ADP Receptor Defects/ADP-Rezeptor-Defekte

Abstract

Platelets possess at least two P2 receptors for adenosine diphosphate (ADP). The P2Y 1 receptor is responsible for the mobilization of ionized calcium from internal stores and mediates the ADP-induced platelet shape change and initial wave of rapidly reversible aggregation. The other receptor, termed P2Y 12 , mediates a sustained ADP-induced aggregation not preceded by shape change. The combined action of P2Y 1 and P2Y 12 is necessary for the full platelet aggregation response to ADP. P2Y 12 is defective in some patients with congenital bleeding disorders. Four patients with severe deficiency of P2Y 12 have been described so far. Sequence analysis of the P2Y 12 locus of three of these patients revealed homozygous mutations producing a frame shift mutation and premature truncation of the protein. The fourth patient had an allele with a frame shift mutation and a normal allele, which could be silenced by an additional, as yet unknown mutation. Recently, we described a patient with a dysfunctional P2Y 12 . The patient is compound heterozygote: one allele contained a G to A transition resulting in an Arg 256 to Gln codon substitution (R256Q) and the other allele contained a C to T transition resulting in an Arg 265 to Trp codon substitution (R265W). Stable CHO cell lines were established expressing either wild-type P2Y 12 , P2Y 12 R256Q or P2Y 12 R265W. Neither mutation blocked the ability of the P2Y 12 receptor to translocate to the CHO cell surface. ADP at all tested concentrations (0.1±10 mM) greatly inhibited the forskolininduced increase of cAMP in CHO cells transfected with wild-type P2Y 12 , while CHO cells transfected with either mutant protein were only partially inhibited by ADP. Thus, the molecular basis for the patient's dysfunctional platelet phenotype is explained by missense mutations and the expression of a dysfunctional P2Y 12 receptor.

Editorial: Analysis of Platelet Function and Dysfunction – From Pathobiochemistry to Diagnostics –

“…As Cattaneo demonstrates, platelet function can be analyzed hand in hand with the molecular background. The finding that some rare congenital bleeding disorders are due to ADP receptor defects underlined the clinical and therapeutic importance of these purinergic receptors (9). Finally, Zotz and Scharf focus on the molecular heterogeneity of platelet receptors.…”