Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 298

procontractile signaling and the G i protein-mediated antiapoptotic signaling
of the cardiac b 2 AR ( Table 12.1 ). On the other hand, b arr signaling stim-
ulated by the b 2 AR can exert some beneficial effects on the cardiac myocyte,
as it can be antiapoptotic and also anti-inflammatory in its own right by pro-
moting extracellular signal-regulated kinase (ERK) activation, which
increases cardiomyocyte survival and proliferation, and by blocking nuclear
factor-kappaB (NF- k B) activation, which leads to proinflammatory cyto-
kine production 28-30 ( Table 12.1 ).
Finally, as far as the cardiac b 3 AR is concerned, this b AR subtype is
pharmacologically unique. Its effects on the myocardium appear to be oppo-
site to the effects of the two more abundant cardiac b AR subtypes, that is, it
relaxes the myocardium and decreases its contractility, presumably via acti-
vation of nitric oxide muscle-relaxing pathways. 64 Again contrary to its
b AR subtype counterparts, the b 3 AR is not a b arr or GRK substrate, as
it does not undergo agonist-dependent desensitization or internalization. 64
However, b 3 AR can heterodimerize (or hetero-oligomerize) with the
b 2 AR and dramatically alter the latter's desensitization and internalization
properties. 65 Thus, b 3 AR might indirectly affect b arr actions on b 2 ARs
in the heart.
To sum up, cardiac b arrs (primarily b arr2) can convert the normally car-
diotoxic G-protein-dependent signaling of the b 1 AR into cardioprotective
signaling via b arr2-dependent EGFR transactivation, an effect of potential
therapeutic benefit in HF ( Table 12.1 ). With regard to the b 2 AR, cardiac
b arrs can have damaging effects by opposing (desensitizing) the beneficial
G-protein-dependent procontractile and antiapoptotic b 2 AR signaling,
but they might also help preserve it in situations where this signaling goes
awry, such as in HF ( Table 12.1 ). Finally, the cardiac b 3 AR does not engage
directly in b arr interaction/binding.
2.3.4 Other cardiovascular b ARs and b arrs
It is widely known that b ARs (mainly of the b 2 subtype) are highly expressed
in VSM, where they exert vasodilation by increasing cAMP levels. 64 VSM
b arrs are bound to limit this vasodilation via classical desensitization of these
receptors, thereby increasing vascular tone and promoting hypertension.
The fact that GRK2 activity is elevated in human hypertension, 66,67
although it is not known whether it is elevated in VSM per se , argues in favor
of vascular b arrs opposing b AR-dependent VSM relaxation, since enhanced
GRK activity generally translates into enhanced GPCR desensitization by
b arrs. However, b arr mRNA levels are unaltered in circulating lymphocytes