Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 295

suggest that this sedation may be related to b arr2-mediated signaling of
a 2 ARs. 19 Thus, an a 2 AR-biased agonist lacking b arr2 stimulation properties
but retaining the G protein-stimulating ones might be of therapeutic value in
hypertension 20 ( Table 12.1 ).

2.3. -Adrenergic receptors

2.3.1 Cardiac b ARs and b arrs — General considerations
The principal role of b ARs in the heart is regulation of cardiac rate and con-
tractility in response to catecholamines. Of the three known mammalian
b AR subtypes ( b 1 AR, b 2 AR, b 3 AR), the b 1 AR is the predominant one
in cardiac myocytes, representing 75-80% of total b AR density, followed
by the b 2 AR, which comprises about 15-18% of total cardiomyocyte b ARs,
and the b 3 AR that makes up the remaining 2-3% (under normal condi-
tions). 49

b

b 1 AR stimulation by catecholamines results in the dissociation of
the stimulatory G protein alpha subunit (G a s ) from G bg .G a s stimulates
adenylyl cyclase (AC) to produce 3 0 -5 0 -adenosine monophosphate (cAMP),
which in turn, by activating protein kinase A (PKA), regulates different
intracellular, sarcolemmal, and myofibrillar substrates, exerting the cellular
effects of b 1 AR activation on cardiac chronotropy, inotropy, and lusitropy.
In addition, G bg can activate downstream effectors that participate in cardiac
signaling regulation. 49

b 2 AR also mediates the effects of catecholamines on
the heart, but in a qualitatively different manner from b 1 AR, as it can also
couple to the AC inhibitory G protein (G i ). It is now generally accepted that
in the heart, b 2 ARs signal and function in a substantially different way than
b 1 ARs. 50-52 Importantly, whereas b 1 AR activation enhances car-
diomyocyte apoptosis, b 2 ARs exert beneficial antiapoptotic effects in the
heart, 50-53 purportedly through this G i -mediated signaling. 51 Several studies
using transgenic mice, b 2 AR-selective stimulation, and adenoviral-
mediated b 2 AR overexpression have established a consensus that b 2 AR sig-
naling is predominantly cardioprotective, improving cardiac function and
decreasing apoptosis, whereas b 1 AR-elicited signaling has detrimental

effects. 53,54
Of note, the differences between the signaling properties of these two
predominant cardiac b ARs might take a quite different shape in the setting
of HF. For instance, the b 1 AR is selectively downregulated in HF, that is,
the total cellular receptor number is reduced, thus shifting the stoichiometry
of b 1 AR: b 2 AR from approximately 75:25 in the normal healthy heart
toward 50:50 in the failing heart. 55,56 However, b 2 AR is also nonfunctional
and does not signal properly in the failing heart. 56,57 In addition, b 2 AR