Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 291

receptors in the central nervous system (CNS), and/or antagonism of VSM-
constrictive a 2B AR signaling/function, for example, enhancement of b arr
desensitizing action on vascular a 2B ARs, is desired in treatment of

hypertension.
On the latter point, a polymorphic variant of the human a 2B AR gene
(Del 301-303 a 2B AR) containing a nine-nucleotide deletion that eliminates
three Glu residues from the third intracellular loop of the encoded receptor,
displays severely impaired GPCR kinase (GRK)-dependent phosphoryla-
tion and is incapable of undergoing desensitization. 10,11 This variant has
been genetically associated with acute coronary vasospasm and hypertension
in certain populations, as well as under specific conditions, such as stressful
work environment. 12-14 Although the effect of this polymorphism on b arr
binding to the a 2B AR has never been directly tested in vitro or in vivo , it is safe
to surmise that b arrs fail to interact with and desensitize this a 2B AR deletion
variant, given its complete failure to desensitize. Thus, this constitutes an
example of a beneficial cardiovascular role of b arrs as receptor desensitizers,
that is, blockade of vascular a 2B AR-dependent vasoconstriction, augmenta-
tion of which could confer a significant advantage in the treatment of car-
diovascular disease (i.e., hypertension, in this particular case; Table 12.1 ).
The opposite is true for b arrs acting as a 2 AR desensitizers in the adrenal
gland. Here, as in the CNS, a 2 ARs function as presynaptic inhibitory
autoreceptors, blocking catecholamine release from the chromaffin cells
of the adrenal medulla, a process normally dependent on tonic activation
of nicotinic cholinergic receptors by acetylcholine. 9

b arrs, acting in concert
with their cofactor in receptor desensitization, GRK2, which is significantly
upregulated in the adrenal medulla during HF, promote desensitization and
downregulation of adrenal a 2 ARs. This increases adrenal catecholamine
secretion, leading to the enhanced circulating levels of norepinephrine
and epinephrine that accompany and aggravate HF. 15-18 Thus, in the case
of adrenal a 2 ARs, desensitization by b arrs plays a detrimental role in HF
pathophysiology and blockade of adrenal b arr action on a 2 ARs, either
directly or indirectly, for example, by blocking adrenal GRK2, could be
pursued for the treatment of HF ( Table 12.1 ).

2.2.2 Cardiovascular a 2 ARs and b arrs as signal transducers
The beneficial hypotensive response to activation of centrally located a 2 ARs
comes with an important caveat: the unwanted effect of sedation. 48 Sedation
tests in b arr2KO mice treated with the a 2 AR agonist 5-bromo- N -(4,5-
dihydro-1 H- imidazol-2-yl)-6-quinoxalinamine (brimonidine or UK14304)