Biology Reference
In-Depth Information
transactivation of the EGF receptor and promoting cardiomyocyte sur-
vival.
165
Both
b
-arrestin 1 and
b
-arrestin 2 are required for
b
1AR trans-
activation of the EGF receptor.
165
Mechanical stretch in the heart triggers
activation of AT1AR and
b
-arrestin recruitment to the receptor in the
absence of ligand.
166
b
-Arrestin-deficient hearts failed to induce a cardi-
oprotective response to mechanical stretch and demonstrated enhanced
myocyte apoptosis,
166
suggesting that the heart responds to mechanical stress
by activating
b
-arrestin-mediated cell survival signals.
167,168
7.
b
-ARRESTINS IN THERAPEUTIC DEVELOPMENT
FOR INFLAMMATORY DISEASES
Understanding
b
-arrestin biology offers the potential to accelerate
drug development in targeting GPCR functions (reviewed in Refs.
169,170
). Several assay systems have been proposed and tested to target
b
-arrestins. For example,
b
-arrestin conformational changes were used to
develop a biased agonist to the GPR109A receptor that retains the therapeu-
tic lipolytic effect, but is devoid of cutaneous side effects.
171
RNA interference targeting
b
-arrestins has been used to demonstrate the
role of arrestins in GPCR desensitization, internalization, and signaling
functions.
125,172
Furthermore, these specific siRNAs have been used in
in
vivo
as well as
in vitro
settings. Silencing
b
-arrestin 2 with RNA interference
in allergic asthmatic mice reduced Th2 cytokines such as IL-4.
47
Silencing
b
-arrestin 2 reduced fibroblast invasiveness.
131
Suppression of
b
-arrestin 2
expression using siRNA eliminated AT(1A)R- and LPAR1-mediated
chemotaxis.
86
There are few reports exploring the interplay between microRNAs and
b
-arrestins. For example,
b
-arrestin 2-mediated ERK phosphorylation is
required for the downregulation of miR-190.
173
Expression of miR-326
is decreased in human glioblastomas and correlated with decreased expres-
sion of the host gene
b
-arrestin 1.
174
Although there are no reports identi-
fying
b
-arrestins as targets of any microRNAs thus far, microRNAs
regulating
b
-arrestin expression may prove to be a powerful strategy for
therapeutic development.
Therapeutic targeting of
b
-arrestins has been challenging thus far.
b
-Arrestins have been shown to interact with an array of receptors as well
as downstream proteins. For example, by proteomic analysis, there are over
a hundred proteins interacting with either
b
-arrestin 1 or
b
-arrestin 2 when
the AT1AR is activated.
175
Furthermore, there are 171 proteins with
Search WWH ::
Custom Search