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In-Depth Information
heart secondary to its phosphorylation by GRKs, which has been demon-
strated
in vivo.
71
However,
b
arr-mediated AT
1
R desensitization
per se
has
never been directly investigated
in vivo
. Intriguingly, the AT
1
R displays a
somewhat peculiar behavior in terms of its desensitization. Not only is it sub-
ject to phosphorylation by other kinases, for example, PKA and protein
kinase C (PKC), in addition to GRKs,
72
sometimes its phosphorylation is
not required for desensitization.
73
Thus, it apparently can desensitize
through multiple mechanisms and interactions with various other
proteins.
74-77
What is more, the signaling pathways it elicits display variable
desensitization kinetics, for example, Ca
2
รพ
transients induced by AT
1
Rs
readily and rapidly desensitize, whereas ERK activation and Janus kinase/
signal transducer and activator of transcription signaling emanating from this
receptor persist for long periods of time.
77,78
Given the prominent role of
cardiac AT
1
Rs in cardiac disease, such as post-MI HF, enhancement of
b
arr-dependent desensitization would theoretically be beneficial/therapeutic.
But since classical
b
arr-mediated desensitization of AT
1
Rs has never been
directly demonstrated, especially
in vivo
, there is no real evidence for its
occurrence in the heart,
let alone evidence that
b
arr-mediated AT
1
R
desensitization in the heart
is physiologically or pathophysiologically
relevant.
3.1.2 Cardiac AT
1
Rs and
b
arrs as signal transducers
Much more has come to light over the past several years regarding the physi-
ological roles of cardiac
b
arrs as mediators of G-protein-independent signal
transduction by AT
1
Rs in the heart. The first such study, by Zhai
et al.
in
2005, showed, remarkably, that myocardial overexpression of an artificially
constructed AT
1A
R mutant (AT1-i2m), which was incapable of activating
G proteins but retained the ability to interact with
b
arrs, produced significantly
less myocardial apoptosis and fibrosis, and enhanced cardiomyocyte hypertro-
phy, bradycardia, and fetal cardiac gene expression, compared to wild-type
AT
1
Rs expressedat similar levels.
31
Inprimary cardiomyocytes, the
b
arr-biased
AT
1
R agonist peptide Sarcosine
1
-Isoleucine
4
-Isoleucine
8
-AngII (SII; see
Section 6
) stimulates cardiomyocyte proliferation independently of G protein
activation, but not hypertrophy, which requires G
q/11
protein signaling.
32
In
addition, SII produces positive inotropic and lusitropic effects in isolated
murine cardiomyocytes throughGRK6-mediated phosphorylation of the car-
diomyocyte AT
1
R and subsequent
b
arr2 activation.
33
Interestingly, GRK2-
mediated phosphorylation of the AT
1
R in cardiacmyocytes leads to activation
of the other
b
arr isoform (
b
arr1), and cardiac
b
arr1 seems tooppose the positive
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