Molecular defects of the platelet P2 receptors

Human platelets express three types of P2 receptors, which play important roles in platelet function: P2X(1), P2Y(1) and P2Y(12). Only patients with either quantitative or qualitative abnormalities of the platelet P2Y(12) receptor have been well-characterized so far. Deficiencies of P2Y(12) are associated with nucleotide deletions in the open-reading frame, frameshifts, and early truncation of the protein, or with a nucleotide substitution in the transduction initiation codon. Congenital dysfunctions of P2Y(12) are associated with molecular defects involving the sixth trans-membrane domain or the adjacent third extracellular loop of the receptor, which identify a region of the protein whose integrity is necessary for normal receptor function. A mutation, predicting a lysine to glutamate (Lys174Glu) substitution was associated with decreased ligand binding to the receptor, suggesting that it is responsible for disruption of the adenosine diphosphate (ADP)-binding site of the receptor. Patients with P2Y(12) defects display a mild-to-moderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and post-traumatic blood loss. Defects of P2Y(12) should be suspected when ADP, even at high concentrations (a parts per thousand yen10 mu M), is unable to induce full, irreversible platelet aggregation. Tests that evaluate the degree of inhibition of adenylyl cyclase by ADP should be used to confirm the diagnosis.