Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 310

4.5. Protease-activated receptors
Another family of GPCRs with important cardiovascular system effects is
the protease-activated receptor (PAR) family, which responds to thrombin
and other proteases that activate the receptor by proteolytic cleavage of its
extracellular N-terminus. 104 They are divided into four distinct types
(PAR 1-4 ), all of which couple primarily to the G q/11 protein-phospholipase
C-Ca 2 þ signaling pathway, although PAR 1 and PAR 2 can also couple to G i
proteins, leading to inhibition of AC and lowering of cAMP levels. They
reside in membranes of endothelial cells and platelets, among other cell
types, wherein they mediate blood clot formation, that is, thrombosis. 104
PARs are well-characterized b arr substrates, with b arrs acting upon them
as either desensitizers/internalizers or signal transducers. 104
A recent study in b arr1KO mouse platelets suggests that b arr1 can medi-
ate signaling from thrombin-stimulated PAR4, in addition to its role in ADP
P2Y receptor signaling in these cells. b Arr1, but not b arr2, was found to
transduce the agonist-activated PAR4 signal to phosphatidylinositol-3
kinase (PI3K) and subsequent Akt/PKB activation in platelets, leading to
increased fibrinogen binding and thrombus formation. 47 Interestingly, the
authors also found that this b arr1-dependent PAR4 signaling was potenti-
ated by ADP P2Y receptors, as P2Y 1 receptor activation appears to enhance
it via PKC activation and the P2Y 12 receptors appear to heterodimerize with
PAR4, facilitating its interaction with b arr1. 47 These signaling effects of
b arr1 on PAR4 are consistent with the reduced development of ferric
chloride-stimulated thrombosis observed in b arr1KO mice. 45,47 Thus,
platelet b arr1 seems to mediate not only the prothrombotic signaling of
P2Y receptors but also that of PARs ( Table 12.1 ). Taken together, these
findings on P2Y receptor and PAR b arr1-dependent signaling in platelets
make platelet b arr1 an attractive therapeutic target for treatment of various
thromboembolic and other blood coagulation disorders.
5. CARDIOVASCULAR NON-GPCRs AND b ARRS
As already described in several examples of b arr-dependent signaling
by cardiac GPCRs, an important mechanism by which b arrs direct ERK1/2
signaling in the heart, regulating cardiomyocyte hypertrophy and survival/
apoptosis, is transactivation of the cardiac EGFR, a receptor belonging to the
receptor tyrosine kinase family. 105 In this pathway, b arrs act “upstream” of
the EGFR and “downstream” of a GPCR. In some cases, b arrs are known to