Biology Reference
In-Depth Information
transcript due to loss of a functional ECS region (Lomeli
, 1994). Therefore,
the range of receptor subunits available is considerably increased through alterna-
tive splicing and editing.
The calcium permeability of kainate receptors is also regulated by
editing at the position which corresponds to the Q/R site in the
et al.
tran-
script. Editing of the transcripts encoding the kainate receptor subunits GluR-5
and GluR-6 is both spatially and developmentally regulated, and editing of each
subunit transcript is independent of the other (Bernard and Khrestchatisky,
1994; K¨hler
GluR-B
et al.
, 1993).
2. ADAR2 knockout and transgenic mice
In contrast to the embryonic lethal phenotype of the
Adar2
/
mice survive to birth but die by postnatal day 20 with an increasing predisposi-
tion to epileptic seizures (Higuchi
Adar1
/
gene,
, 2000). The ADAR2-null phenotype
could be completely rescued by a pre-edited version of the endogenous GluR-B
gene in which the genome-encoded glutamine is mutated to arginine. This
indicates that the primary function of ADAR2 is to edit the
et al.
GluR-B Q/R
site
(Higuchi
et al.
, 2000). The rescue also confirmed that there is no obvious role for
the unedited
GluR-B
(
Q
) allele as the rescued mice were phenotypically wild
Adar2
/
mice have reduced editing at the
type. The
site: 10% of
pre-mRNA transcripts were edited but 40% of mature messages were edited in
these mice due to facilitated splicing of the edited
GluR-B Q/R
GluR-B
transcript. ADAR1 is
probably responsible for the residual
site editing as expression of
ADAR1 is unaffected by alterations in ADAR2. Inefficient editing led to
accumulation of unspliced pre-mRNA in the nucleus that retained intron 11
where the ECS is located (Higuchi
GluR-B Q/R
, 2000), and consequentially there was a
fivefold decrease in the amount of mature
et al.
mRNA.
Transgenic mice were generated with an asparagines (N) residue at the
Q/R site to allow mice to live longer and develop more extensive neurodegenera-
tion (Kuner
GluR-B
, 2005). An asparagine residue was chosen as it conferred a
twofold increase in calcium permeability but did not significantly alter the AMPA
channel conductance. Selective death of motor neurons was observed that
increased with age. The motor neuron phenotype was similar to that observed
in a mouse model of familial amyotrophic lateral sclerosis (fALS) in which a
mutation in the superoxide dismutase 1 (
et al.
SOD1
) gene results in selective motor
neuron pathology (Gurney
et al.
, 1994). Indeed, crossing the
GluR-B (N)
mice
with
mutants enhanced the motor neuron degeneration, implicating a role
of GluR-B mediated calcium homeostasis in human motoneuron diseases such as
ALS (Kuner
SOD1
et al.
, 2005).
