Semin Thromb Hemost 2005; 31(2): 168-173
DOI: 10.1055/s-2005-869522
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

The P2 Receptors and Congenital Platelet Function Defects

Marco Cattaneo1
  • 1Professor, Unit of Hematology and Thrombosis, Ospedale San Paolo, Department of Medicine, Surgery and Dentistry, University of Milano, Milan, Italy
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26. April 2005 (online)


Platelets possess three P2 receptors: two (P2Y1 and P2Y12) are receptors for adenosine diphosphate (ADP), and one (P2X1) is a receptor for adenosine triphosphate (ATP). The P2Y1 receptor, which is coupled to Gq and phospholipase C-β, is responsible for mobilization of ionized calcium from internal stores and mediates the ADP-induced platelet shape change and initial wave of rapidly reversible aggregation. The other ADP receptor, P2Y12, is negatively coupled to adenylyl cyclase through Gi and mediates a progressive and sustained ADP-induced aggregation not preceded by shape change. In addition, this receptor plays an important role in the potentiation of platelet secretion induced by several platelet agonists. The combined action of P2Y1 and P2Y12 is necessary for the full platelet aggregation response to ADP. Four patients with severe deficiency of P2Y12 have been described so far. Sequence analysis of the P2Y12 locus of three of these patients revealed homozygous mutations that produced 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. More recently, we described a patient with a congenital bleeding disorder and a dysfunctional P2Y12. The patient is a compound heterozygote, in whom one allele contained a G to A transition resulting in an Arg256 to Gln codon substitution (R256Q) and the other allele contained a C to T transition resulting in an Arg265 to Trp codon substitution (R265W). The two substitutions are located in TM6 and EL3 of the receptor. Stable Chinese hamster ovaries (CHO) cell lines were established expressing either wild-type P2Y12 and P2Y12 R256Q or P2Y12 R265W. Neither mutation blocked the ability of the P2Y12 receptor to translocate to the CHO cell surface. ADP at all tested concentrations (0.1 to 10 μM) greatly inhibited the forskolin-induced increase of cyclic adenosine monophosphate (cAMP) in CHO cells transfected with wild-type P2Y12, whereas 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 P2Y12 receptor. The localization of both mutations in TM6 and EL3 identifies this region of P2Y12 as a structurally and functionally critical region of the receptor.


Marco Cattaneo

Unit of Hematology and Thrombosis, Ospedale San Paolo, DMCO University of Milano

Via di Rudinì, 8, 20142 Milan, Italy