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 Ca 2+ 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 vul...

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Veröffentlicht in:	Neuron (Cambridge, Mass.) Mass.), 2006-03, Vol.49 (5), p.719-733
Hauptverfasser:	Peng, Peter L., Zhong, Xiafen, Tu, Weihong, Soundarapandian, Mangala M., Molner, Peter, Zhu, Dongya, Lau, Lorraine, Liu, Shuhong, Liu, Fang, Lu, YouMing
Format:	Artikel
Sprache:	eng
Schlagworte:	Adenosine Deaminase - metabolism Animals Animals, Newborn Blotting, Northern - methods Blotting, Western - methods Brain Calcium - metabolism Cell Count - methods Cell Survival - physiology Cells, Cultured CREB-Binding Protein - metabolism Disease Models, Animal Editing Electric Stimulation - methods Gene expression Gene Expression - drug effects Gene Expression - physiology Green Fluorescent Proteins - metabolism Hippocampus - cytology HUMDISEASE Immunohistochemistry - methods In Vitro Techniques Ischemia Ischemic Attack, Transient - pathology Medical research Membrane Potentials - drug effects Membrane Potentials - physiology Membrane Potentials - radiation effects MOLNEURO Neurons Neurons - cytology Neurons - metabolism Permeability Phosphopyruvate Hydratase - metabolism Prosencephalon - cytology Proteins Rats Receptors, AMPA - metabolism Reverse Transcriptase Polymerase Chain Reaction - methods RNA Editing - physiology RNA, Messenger - biosynthesis RNA, Small Interfering - pharmacology RNA-Binding Proteins SIGNALING Sucrose
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Zusammenfassung:	ADAR2 is a nuclear enzyme essential for GluR2 pre-mRNA editing at Q/R site-607, which gates Ca 2+ 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(R 607), rescues ADAR2 degeneration. Thus, ADAR2-dependent GluR2 Q/R site editing determines vulnerability of neurons in the rat hippocampus to forebrain ischemia.
ISSN:	0896-6273 1097-4199
DOI:	10.1016/j.neuron.2006.01.025