Biology Reference
In-Depth Information
These mechanisms have turned out to be quite general though the specifics
with respect to the individual roles of
b
-arrestin1 and 2 differ substantially
from one receptor to another. Detailed biochemical studies of
b
-arrestin
interaction with components of the ERK cascade enzymes have been pub-
lished and strongly support a scaffolding mechanism.
45,50
Initial studies of “
b
-arrestin-mediated” signaling by 7TMRs were not
interpreted as necessarily suggesting wider roles for
b
-arrestins. However,
subsequent proteomics studies analyzed the
b
-arrestin “interactome”
51
and also provided a quantitative global phosphorylation analysis downstream
of
b
-arrestin activation by the angiotensin II type 1A receptor.
52
These stud-
ies indicated a surprisingly rich network of
b
-arrestin-binding partners and
linked downstream signaling elements. Subnetworks engaged downstream
of
b
-arrestins include, in addition to a multiplicity of MAP kinase pathways,
elements of systems involved in PI3kinase/AKT signaling, DNA damage
repair, cell cycle and development, and cytoskeletal reorganization among
others.
52
Hundreds of papers published over the past few years attest to
the diversity and number of signaling mechanisms in which the
b
-arrestins
are involved.
53
An interesting and as yet unexplained feature of this signaling is the
involvement, or lack of involvement, of G proteins. For most cases, where
the 7TMR appears to be G
s
or G
q
coupled,
b
-arrestin-mediated signaling
appears to be independent of G proteins. However, in the case of many
G
i
-coupled receptors, signaling appears to simultaneously require involve-
ment of G
i
(can be blocked by pertussis toxin) as well as
b
-arrestin (blocked
by
b
-arrestin siRNA). The explanation for this is not known.
8. BIASED SIGNALING
Biased agonism, also known as ligand-directed signaling or functional
selectively, refers to the ability of ligands for a single receptor to demonstrate
differential efficiency for different responses. The phenomenon was first
noted in the 1990s in the context of several GPCRs that could stimulate
more than one G protein, for example, G
s
and G
i
,orG
s
and G
q
.
54
Some
ligands show preferential activity for one signaling pathway over the other.
However, after the discovery of
b
-arrestin-mediated signaling, this phe-
nomenon received increasing attention as ligands were discovered which
were either G protein or
b
-arrestin biased.
55
Such biased signaling strongly
implies the existence of distinct conformations of the receptor, preferentially
stabilized by distinct ligands, which lead to the different signaling pathways.
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