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Vol. 60, Issue 3, 432-439, September 2001
Molecular Medicine Laboratories, Institute for Drug Discovery
Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan
Platelet activation plays an essential role in thrombosis. ADP-induced
platelet aggregation is mediated by two distinct G protein-coupled ADP
receptors, Gq-linked P2Y1, and Gi-linked P2TAC, which has not been cloned. The cDNA encoding a novel G protein-coupled receptor, termed HORK3, was isolated. The HORK3
gene and P2Y1 gene were mapped to
chromosome 3q21-q25. HORK3, when transfected in the rat glioma cell
subline (C6-15), responded to 2-methylthio-ADP (2MeSADP)
(EC50 = 0.08 nM) and ADP (EC50 = 42 nM) with inhibition of forskolin-stimulated cAMP accumulation. 2MeSADP
(EC50 = 1.3 nM) and ADP (EC50 = 18 nM) also induced intracellular calcium mobilization in
P2Y1-expressing cells. These results show that HORK3 is a
Gi/o-coupled receptor and that its natural ligand is ADP. AR-C69931 MX
and 2MeSAMP, P2TAC antagonists, selectively inhibited
2MeSADP-induced adenylyl cyclase inhibition in HORK3-expressing cells.
On the other hand, A3P5PS, a P2Y1 antagonist, blocked only 2MeSADP-induced calcium mobilization in P2Y1-expressing
cells. HORK3 mRNA was detected in human platelets and the expression level of HORK3 was equivalent to that of P2Y1. These
observations indicate that HORK3 has the characteristics of the
proposed P2TAC receptor. We have also determined that
[3H]2MeSADP binds to cloned HORK3 and P2Y1.
Competition binding experiments revealed a similarity in the rank
orders of potency of agonists and the selectivity of antagonists as
obtained in the functional assay. These results support the view that
P2Y1 functions as a high-affinity ADP receptor and
P2TAC as a low-affinity ADP receptor in platelets.
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