. The editing efficiency at the GluR2 Q/R site was significantly increased after treatment with seven out of eight antidepressants at a concentration of no more than 10 microM for 24h. The relative abundance of ADAR2 mRNA to GluR2 pre-mRNA or to beta-actin mRNA was increased after treatment with six of the effective antidepressants, whereas it was unchanged after treatment with milnacipran. Our results suggest that antidepressants have the potency to enhance GluR2 Q/R site-editing by either upregulating the ADAR2 mRNA expression level or other unidentified mechanisms. It may be worth investigating the in vivo efficacy of antidepressants with a specific therapeutic strategy for sporadic ALS in view.
Sawada
Jun
J
Division of Neurology, Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Japan.
Yamashita
Takenari
T
Aizawa
Hitoshi
H
Aburakawa
Yoko
Y
Hasebe
Naoyuki
N
Kwak
Shin
S
D000243:Adenosine Deaminase / Q000096:biosynthesis / Q000235:genetics; D000639:Amitriptyline / Q000008:administration & dosage; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001120:Arginine / Q000378:metabolism; D003521:Cyclopropanes / Q000008:administration & dosage; D003891:Desipramine / Q000008:administration & dosage; D005473:Fluoxetine / Q000008:administration & dosage; D016666:Fluvoxamine / Q000008:administration & dosage; D005973:Glutamine / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007099:Imipramine / Q000008:administration & dosage; D000078764:Milnacipran; D009025:Morpholines / Q000008:administration & dosage; D017374:Paroxetine / Q000008:administration & dosage; D017393:RNA Editing / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D000077593:Reboxetine; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*
D000928:Antidepressive Agents; D003521:Cyclopropanes; D009025:Morpholines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; D005473:Fluoxetine; D005973:Glutamine; D000639:Amitriptyline; D017374:Paroxetine; D000077593:Reboxetine; D001120:Arginine; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D000078764:Milnacipran; D016666:Fluvoxamine; D007099:Imipramine; C104722:glutamate receptor ionotropic, AMPA 2; D003891:Desipramine