Biology Reference
In-Depth Information
9. BAR CODE HYPOTHESIS
The remarkable diversity of
b
-arrestin functions raises the issue of how,
once bound to a GRK phosphorylated receptor, the
b
-arrestin “knows” what
it is supposed to do. This situation suggests that there might be some code in
the receptor that leads to
b
-arrestin assuming a variety of conformations with
distinct functional capacities. In fact, several approaches including limited pro-
teolysis of
b
-arrestins 1 and 2
68,69
and studies with an intramolecular
b
-arrestin2 BRET probe among others
70
have confirmed the existence of
such differing
b
-arrestin conformations. Moreover, the BRET studies clearly
indicate that different conformations of
b
-arrestin are stabilized after receptor
stimulation by unbiased versus
b
-arrestin-biased agonists.
70
These results in turn beg the question of how different receptor conforma-
tions, presumably formed in response to agonists of differing bias, can impart
this information to the arrestins. This question has given rise to what has been
called the “bar code hypothesis.” The idea is that GRK isoforms differentially
recognize various receptor conformations stabilized by different types of ago-
nists and then phosphorylate them on different sites. These distinctive phos-
phorylation patterns would then form a “bar code” of sorts, read by the
b
-arrestin, thereby determining its conformation and functional activity.
71,72
Data consistent with this hypothesis have already been published for the
b
2AR,
73
angiotensin II type1a receptor,
71
V2vasopressin receptor,
72
M3mus-
carinic acetylcholine receptor,
74
and CCR7 receptor.
60
For example, in the
case of the
b
2AR expressed in HEK cells, stimulation by the unbiased ligand
isoproterenol leads to phosphorylation on twoGRK6 sites and sixGRK2 sites,
whereas stimulation by the weak
b
-arrestin-biased ligand carvedilol leads to
phosphorylation only on the two GRK6 sites.
73
Phosphorylation of the
GRK2 sites appears to inhibit phosphorylation on the GRK6 sites. Moreover,
phosphorylation by the different GRKs promotes distinct functional profiles of
the subsequently bound
b
-arrestin. Phosphorylation by GRK2 or 6 supports
desensitization of G protein signaling though with greater effectiveness noted
forGRK2. Similarly, bothkinases can support
b
-arrestin-mediatedendocytosis
though againwith an advantage forGRK2.However,whereasGRK6 is essen-
tial for
b
-arrestin-mediated ERK activation, GRK2 phosphorylation actually
inhibits this process.
73
Moreover, this antithetical relationshipof the twoGRKs
for
b
-arrestin-mediated ERK activation has been noted for a number of
different receptors.
75
Whether this is simply a reflection of GRK2 phosphor-
ylation inhibiting GRK6 phosphorylation or whether additional factors play a
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