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nonreceptor
b
-arrestin-interacting protein in 1996.
67
AP-2 is involved in
the recruitment of clathrin and the subsequent assembly of clathrin lattices,
the major components of the coat of the internalized membrane. Binding of
clathrin and AP-2 is facilitated by
b
-arrestin binding to the receptor, which
leads to the release of the
b
-arrestin carboxy-terminal tail, the region where
both interaction partners bind. Thus, clathrin and AP-2 binding to
b
-arrestins during endocytosis has turned out to be a critical step in
internalization.
12
Whether GPCR sequestration involves clathrin-coated pits, caveolae,
and/or other uncoated vesicles, internalization rates are highly receptor
and cell-type dependent. Almost every possible internalization mechanism
for different GPCRs has been described in the literature:
b
-arrestin- and
clathrin-dependent,
b
-arrestin- and clathrin-independent,
b
-arrestin-
independent and clathrin-dependent, and also
b
-arrestin-dependent and
clathrin-independent.
62
Thus, it seems that
b
-arrestins are sometimes redun-
dant for the internalization of some GPCRs.
70
There is also evidence that
certain receptors can choose different internalization pathways and can also
dictate whether they internalize via either
b
-arrestin-dependent or indepen-
dent pathways. For example, the chemokine receptor CCR5 and m2 mus-
carinic receptors internalize in a
b
-arrestin-dependent manner and, although
bound to
b
-arrestin, can also internalize in a
b
-arrestin-independent man-
ner.
71
Other examples include the full length A2B adenosine receptor and
the neuropeptide Y2 receptor, which typically internalize via a
b
-arrestin-
dependent pathway. However, carboxyl terminal truncations of both
receptors serve to redirect them to a
b
-arrestin-independent internalization
pathway.
72,73
Thus,
b
-arrestins provide GPCRs with the ability to interact
with the clathrin-coated pit internalization machinery, but this interaction
does not necessarily predetermine whether GPCRs are endocytosed in
clathrin-coated vesicles. However, it is now clear that the majority of
GPCRs utilize the
b
-arrestin-dependent, clathrin-mediated internalization
pathway (
Fig. 4.2
).
The two nonvisual mammalian
b
-arrestins display different characteris-
tics with respect to cellular distribution patterns, and binding properties to
their GPCR substrates. While
b
-arrestin-1, comparable to visual arrestin, is
localized in the cytoplasm and the nucleus,
b
-arrestin-2 is limited to the
cytoplasm.
34,74
They also have different abilities to mediate internalization.
Evidence to support this has come from studies with knockout mice either
lacking
b
-arrestin-1 or -2. Although both
b
-arrestin-1 and -2 contribute to
the desensitization of the
b
2AR,
b
-arrestin-2 appears to be significantly
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