Biology Reference
In-Depth Information
They are constitutively active and negatively regulated by phosphorylation on
Ser21 for GSK3
a
and Ser9 for GSK3
b
.
55-59
The involvement of
b
-arrestin 2 in D2R-regulated AKT inhibition has
been demonstrated.
45,52
The hypothesis that dopaminergic signaling is reg-
ulated by a
b
-arrestin 2-dependent D2R signaling pathway is supported by
both behavioral and direct
in vivo
biochemical observations in pharmacolog-
ical and genetic models. Thus,
b
-arrestin 2-deficient mice exhibit a lower
locomotor response to DA-dependent drugs, and the increased locomotor
activity observed in mice lacking the dopamine transporter (DAT) is
abolished by the absence of
b
-arrestin 2 in the DAT/
b
-arrestin 2 double
knockout mice.
4,45
While both amphetamine and apomorphine treatments
inhibit AKT phosphorylation in the striatum of WT animals, this biochem-
ical effect of dopaminergic drugs is lost in the absence of
b
-arrestin 2.
Furthermore, while the genetically increased DA tone produced by DAT
depletion affects AKT activity, it fails to act in the absence of
b
-arrestin 2,
suggesting an important role of this scaffolding protein in AKT regulation
by DA. This has been confirmed by the discovery that a protein complex
formed between AKT, protein phosphatase 2A (PP2A), and
b
-arrestin 2
is involved in D2R signaling.
45
In this complex, PP2A dephosphorylates
and deactivates AKT, which in turn fails to inhibit GSK3 and leaves
the kinase activated.
45,52
These results showed for the first time an
in vivo
role of
b
-arrestin 2 scaffolds in GPCR regulation beyond in its well-known
function in desensitization of receptors. Thus,
b
-arrestin 2 signaling has a
functional role in the expression of DA-associated behaviors.
Among the mood stabilizers used clinically, lithium is known for its ther-
apeutic effects in the treatment of bipolar affective disorder.
60-63
These
Figure 11.2 Cont'd—of downstream MAPK pathway effectors. (B) D2R activation
modulates a protein complex composed of b-arrestin 2/PP2A/AKT. This complex induces
inhibition of AKT via PP2A and the subsequent activation of GSK3 and related pathways.
(C) Besides the effect of b-arrestin 2 on ERK1/2, b-arrestin 1 can translocate to the nucleus
in response to activation of DOR, and potentially other GPCR. There, a protein complex is
formed containing the histone acetyltransferase p300 and the transcription factor CREB.
This complex promotes chromatin reorganization and b-arrestin-dependent gene
transcription. (D) GRK5 is a direct interaction partner of 5HT4 receptors and a negative
regulator of the ERK1/2 signaling pathway. GRK5 inhibits G protein-independent signal-
ing pathways, including activation of ERK1/2, by phosphorylating b-arrestin 1 on Ser412,
inhibiting both b-arrestin 1 binding to clathrin and receptor internalization. (E) Serotonin
5HT2A receptors induce b-arrestin 2-dependent ERK1/2 activation and also regulate the
AKT pathway by forming a complex containing c-Src and PI3 kinase. This complex has
been implicated in serotonergic behavioral responses like head twitch.
Search WWH ::
Custom Search