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2.3. Arrestins in DA receptor desensitization and
internalization
Several
in vitro
studies support a role for
b
-arrestin 1
38,39
and
b
-arrestin 2 in
D1R, D2R, and D3R desensitization.
4,38-40
Both
b
-arrestin isoforms are
expressed along with DA receptors in striatal neurons.
41
Furthermore, there
is evidence for a role of
b
-arrestin 1 in D2R internalization in striatal neu-
rons.
42,43
However, behavioral studies of the role of
b
-arrestin isoforms have
provided little support for this
in vivo
, since mice lacking either
b
-arrestin
isoform are not hypersensitive to DA receptor agonists or to drugs such
as amphetamine, cocaine, and morphine that exert part of their action by
increasing DA tone. More specifically, mice deficient in
b
-arrestin 1 do
not show any impairment beyond a reduction of cocaine and
apomorphine-induced locomotor responses,
4
while
b
-arrestin 2-deficient
mice show attenuated behavioral responses following amphetamine, mor-
phine and apomorphine administration, and normal or slightly attenuated
responses to cocaine.
44,45
A simplistic interpretation of these data would sug-
gest that
b
-arrestin 1 and 2 are not directly involved in DA receptor desen-
sitization. However, the apparent lack of effect
b
-arrestin also points toward
more complex roles of
b
-arrestins in mediating both DA receptor desensi-
tization and signaling.
2.4. Alternative pathways
Substantial evidence supports a role for
b
-arrestin in the DA-dependent regu-
lation of AKT/glycogen synthase kinase 3 (GSK3) signaling. AKT, also termed
protein kinase B, is involved in cellular processes such as transcription, glucose
metabolism, proliferation, migration, and insulin and neurotrophin res-
ponse via receptor tyrosine kinase (RTK) stimulation.
46-48
Following acti-
vation of RTK and some GPCR, phosphatidylinositol-3-kinase converts
phosphatidylinositol-2-phosphate into phosphatidylinositol-3-phosphate
(PIP3). PIP3 interacts with AKT and initiates its recruitment to the plasma
membrane, where AKT is activated by phosphorylation of residues Thr308
and Ser473 by proline-directed kinase (PDK)1 and PDK2/rictor-mTOR,
respectively.
48,49
Activated AKT phosphorylates in turn several proteins
includingGSK3
50
(
Fig. 11.2
). Originally identified as a component of the insu-
lin signaling pathway, GSK3 is also implicated in a wide range of cellular pro-
cesses, such as embryonic development, cell differentiation and survival, and
Wnt signaling, as well as serotonergic and dopaminergic transmission.
51-54
Two GSK3 isoforms (GSK3
a
and GSK3
b
) are expressed in mammalian cells.
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