Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 309

refractory to restimulation, a phenomenon that has been attributed to P2Y 1
receptor desensitization and internalization. 102 Although a substantial
fraction of P2Y 12 receptors also rapidly internalize upon stimulation, it
remains uncertain whether this ADP receptor type is also subject to
desensitization. 103
Very recently, it was shown in platelets derived from b arr1KO mice that
b arr1 can promote thrombus formation, not by desensitizing P2Y receptors
but by transducing their signaling to integrin a IIb b 3 . 45 In fact, neither b arr
appears to be involved in agonist (ADP)-induced platelet activation and P2Y
receptor desensitization. 45 Platelets from either b arr1KO or b arr2KO mice
responded normally to a series of agonists, and displayed similar desensitiza-
tion to ADP as wild-type mouse platelets, suggesting no role for b arrs in
these processes. 45 No defect in hemostasis was observed in either KO line.
In b arr1KO platelets only, defects in arterial thrombosis formation attributed
to defective integrin a IIb b 3 shape change were observed, 45 suggesting a role
for b arr1, but not for b arr2, in thrombosis and P2Y receptor signaling
toward integrin a IIb b 3 . This b arr1-dependent signaling to integrin a IIb b 3
was Src kinase- and Akt kinase-mediated. 45 Thus, it appears that b arr1, act-
ing as signal transducer of platelet ADP P2Y receptors, can promote arterial
thrombosis ( Table 12.1 ). Therefore, inhibition of platelet b arr1 might be of
therapeutic value in thromboembolic disease treatment.
P2Y receptors are also present in arterial smooth muscle cells, wherein
they induce vasoconstriction, hypertrophy, and hyperplasia, via typical cou-
pling to the G q/11 protein-phospholipase C-Ca 2 þ signaling pathway. 46
Using b arr isoform-specific siRNA knockdown, b arr1 was recently shown
to act as a desensitizer of P2Y receptor-induced contractility in adult Wistar
rat mesenteric arterial smooth muscle cells in vitro , in response to uridine 5 0 -
triphosphate (UTP), another purine nucleotide. 46

b arr1 appears to be the
only b arr isoform capable of conferring P2Y receptor desensitization in these
cells and it does so following phosphorylation of the receptors by GRK2
only. 46 In addition, siRNA-mediated depletion of b arr1 in rat aortic smooth
muscle cells in vitro prolongs signaling of UTP-stimulated P2Y receptors
toward activation of p38 MAPK and ERKs, providing additional evidence
that b arr1, but not b arr2, acts as a desensitizer of arterial smooth muscle cell
P2Y receptors. 41 Thus, with regard to VSM cell-residing P2Y receptors,
b arr1 appears capable of antagonizing purine nucleotide-dependent vaso-
constriction and arterial smooth muscle cell migration, which suggests that
enhancing its activity in VSM cells might be beneficial in treatment of
hypertension and vascular stenosis/arteriosclerosis ( Table 12.1 ).