Defective signal transduction induced by thromboxane A2 in a patient with a mild bleeding disorder: impaired phospholipase C activation despite normal phospholipase A2 activation.
A patient with a mild bleeding disorder whose platelets responded defectively to thromboxane A2 (TXA2) was identified, and the mechanism of this dysfunction was analyzed. The platelets were defective in shape change, aggregation, and release reaction in response to synthetic TXA2 mimetic (STA2). When the platelet TXA2 receptor was examined with both a 125I-labeled derivative of a TXA2 receptor antagonist ([125I]-PTAOH) and [3H]-labeled TXA2 agonist ([3H]U-46619), the equilibrium dissociation rate constants (kd) and the maximal concentrations of binding sites (Bmax) of the platelets to both ligands were within normal ranges, suggesting that the binding capacity of their TXA2 receptor was normal. STA2 could not induce IP3 formation and intracellular Ca2+ mobilization, whereas these responses to thrombin were within normal ranges. GTPase activity was also decreased when the patient's platelet membrane was challenged with STA2. On the other hand, lysophosphatidylinositol formation, which is a direct indicator of phospholipase A2 (PLA2) activation, was found to be normal when the [3H]-inositol-labeled platelets were challenged with STA2. Thromboxane B2 (TXB2) was also produced in response to STA2. These results suggested that the abnormality in these platelets was impaired coupling between TXA2 receptor and phospholipase C (PLC) activation. Furthermore, it is also suggested that the activation of PLA2 and PLC are separable events in thromboxane-induced platelet activation.
Fuse
I
I
First Department of Internal Medicine, Niigata University School of Medicine, Japan.
Mito
M
M
Hattori
A
A
Higuchi
W
W
Shibata
A
A
Ushikubi
F
F
Okuma
M
M
Yahata
K
K
D000328:Adult; D001778:Blood Coagulation Disorders / Q000097:blood / Q000201:enzymology*; D001792:Blood Platelets / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D002118:Calcium / Q000097:blood; D004789:Enzyme Activation; D005260:Female; D020558:GTP Phosphohydrolases / Q000097:blood; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000097:blood; D008297:Male; D008875:Middle Aged; D010741:Phospholipases A / Q000097:blood*; D054467:Phospholipases A2; D010974:Platelet Aggregation; D017482:Receptors, Thromboxane / Q000378:metabolism; D015398:Signal Transduction; D013917:Thrombin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000097:blood*
D017482:Receptors, Thromboxane; D013928:Thromboxane A2; C037866:STA 2; D015544:Inositol 1,4,5-Trisphosphate; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D013917:Thrombin; D020558:GTP Phosphohydrolases; D002118:Calcium