Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 312

by which cardiovascular b arrs stimulate cardiomyocyte or VSM cell prolifer-
ation and survival.
6. BIASED AGONISM/ANTAGONISM OF
CARDIOVASCULAR GPCR LIGANDS
Numerous studies have investigated the ability of ligands to “bias”
GPCR activation of b arr- versus G-protein-dependent signaling pathways.
Among the GPCRs studied are the b 2 AR and the AT 1 R, two of the most
important cardiovascular GPCRs. Thus, a short discussion of the properties
of ligands for these two receptors with regard to their “biased” agonism/
antagonism of b arr-mediated signaling is worthwhile to have a more com-
plete picture of the physiology and pharmacology of cardiovascular b arrs.
This section gives a brief overview of what is currently known, first about
b arr signaling “bias” of b 2 AR ligands, followed by what is known about b arr
signaling “bias” of AT 1 R ligands. Some examples of b arr-biased ligands for
other cardiovascular GPCRs, for example, a 2 AR and GPR109A, have
already been given in preceding sections.
With regard to the b 2 AR, considerable bias toward b arr activation was
observed for compounds containing an ethyl substitution of the a -carbon
within a series of phenylethylamines. 114 Stereoisomers of fenoterol, a
b 2 AR-selective agonist, differentially activate G s and G i proteins in rat
cardiomyocytes. 115 It is now known that, in addition to blockade of
b AR-induced G protein activation, some b -blockers produce activation
of ERKs through b arr. 116 In view of the fact that a number of b -blockers
have been tested in clinical trials for therapy of congestive HF and only a
few have shown beneficial effect, this ERK1/2-stimulating effect may be
physiologically and therapeutically relevant. In particular, carvedilol
( Fig. 12.1 ), a non-subtype selective b -blocker that is beneficial for the treat-
ment of congestive HF, 63 has been shown to stimulate b arr-mediated acti-
vation of ERK1/2, while blocking G protein activation by b ARs; in other
words, it is a fully “biased” agonist for b arr signaling at b ARs. 117 Bucindolol,
another b -blocker that is very similar to carvedilol in terms of stimulating
ERK1/2 while blocking b 2 AR activation of G proteins, 116 has also shown
some benefit in HF treatment. 118
A recent study by the Raymond Stevens' group investigated the biophys-
ical basis of b arr “biased” signaling. 119 Using site-specific 19 F (fluorine-19)-
labeled b 2 AR bound to a panel of structurally diverse b 2 AR ligands and
NMR (nuclear magnetic resonance) spectroscopy, these authors were able