Biology Reference
In-Depth Information
b
-arrestin ubiquitinylation is fundamental to subsequent clathrin-mediated
endocytosis.
15
Recently, a new interaction partner for
b
-arrestin, phosphatidylinositol
4-phosphate 5-kinase, has been shown to be involved in the agonist-
mediated sequestration of the
b
2AR receptor. The complex formation of
b
-arrestin-2, phosphatidylinositol 4-phosphate 5-kinase, and the agonist-
bound
b
2AR appears to be essential to regulate receptor internalization.
91
Thus, strong evidence is provided that the function of
b
-arrestins at the level
of GPCR sequestration goes far beyond the fact that
b
-arrestin binds
agonist-activated and GRK-phosphorylated receptors.
3.2. Postendocytic vesicular trafficking of GPCRs
Once GPCRs are sequestered and transported into intracellular compart-
ments,
b
-arrestins also have the ability to influence the intracellular fate
of GPCRs by regulating their postendocytic trafficking. The majority of
GPCRs are either recycled or degradated. It is still largely unknown how
cells decide which pathway a particular receptor will take. There is a grow-
ing body of evidence suggesting that cells decide on the ultimate fate of cer-
tain receptors based on the properties of the receptor/
b
-arrestin complex.
The division of GPCRs into class A and B reflects the apparent affinities
for
b
-arrestin. While class A receptors, which show higher affinity for
b
-arrestin-2 than
b
-arrestin-1, traffic to endosomes and recycle directly back
afterward, class B receptors, which bind both
b
-arrestins equally well, form a
stable complex with arrestin and are either retained in endosomes for hours
before being recycled or are targeted to lysosomes for final degrada-
tion.
20,33,34,76,92
Apparently,
b
-arrestin and its receptor affinity represent a
critical determinant for GPCR postendocytic sorting as it determines the
rate of receptor resensitization (
Fig. 4.3
). Evidence is provided by studies
with chimeric
b
2AR and V2 vasopressin receptors: exchange of the car-
boxyl terminal tails of the rapidly recycling
b
2AR and the extremely slow
recycling V2 vasopressin receptor completely reverses the pattern of
b
-arrestin binding and the propensity of these receptors to dephosphorylate,
recycle, and resensitize.
92
The same effect was observed for the exchange of
the C-termini of two vasopressin receptor subtypes: V1A, which recycles
rapidly, and V2, which moves slowly. Exchange of the carboxyl termini
between these two receptors also switches the trafficking pattern of the
receptors.
93
As the stable association of
b
-arrestin is promoted by a specific
cluster of phosphorylated Ser/Thr residues within the carboxyl terminus,
the interaction of
b
-arrestins with such a specific phospho-cluster, a
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