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In
a
2A
AR expressing cells, the
b
-arrestin is rapidly redistributed from the
cytosol to the plasma membrane after agonist stimulation. This mechanism
is absent in
a
2C
AR-expressing cells. When the receptors are coexpressed,
there is a dose-dependent reduction in agonist-induced redistribution of
b
-arrestin 2 as the ratio of
a
2C
AR-
a
2A
AR expression is increased. This con-
firms that the loss of
b
-arrestin 2 recruitment observed with the heterodimer
is due to the loss of GRK phosphorylation.
121
In a pharmacological context, DMI, an antidepressant classically charac-
terized as an inhibitor of NE reuptake, induces a robust internalisation of
a
2A
AR in transfected cells and primary neuron cultures that is indistinguish-
able from the one induced by NE.
122
Because this effect is lost in
b
-arrestin 1
and 2 knockout cells, it suggests that DMI is able to drive arrestin recruit-
ment to the receptor and drive
a
2A
AR internalization via the canonical
arrestin-dependent pathway. DMI induces a dose-dependent interaction
between
a
2A
AR and
b
-arrestin 2 over its entire therapeutic range. It also
promotes an interaction with
b
-arrestin 1 but with a weaker efficacy.
122
4.4. Alternative pathways
In parallel to receptor internalization and contrary to what is observed with
DMI stimulation, stimulation with NE in a
a
2A
AR-expressing cell model
induces a robust activation of both ERK1/2 and AKT (
Fig. 11.2
). However,
this effect is lost if the NE stimulation follows a long-term DMI treatment in
control, but not in
b
-arrestin 1/2 knockout, murine embryo fibroblasts.
This indicates that the DMI-induced
a
2A
AR downregulation of ERK1/2
signaling also requires arrestins.
122
The same treatment reduces ERK1/2 sig-
naling in primary cultures of neurons.
In vivo
studies have shown that
chronic DMI treatment leads to a clear reduction in synaptosomal
a
2A
AR
expression in wild type, but not in
b
-arrestin 2 knockout mice. This indi-
cates that long-term DMI exposure can downregulate synaptic
a
2A
AR
expression in a
b
-arrestin 2-dependent fashion.
122
b
2
AR expression is also found in the nucleus, suggesting a specific role
for this receptor in nuclear functions.
106
Thus, a chronic stimulation of
b
2
AR leads to an activation of Mdm2 and the subsequent degradation of
p53 in a
b
-arrestin 1-dependent manner.
123
In this case,
b
-arrestin appears
to play a dual role. While in the cytosol, it mediates catecholamine-induced
activation of AKT and Mdm2, while in the nucleus as adaptor for
Mdm2-p53 interaction, leading to p53 ubiquitination and degradation.
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