ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia.
ADAR2 is a nuclear enzyme essential for GluR2 pre-mRNA editing at Q/R site-607, which gates Ca2+ entry through AMPA receptor channels. Here, we show that forebrain ischemia in adult rats selectively reduces expression of ADAR2 enzyme and, hence, disrupts RNA Q/R site editing of GluR2 subunit in vulnerable neurons. Recovery of GluR2 Q/R site editing by expression of exogenous ADAR2b gene or a constitutively active CREB, VP16-CREB, which induces expression of endogenous ADAR2, protects vulnerable neurons in the rat hippocampus from forebrain ischemic insult. Generation of a stable ADAR2 gene silencing by delivering small interfering RNA (siRNA) inhibits GluR2 Q/R site editing, leading to degeneration of ischemia-insensitive neurons. Direct introduction of the Q/R site edited GluR2 gene, GluR2(R607), rescues ADAR2 degeneration. Thus, ADAR2-dependent GluR2 Q/R site editing determines vulnerability of neurons in the rat hippocampus to forebrain ischemia.
Peng
Peter L
PL
Biomolecular Science Center, College of Biomedical Sciences, University of Central Florida, Orlando, Florida 32816, USA.
Zhong
Xiafen
X
Tu
Weihong
W
Soundarapandian
Mangala M
MM
Molner
Peter
P
Zhu
Dongya
D
Lau
Lorraine
L
Liu
Shuhong
S
Liu
Fang
F
Lu
Youming
Y
D000243:Adenosine Deaminase / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D050882:CREB-Binding Protein / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology*; D017393:RNA Editing / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; D049452:Green Fluorescent Proteins; D050882:CREB-Binding Protein; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D010751:Phosphopyruvate Hydratase; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium