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Molecular Pharmacology

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Rapid CommunicationAccelerated Communication

Molecular Cloning of the Platelet P2TAC ADP Receptor: Pharmacological Comparison with Another ADP Receptor, the P2Y1 Receptor

Jun Takasaki, Masazumi Kamohara, Tetsu Saito, Mitsuyuki Matsumoto, Shun-ichiro Matsumoto, Takahide Ohishi, Takatoshi Soga, Hitoshi Matsushime and Kiyoshi Furuichi
Molecular Pharmacology September 2001, 60 (3) 432-439;
Jun Takasaki
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Masazumi Kamohara
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Tetsu Saito
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Mitsuyuki Matsumoto
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Shun-ichiro Matsumoto
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Takahide Ohishi
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Takatoshi Soga
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Hitoshi Matsushime
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Kiyoshi Furuichi
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Abstract

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 HORK3gene 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.

Footnotes

  • Abbreviations:
    GPCR
    G protein-coupled receptor
    RACE
    rapid amplification of cDNA ends
    PCR
    polymerase chain reaction
    ORF
    open-reading frame
    IBMX
    3-isobutyl 1-methylxanthine
    2MeSADP
    2-methylthio-ADP
    RT-PCR
    reverse transcription-polymerase chain reaction
    PPADS
    pyridoxal-phosphate-6-azophenyl-2′,4′disulfonic acid
    AR-C69931 MX
    N6-[2-methlthio]ethyl]-2-[3,3,3-trifluoropropylthio]-5′-adenylic acid, monohydride with dichloromethylenebiphosphonic acid
    2MeSATP
    2-methylthio-ATP
    ADPβS
    adenosine 5′-O-(2-thiodiphosphate)
    2MeSAMP
    2-methylthio-AMP
    A3P5PS
    adenosine 3′-phosphate 5′-phosphosulfate
    GTPγS
    guanosine 5′-O-(thiotriphosphate)
    • Received February 7, 2001.
    • Accepted May 7, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (3)
Molecular Pharmacology
Vol. 60, Issue 3
1 Sep 2001
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Rapid CommunicationAccelerated Communication

Molecular Cloning of the Platelet P2TAC ADP Receptor: Pharmacological Comparison with Another ADP Receptor, the P2Y1 Receptor

Jun Takasaki, Masazumi Kamohara, Tetsu Saito, Mitsuyuki Matsumoto, Shun-ichiro Matsumoto, Takahide Ohishi, Takatoshi Soga, Hitoshi Matsushime and Kiyoshi Furuichi
Molecular Pharmacology September 1, 2001, 60 (3) 432-439;

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Rapid CommunicationAccelerated Communication

Molecular Cloning of the Platelet P2TAC ADP Receptor: Pharmacological Comparison with Another ADP Receptor, the P2Y1 Receptor

Jun Takasaki, Masazumi Kamohara, Tetsu Saito, Mitsuyuki Matsumoto, Shun-ichiro Matsumoto, Takahide Ohishi, Takatoshi Soga, Hitoshi Matsushime and Kiyoshi Furuichi
Molecular Pharmacology September 1, 2001, 60 (3) 432-439;
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