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b
-arrestins regulate a GPCR's ability to resensitize and ultimately reestablish
responsiveness.
96
Both
b
-arrestin expression levels and the rate of
b
-arrestin
release dictate fate.
44,96
Not surprisingly, exceptions to the rule exist as not all GPCRs fit into
the class A/B dichotomy. Somatostatin (sst) receptors, for example, do
not follow the classical postendocytic trafficking patterns for class A and
B receptors as described earlier. While the sst2A somatostatin receptor
exhibits a typical class B receptor
b
-arrestin-dependent trafficking pattern
(stable
b
-arrestin-receptor complexes, cointernalization), this receptor is
rapidly recycled and resensitized rather than targeted for degradation.
In contrast, the somatostatin receptor subtypes sst3 and sst5 display typical
class A receptor properties (transient
b
-arrestin-receptor complexes, recep-
tor internalization without
b
-arrestin), but unlike other class A receptors, are
targeted to lysosomes for degradation.
97
Similar observations were made for
the spontaneous internalization of the
a
1A-adrenergic receptor. Although
this receptor internalizes in a
b
-arrestin-dependent manner, it travels with
b
-arrestin bound to recycling endosomes.
98
A third example is the meta-
botropic glutamate receptor 1, which interacts selectively with
b
-arrestin-
1, not
b
-arrestin-2.
99
Even so, for most GPCRs, the stability of the
receptor-
b
-arrestin complex strongly affects the postendocytic trafficking
pattern, and thereby determines the ultimate subcellular fate.
In the past few years, it has become evident that the capacity of
b
-arrestins to engage in protein-protein interactions is not limited to recep-
tors and components of the clathrin-mediated endocytosis machinery, or
dedicated to the control of receptor desensitization and internalization.
The number of identified
b
-arrestin-interacting partners is growing rapidly.
b
-Arrestins are capable of forming an interface between intracellular com-
ponents of the vesicular trafficking and sorting machinery and internalized
receptors. Recently, novel intracellular interaction partners involved in
arrestin-promoted clathrin-mediated trafficking have been identified.
Among them are the small G protein ADP-ribosylation factor 6 and its
guanine nucleotide exchange factor ADP-ribosylation factor nucleotide-
binding site opener,
100
and the
N
-ethylmaleimide-sensitive fusion protein
101
(
Fig. 4.3
). These proteins subsequently act as adaptors to facilitate the
clathrin-mediated endocytosis of GPCRs.
Another regulatory factor in
b
-arrestin-mediated postendocytic sorting
is the ubiquitination status of
b
-arrestin, which dramatically influences the
subcellular fate of GPCRs. For example, a constitutively ubiquitinated
b
-arrestin-ubiquitin chimera is unable to dissociate from the
b
2AR, and
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