Glutamate receptors: RNA editing and death of motor neurons

  title={Glutamate receptors: RNA editing and death of motor neurons},
  author={Yukio Kawahara and Kyoko Ito and Hui Sun and Hitoshi Aizawa and Ichiro Kanazawa and Shin Kwak},
The aetiology of sporadic amyotrophic lateral sclerosis (ALS), a fatal paralytic disease, is largely unknown. Here we show that there is a defect in the editing of the messenger RNA encoding the GluR2 subunit of glutamate AMPA receptors in the spinal motor neurons of individuals affected by ALS. This failure to swap an arginine for a glutamine residue at a crucial site in the subunit, which occurs normally in the affected brain areas of patients with other neurodegenerative diseases, will… 
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Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons
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Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS
The first quantitative measurements of the expression profile of AMPA receptor subunits mRNAs in human single neurons are provided by means of quantitative RT–PCR with a laser microdissector, showing that among the AMPA subunits, GluR2 shared the vast majority throughout the neuronal subsets and tissues examined.
Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis
The decrement of GluR2 mRNA editing efficiency is unique to the ventral gray of ALS cases and may be closely linked to the etiology of ALS.
Early-Onset Epilepsy and Postnatal Lethality Associated with an Editing-Deficient GluR-B Allele in Mice
The arginine residue at position 586 of the GluR-B subunit renders heteromeric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptor channels impermeable to calcium.
Neurological dysfunctions in mice expressing different levels of the Q/R site–unedited AMPAR subunit GluR–B
Mouse mutants with targeted AMPA receptor GluR–B subunit alleles, functionally expressed at different levels and deficient in Q/R–site editing have mild to severe neurological dysfunctions, including epilepsy and deficits in dendritic architecture.
Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2
It is concluded that this transcript is the physiologically most important substrate of ADAR2, as it specifies an ion channel determinant, the Q/R site, in AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor GluR-B pre-messenger RNA.
Low editing efficiency of GluR2 mRNA is associated with a low relative abundance of ADAR2 mRNA in white matter of normal human brain
The results suggest that Q/R site of GluRs editing is regulated in a regional, and hence presumably cell‐specific, manner and that the GluR2 Q/ R site editing is critically regulated by ADAR2 in human brain.