Molecular defects of the platelet P2 receptors

Abstract

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-tomoderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and posttraumatic blood loss. Defects of P2Y 12 should be suspected when ADP, even at high concentrations (≥10 μM), 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.

The platelet P2Y12 receptor under normal and pathological conditions. Assessment with the radiolabeled selective antagonist [3H]PSB-0413

“…Similarly, polymorphisms of the P2Y 12 receptor have been proposed to be associated with a gain of function in terms of platelet activation and an increased risk of cardiovascular disease [37][38][39][40][41], but the relative densities and binding properties of the platelet P2Y 12 receptor associated with these polymorphisms are not known. Finally, patients with inherited P2Y 12 defects may present with total absence of receptor expression [6,18,42] while other express abnormal receptors with modified binding properties or normal binding properties and, likely, defective signal transduction [19,42], which require fine characterization [4,20,42]. The [ 3 H]PSB-0413 selective P2Y 12 radioligand was reported recently with only preliminary evaluation as a selective tool using membrane preparations [16] but not intact platelets from healthy control, patients with inherited P2Y 12 defects, P2Y 12 Saturation experiments were performed on human intact platelets from two patients (A,B) with severe P2Y 12 deficiency [6,18] and one patient with dysfunctional P2Y 12 (C) [19] and on ten healthy donors as control.…”

Purinergic Signaling in the Cardiovascular System

“…198 Review articles have been published on various aspects of purinergic signaling in thrombosis and inflammation, including the use of the P2Y 12 receptor antagonists clopidogrel, prasugrel, cangrelor, and ticagrelor 199,200 ; platelets and inflammation 201 ; and P2Y receptor polymorphisms and disease. 202 …”

Influence of Common and Rare Genetic Variation on Warfarin Dose Among African–Americans and European–Americans Using the Exome Array

“…Among them, SNPs exm1279100 (Bonferroni adjusted p = 0.061 and FDR q = 0.019) and exm847442 (Bonferroni corrected p = 0.075 and FDR q = 0.011) showed marginally significant association in the discovery cohort in AAs and EAs, respectively, even after Bonferroni correction. SNP exm1279100 locates on chromosome 17 in gene P2RX1, a member of the purigenic receptor family, associated with bleeding disorders, platelet activation congestive heart failure and neurogenic bladder [51][52][53]. Given that gene P2RX1 is in the platelet activation, signaling and aggregation pathway and is associated with bleeding disorders, it is likely that SNP exm1279100 is associated with warfarin dose response.…”