Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 316

biased the ligand is toward b arr activation. 59,122 Of note, [Sar 1 ,Ile 4 ,Ile 8 ]-
AngII, the “prototypic” b arr-biased agonist at the AT 1 R, has no substitution
at this position; it has a substitution at position 4 instead. 123,124 Substitutions
at positions 1 and 8 are indispensable for an AngII peptide analog to lack any
G protein-activating properties and thus be a pure b arr-biased agonist at the
AT 1 R. 59,122,123
A final note on b arr-biased agonism/antagonism of GPCR ligands: it
should always be kept in mind that ligand “bias” with regard to b arr-
dependent signaling exists not only at the level of receptor interactions with
b arrs and G proteins, which dictates the extent of “bias” for b arr-mediated
versus G-protein-mediated signaling, but also at the level of receptor-
induced b arr activation per se . b arrs can adopt various active conformations
upon their interaction with a GPCR, which apparently dictates their down-
stream signaling, that is, which of the several available cellular signaling path-
ways will be activated. 125 Indeed, a recent study uncovered significant
variation in the extent of “bias” of various AngII analogs for distinct
AT 1 R-bound

b arr active conformations, leading to different signaling

events and cellular responses. 126

7. PERSPECTIVES AND FUTURE DIRECTIONS
Given that b arrs are ubiquitous in the cardiovascular system and reg-
ulate all the important GPCRs within its various parts, organs, and tissues,
the recently discovered and increasingly expanding field of b arr-dependent
GPCR signaling offers several exciting opportunities for therapeutic inter-
vention in cardiovascular disease. Although cardiovascular b arr physiology
and pharmacology are still in their infancy, with a lot of blank or shady areas
awaiting elucidation, the potential advantages of targeting cardiovascular
b arrs for therapeutic purposes are enormous.
Admittedly, the picture is still hazy regarding several physiological
actions of b arrs in the cardiovascular system, especially when it comes to
ascribing certain physiological/pathophysiological effects to specific b arr
isoforms in specific tissues/organs. For instance, cardiac b arr2 reduces
b AR-stimulated contractility (which is G protein-dependent), but, at
the same time, appears to enhance AT 1 R-dependent contractile function.
This b arr isoform also appears to have beneficial effects in the heart as it
increases survival and cardiomyocyte proliferation; however, it promotes
atherosclerosis in the vasculature. On the other hand, b arr1 seems to have
negative effects in most cardiovascular tissues/organs. It opposes cardiac