Biology Reference
In-Depth Information
GPCRs by
b
-arrestins.
22
To bind arrestins with high affinity, many GPCRs
must be phosphorylated. This was first shown for rhodopsin
36
and later for
numerous other GPCRs such as the
b
2AR,
24,37-40
angiotensin II type 1
receptor,
41
a
2-adrenergic receptor,
42
m2 muscarinic receptor,
38
and neuro-
peptide Y1 receptor.
43
The majority of relevant phosphorylation sites are
localized to the carboxyl terminal tails of most GPCRs, but relevant phos-
phorylation sites have been mapped to any intracellular domain including
the intracellular loops (as reviewed in Ref.
44
). Nonetheless,
b
-arrestins
were also found to bind to several unphosphorylated receptors.
45-47
Phosphorylation-independent
b
-arrestin binding can be explained by acidic
amino acid stretches within intracellular domains. Acidic amino acids can
successfully mimic phosphate groups
48,49
; thus, the density of negative char-
ges is sufficient to activate the arrestin phospho-binding site which leads to
receptor interaction, such has been demonstrated for the D6 chemokine
receptor.
50
Due to the vast complexity of phosphorylation events that occur on
different GPCRs, it is still a matter of debate how only seven GRKs and
four arrestins can specifically regulate several hundred different GPCRs. For
many GPCRs, it appears that all GRKs or arrestins (except retinal arrestins)
contribute to the regulation of their desensitization. However, many GPCRs
display a distinct preference for a specific GRK and arrestin isoform to mediate
their desensitization. For example, GRK6 and
b
-arrestin-2 regulate
m
-opioid
receptors andD2-like dopamine receptors in striatum.
21
It has also become evi-
dent that the regulation of a given GPCR depends on cell background, as
its regulation can be affected by differences in the expression levels of distinct
GRKs and
b
-arrestins between different cell types and tissues. It remains
an open question whether certain GPCRs are regulated either randomly by
various GRK/
b
-arrestin combinations or by specific GRK and
b
-arrestin
pairs, and whether a particular GRK/
b
-arrestin pairing takes precedence over
other pairings.
21
To add an additional level of complexity to GRK and
b
-arrestin regulation of GPCR activity, Schulz
et al.
51
recently identified a
novel mechanism whereby distinct opioid agonists stimulated site-specific
m
-opioid receptor phosphorylation patterns. Thus, morphine binding results
in a
m
-opioid receptor conformation with next to no affinity for
b
-arrestins,
whereas enkephalin analogs induce a rapid high-affinity binding of both
b
-arrestin-1 and -2.
51,52
Similarly, the chemokine receptor CCR2 displays dif-
ferent affinities for both
b
-arrestin-1 and -2, depending on whether the recep-
tor was stimulated with different CCR2 ligands. Furthermore, while CCL7
induces transient binding of
b
-arrestins, CCL8/13 leads to the stable formation
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