Arrestins: Role in the Desensitization, Sequestration, and Vesicular Trafficking of G Protein-Coupled Receptors - Progress in Molecular Biology and Translational Science - page 93

“arrest” receptor signaling via G proteins. However, there is clearly a tight
interplay of GRKs and b -arrestins to control the desensitization process.
It has been found for numerous receptors that predominantly GRK2 and
GRK3 over GRK5 and GRK6 are responsible for phosphorylation and sub-
sequent b -arrestin recruitment. 25,26 However, several studies exist, where
primarily GRK5 and GRK6 have been implicated in desensitization, for
example, calcitonin gene-related peptide receptors 27 and dopamine D1A
receptors. 28 A proposed GRK-specific “bar code” 29,30 dictates subsequent
downstream effects and whether or not a specific b -arrestin isoform binds
to the GPCR. For example, GRK2- and GRK3-mediated phosphorylation
of CXCR4 receptors leads to b -arrestin-1 recruitment, whereas GRK2-/6-
dependent events involve b -arrestin-2 binding. 31 Comparably, the stimula-
tion of the CCR7 receptor by different ligands either leads to the activation
of both GRK3 and GRK6 or just GRK6 alone. Different phosphorylation
patterns subsequently lead to distinct b -arrestin recruitment: either to the
membrane or to endocytic vesicles. 32 Thus, it has become evident that
the cellular GRK repertoire, depending on the respective receptor and tissue
studied, may dictate the characteristics and scope of receptor responsiveness
and desensitization. 28
Generally, b -arrestin binding to GRK-phosphorylated receptors is
determined by the absence or presence of conserved clusters of Ser/Thr
residues within the carboxyl terminal tails of the receptor. GPCRs can be
broadly divided into two classes, A and B, depending on the stability of
b -arrestin binding to the receptor. 33,34 The carboxyl terminal tails of class
A receptors, such as the b 2-adrenergic receptor ( b 2AR), consist of a dif-
fusely Ser/Thr-rich cluster and only transiently recruit b -arrestin-2 upon
phosphorylation. In contrast, class B receptors like the V2 vasopressin recep-
tor and the angiotensin II type 1A receptor recruit b -arrestin-1 as well as
b -arrestin-2 with high affinity and allow for the stable association of
b -arrestin with the receptors.
How is this b -arrestin selectivity mechanistically achieved? A “multisite
arrestin-receptor interaction” model has been proposed to account for the
differences. 35 This model hypothesizes that b -arrestins have two binding
sites: one that binds distinct receptor elements which are subject to confor-
mational change upon receptor activation, and a second one that binds
receptor-attached phosphates. When a GPCR is activated and subsequently
phosphorylated and b -arrestin binds via both interaction sites, it is subject to
transition into its active high-affinity receptor-binding state. This mecha-
nism most likely contributes to the preferential desensitization of certain