Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 308

b arr1-mediated activation of c PLA 2 , leading to release of arachidonic acid
(AA), the precursor of all prostaglandins, including PGD 2 , and the dilation
of cutaneous vessels that produces the unpleasant “flushing” effect. 44 Thus,
b arr1 mediates signal transduction of the niacin receptor toward vasodilata-
tion, which in this case is a negative (adverse) effect, whereas the therapeu-
tically desirable GPR109A signaling toward lipid lowering is entirely
G-protein-dependent ( Table 12.1 ).
In this setting, b arr1 inhibition at the GPR109A receptor or a “biased”
GPR109A ligand capable of activating G protein signaling without rec-
ruiting b arrs would be therapeutically desirable, as it would confer the same
therapeutic effect of niacin on lipid metabolismwithout the adverse effect of
“flushing” ( Table 12.1 ). Such a G-protein-biased GPR109A receptor ago-
nist might not only reduce the adverse effect of flushing, but also have the
added benefit of enhancing the therapeutic effect of lipid level reduction,
given that b arr1 desensitizes the beneficial G-protein-dependent signaling
of the GPR109A receptor. Notably, a series of pyrazole derivatives with
GPR109A receptor agonist properties have been synthesized that are devoid
of the ability to internalize the GPR109A receptor and activate ERK, that is,
the classic b arr-dependent signaling effects, and, indeed, they do not
cause “flushing.” 99 These compounds, including one with very potent
serum free fatty acid-lowering properties, 3-(1 H -tetrazol-5-yl)-1,4,5,6-
tetrahydrocyclopentapyrazole (MK-0354), 100 appear superior to niacin for
lipid-lowering therapy and are most probably G-protein-selective “biased”
agonists at the GPR109A receptor, that is, they activate G protein signaling
while blocking b arr1 activation. In conclusion, b arr1 blockade has potential
as a strategy to improve the lipid-lowering treatment with niacin
( Table 12.1 ), which despite some recent controversies, 95 is still thought
to be useful for the prevention of cardiovascular diseases, such as atheroscle-
rosis and acute coronary syndrome.
4.4. P2Y Receptors
The P2Y family of purinergic receptors (receptors for purine nucleosides
and nucleotides, such as adenosine 5 0 -diphosphate, ADP; and adenosine
5 0 -triphosphate, ATP) constitutes the metabotropic purinergic receptor
family, all the members of which are GPCRs. 101 P2Y 1 and P2Y 12 receptors
for ADP are expressed in platelets and play a key role in platelet activation
and thrombosis. 101 They are targeted by several antiplatelet drugs, such as
clopidogrel, prasugrel, and ticagrelor. 101 Platelets activated by ADP become