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carboxyl terminus determines the stability of the GPCR/
b
-arrestin com-
plex and subsequent cellular distribution of
b
-arrestin.
76
This is likely
achieved by the distinct phosphorylation patterns induced by different
GRKs, the density of phosphorylation sites within a given GPCR C-tail
or intracellular loop domain, and the induction of conformational changes
in receptor-bound
b
-arrestins, as these conformational states may vary and
will likely reflect dynamic changes in the binding of downstream accessory
proteins.
33,44
The list of GPCRs that have been shown to bind to
b
-arrestins via the
phosphorylated Ser/Thr residues within their carboxyl terminal tails initially
consisted only of the rhodopsin receptor and the
b
2AR. However, due to
intense investigation in this field over the past two decades worldwide, this
list is continuously expanding. To date, evidence for receptor/
b
-arrestin
interactions involved in internalization is provided for
b
2AR,
60,78,79
M2-
muscarinic acetylcholine receptors,
70,80,81
d
-opioid receptors,
82
angiotensin
II type 1 receptors,
83
human P2Y1 receptors,
84
dopamine D1 receptors,
85
neuropeptide Y1, Y2, and Y4 receptors,
43,73,86,87
and many more. The con-
tribution of specific intracellular receptor domains to
b
-arrestin binding and
subsequent sequestration has been studied intensively. Most commonly, the
carboxyl terminus (prototypical model) and, to a lesser extent, the third
intracellular loop contribute to endocytic trafficking. However, even within
the class of adrenergic receptor subtypes, specific differences occur. For
example,
b
-arrestins bind to the carboxyl terminus of the
b
2AR, but they
bind to the third intracellular loop of
a
-adrenergic receptors.
88
Similar char-
acteristics have been documented for the muscarinic acetylcholine receptors
2 and 3.
88,89
Clearly, receptor domains are significantly involved in the reg-
ulation of sequestration.
Another important regulator of
b
-arrestin-promoted clathrin-dependent
receptor internalizations is the posttranslational modification of
b
-arrestin
itself.
b
-Arrestin-1 is regulated by phosphorylation/dephosphorylation.
Ser412 within the carboxyl termini of
b
-arrestin-1 is constitutively phos-
phorylated and recruited to the plasma membrane as soon as the receptor
is activated in an agonist-dependent manner. Subsequently,
b
-arrestin-1
becomes dephosphorylated, which is required for clathrin binding and
targeting to clathrin-coated pits.
49
Besides phosphorylation, ubiquitination
of
b
-arrestins is another required process for effective internalization.
b
-Arrestin-2 binds the mouse double minute 2 (mdm2) protein, an E3
ubiquitin ligase, and becomes ubiquitinated, a process shown to regulate
the stability of the
b
2AR/
b
-arrestin interaction internalization.
90
Likewise,
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