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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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