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Figure 4.3 Postendocytic trafficking of GPCRs strongly depends on the stability of
receptor/arrestin complexes as well as the interaction with various other intracellular
proteins that interact with the receptor-bound b-arrestin during the internalization
process. The magnified region depicts those arrestin-interacting proteins influencing
internalization and thus subsequent trafficking to intracellular compartments.
As internalization is the prerequisite for subcellular trafficking, these arrestin-interacting
proteins are involved in both mechanisms and boundaries are blurred. Once internal-
ized, GPCRs can be divided into two classes, depending on the properties of the recep-
tor
arrestin complex. Class A receptors, which preferentially bind b-arrestin-2,
dissociate rapidly from the bound arrestin, become dephosphorylated, and transit
through recycling endosomes before reaching the plasma membrane for efficient re-
sensitization. In contrast, class B receptors, which recruit both arrestins with equal affin-
ity, remain associated with arrestin during internalization and are targeted to lysosomes
for final degradation. Occasionally, class B receptors are retained in early endosomes for
a prolonged period before undergoing recycling. A, agonist; P, phosphate moiety;
b-ARR, b-arrestin; ARF6, G protein ADP-ribosylation factor 6; ARNO, ARF nucleotide-
binding site opener; Mdm2, mouse double minute protein 2, an E3 ubiquitin ligase;
NSF, N -ethylmaleimide-sensitive fusion protein; Ub, Ubiquitin.
-
predetermined distance from the seventh transmembrane domain, appears
to dictate the rate of dephosphorylation, recycling, and resensitization. 92
Studies examining b 2AR endocytosis in the presence of b -arrestin mutants
that have either decreased or increased affinities for GPCRs and endocytic
adaptor proteins revealed that arrestin directs the receptor to recycling or
degradation pathways, respectively. 94,95 Therefore, it can be concluded that
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