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D2-receptor binding affinity and ability to antagonize the receptor. In an
in vitro
screen using fluorescence-based reporters, it was found that while
different classes of antipsychotics exhibit complex efficacy profiles with
respect to D2 receptor-G protein coupling, they share the property of antag-
onizing the D2 receptor-arrestin3 interaction.
105
PP2A also plays an important role in receptor trafficking and res-
ensitization, and some of these effects may be arrestin dependent.
Arrestin2-bound PP2A reportedly dephosphorylates Ser
412
on arrestin2, a
step that regulates the interaction between arrestin and the clathrin-coated
pit and subsequent internalization.
106
Dephosphorylation of GRK-
phosphorylated receptors, a prerequisite for receptor resensitization, also
involves PP2A. A 150-kDa oligomeric form of PP2A catalyzes the dephos-
phorylation of
b
2- and
a
2-adrenergic receptors.
107
The acidic microenvi-
ronment of endosomes is important for PP2A association with
internalized
b
2-adrenergic receptors, their dephosphorylation, and subse-
quent recycling to the plasma membrane.
108
At present, it is not clear
whether the PP2A pool involved in receptor dephosphorylation is targeted
by the arrestin. Finally, PP2A is known to promote ERK1/2 activation by
acting on c-Raf1 Ser
259
, an inhibitory site that must be dephosphorylated for
Raf activation.
109
Since PP2A both positively regulates c-Raf
109,110
and
negatively regulates ERK1/2,
111,112
its presence in the signalsome may play
a role in arrestin-dependent ERK1/2 regulation.
4.4.2 Cofilin
-
chronophin
-
LIM kinase
Arrestin kinase/phosphatase scaffolds play a central role in the control of
GPCR-mediated chemotaxis, the process whereby migrating cells follow
a concentration gradient to its source. Chemoattractant receptor activation
induces actin cytoskeletal rearrangement forming leading and trailing edges.
A dominant pseudopodium forms at the leading edge that protrudes forward
driven by F-actin polymerization and actin-myosin contraction forces.
113
Splenocytes derived from arrestin3 null mice exhibit strikingly impaired
chemotactic responses to stromal cell-derived factor-1, CXCL12.
114
While
impaired gradient sensing due to the loss of arrestin-mediated desensitization
might be a contributing factor,
115
evidence suggests that arrestin-dependent
regulationof ERK1/2 andcortical actin assembly at the leading edge is required
for GPCR-mediated chemotaxis.
49,116-118
In addition, arrestins scaffold
a complex containing the actin filament-severing protein, cofilin, LIM
kinase, and the cofilin-specific phosphatase, chronophin, which is required
for the dephosphorylation and activation of cophilin.
21
Arrestin-bound
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