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1. Editing of glutamate receptor transcripts by ADAR2
Although the biological role of ADAR1 is unclear, ADAR2 is a genuine RNA-
editing enzyme with a clearly defined key target. ADAR2 is expressed in many
tissues yet the transcripts it specifically edits are expressed within the CNS. The
critical site that it edits is the Q/R site in the transcript encoding subunit B of the
glutamate-gated ion channel receptor (GluR-B also referred to as GluR2). Iono-
tropic glutamate receptors are subdivided into three groups according to the
synthetic agonists that they bind to:
-amino-3-hydroxy-5-methylisoxasole-4-
propionate (AMPA),
-methyl- D -aspartic acid (NMDA), and kainite receptors.
Pre-mRNAs encoding both the AMPA and kainite receptor subunits are edited
leading to variation at key residues within the receptor subunits (Table 3.1).
AMPA receptors mediate fast excitatory synaptic transmission and characteristi-
cally have low calcium permeability. The glutamate receptor is a tetramer
composed of GluR subunits which are GluR-A, GluR-B, GluR-C, or GluR-D.
If the GluR-B subunit is present, then the receptor is impermeable to calcium.
The position that regulates the calcium permeability is the Q/R site and
this is edited by ADAR2. Editing changes the genomically encoded glutamine
(Q) at position 607 to an arginine (R) residue (Higuchi
N
et al.
, 1993; Sommer
et al.
,
1991). Editing of the Q/R site occurs to
99% in the mouse and human CNS.
Thus, one site-specific RNA-editing event has great functional importance for
neuronal calcium homeostasis. Despite sharing considerable sequence and struc-
tural homology, the other three GluR subunit transcripts A, C, and D (also
referred to as GluR1, 3, and 4) do not undergo editing at the Q/R site and retain
a glutamine at the corresponding amino acid and are calcium permeable. Editing
at the Q/R site also results in retention of the GluR-B subunit with the endoplas-
mic reticulumER, while the unedited GluR-B (Q) subunit is efficiently assembled
into receptors and transported to the cell surface (Greger
>
, 2002, 2003). ER
retention is thought to promote inclusion of the GluR-B (R) subunit into hetero-
tetramers, whereas GluR-B (Q) subunits more readily form homotetramers
(Greger
et al.
, 2003). Therefore, RNA processing events determine the kinetics
and assembly of AMPA receptors at the synapse and if editing is prevented at this
position then this leads to increased intracellular levels of calcium and neuronal
cell death.
There is editing at another position in the
et al.
transcript which is
adjacent to the alternatively spliced FLIP/FLOP exons. Editing results in a change
from the genomically encoded arginine to a glycine residue (R/G site). The
resulting glycine substitution increases the rate of recovery of the channel from
desensitization (Lomeli
GluR-B
, 1994). Editing at the R/G site is performed by both
ADAR1 and ADAR2, and occurs at low levels during development increasing to
approximately 75% in adult mouse brain. The same position (R/G) is also edited
in
et al.
GluR-C
and
GluR-D
transcripts; however, it is absent from the
GluR-A
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