Platelet signal transduction defect with G alpha subunit dysfunction and diminished G alpha(q) in a patient with abnormal platelet responses

被引:70
作者
Gabbeta, J
Yang, X
Kowalska, MA
Sun, L
Dhanasekaran, N
Rao, AK
机构
[1] TEMPLE UNIV,SCH MED,DIV HEMATOL & THROMBOEMBOL DIS,DEPT MED,PHILADELPHIA,PA 19140
[2] TEMPLE UNIV,SCH MED,SOL SHERRY THROMBOSIS RES CTR,DEPT MED,PHILADELPHIA,PA 19140
[3] TEMPLE UNIV,SCH MED,DEPT BIOCHEM,FELS INST CANC RES & MOL BIOL,PHILADELPHIA,PA 19140
关键词
D O I
10.1073/pnas.94.16.8750
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
G proteins play a major role in signal transduction upon platelet activation, We have previously reported a patient with impaired agonist-induced aggregation, secretion, arachidonate release, and Ca2+ mobilization, Present studies demonstrated that platelet phospholipase A(2) (cytosolic and membrane) activity in the patient was normal, Receptor-mediated activation of glycoprotein (GP) IIb-IIa complex measured by flow cytometry using antibody PAC-I was diminished despite normal amounts of GPIIb-IIIa on platelets. Ca2+ release induced by guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]) was diminished in the patient's platelets, suggesting a defect distal to agonist receptors, GTPase activity (a function of alpha-subunit) in platelet membranes was normal in resting state but was diminished compared with normal subjects on stimulation with thrombin, platelet-activating factor, or the thromboxane A(2) analog U46619. Binding of S-35-labeled GTP[gamma S] to platelet membranes was decreased under both basal and thrombin-stimulated states, Iloprost (a stable prostaglandin I-2 analog) -induced rise in cAMP (mediated by G alpha(s)) and its inhibition (mediated by G alpha(i)) by thrombin in the patient's platelet membranes were normal, Immunoblot analysis of G alpha subunits in the patient's platelet membranes showed a decrease in G alpha(q) (<50%) but not G alpha(i), G alpha(z), G alpha(12), and G alpha(13). These studies provide evidence for a hitherto undescribed defect in human platelet G-protein alpha-subunit function leading to impaired platelet responses, and they provide further evidence for a major role of G alpha(q) in thrombin-induced responses.
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页码:8750 / 8755
页数:6
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