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

ABSTRACT: 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 microM ADP, similar to normal platelets with blocked P2Y(12) receptor. The response to 20 microM ADP, albeit still decreased, was more pronounced and was reduced by a P2Y(12) antagonist, indicating some residual receptor function. ADP failed to lower the adenylyl cyclase activity stimulated by prostaglandin E(1) in the patient's platelets, even though the number and affinity of 2-methylthioadenosine 5'-[(33)P]diphosphate-binding sites was normal. Analysis of the patient's P2Y(12) 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 P2Y(12) as compared with wild-type receptor. These studies delineate a region of P2Y(12) required for normal function after ADP binding.

SUBMITTER: Cattaneo M

PROVIDER: S-EPMC149944 | biostudies-literature | 2003 Feb

REPOSITORIES: biostudies-literature

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

Cattaneo Marco M Zighetti Maddalena L ML Lombardi Rossana R Martinez Constantino C Lecchi Anna A Conley Pamela B PB Ware Jerry J Ruggeri Zaverio M ZM

Proceedings of the National Academy of Sciences of the United States of America 20030210 4

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 microM ADP, similar to normal platelets with blocked P2Y(12) receptor. The response to 20 microM ADP, albeit still decreased, was more pronounced and was reduced by a P2Y(12) antagonist, indicating some residual receptor function. AD ...[more]

PMID: 12578987

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Dataset Information

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

Publications

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

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