Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding

Marco Cattaneo, Maddalena L. Zighetti, Rossana Lombardi, Constantino Martinez, Anna Lecchi, Pamela B. Conley, Jerry Ware, Zaverio M. Ruggeri

Research output: Contribution to journalArticlepeer-review


We have identified structural attributes required for signal transduction through a seven-transmembrane-domain receptor. Platelets from a patient (AC) with a congenital bleeding disorder had normal shape change but reduced and reversible aggregation in response to 4 μM ADP, similar to normal platelets with blocked P2Y12 receptor. The response to 20 μM ADP, albeit still decreased, was more pronounced and was reduced by a P2Y12 antagonist, indicating some residual receptor function. ADP failed to lower the adenylyl cyclase activity stimulated by prostaglandin E1 in the patient's platelets, even though the number and affinity of 2-methylthioadenosine 5′-[33P]diphosphate-binding sites was normal. Analysis of the patient's P2Y12 gene revealed a G-to-A transition in one allele, changing the codon for Arg-256 in the sixth transmembrane domain to Gln, and a C-to-T transition in the other allele, changing the codon for Arg-265 in the third extracellular loop to Trp. Neither mutation interfered with receptor surface expression but both altered function, since ADP inhibited the forskolin-induced increase of cAMP markedly less in cells transfected with either mutant P2Y12 as compared with wild-type receptor. These studies delineate a region of P2Y12 required for normal function after ADP binding.

Original languageEnglish
Pages (from-to)1978-1983
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number4
Publication statusPublished - Feb 18 2003


  • ADP
  • G-protein coupled receptors
  • Platelet aggregation
  • Platelet function disorder

ASJC Scopus subject areas

  • Genetics
  • General


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