Both TMEM16F-dependent and TMEM16F-independent pathways contribute to phosphatidylserine exposure in platelet apoptosis and platelet activation
| Autor: | Jef L. N. Wolfs, Frauke Swieringa, Edouard M. Bevers, Peter William Collins, Nadine J.A. Mattheij, Marion A.H. Feijge, Roger van Kruchten, Christine Saunders, Johan W. M. Heemskerk |
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| Přispěvatelé: | Promovendi CD, Biochemie, Ondersteunend personeel CD, RS: CARIM School for Cardiovascular Diseases |
| Rok vydání: | 2013 |
| Předmět: |
Blood Platelets
medicine.medical_specialty Immunology Anoctamins Apoptosis Phosphatidylserines Biology Biochemistry Hemostatics Cyclophilins chemistry.chemical_compound Phospholipid scrambling Scott syndrome Internal medicine Crotalid Venoms medicine Humans Lectins C-Type Platelet Platelet activation Phospholipid Transfer Proteins Thrombin Depolarization Convulxin Cell Biology Hematology Phosphatidylserine Blood Coagulation Disorders Flow Cytometry Platelet Activation medicine.disease Mitochondria Endocrinology chemistry Case-Control Studies Caspases Calcium |
| Zdroj: | Blood, 121(10), 1850-1857. The American Society of Hematology |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2012-09-454314 |
| Popis: | Scott syndrome, a bleeding disorder caused by defective phospholipid scrambling, has been associated with mutations in the TMEM16F gene. The role of TMEM16F in apoptosis- or agonist-induced phosphatidylserine (PS) exposure was studied in platelets from a Scott syndrome patient and control subjects. Whereas stimulation of control platelets with the BH3-mimetic ABT737 resulted in 2 distinct fractions with moderate and high PS exposure, the high PS-exposing fraction was markedly delayed in Scott platelets. High, but not moderate, PS exposure in platelets was suppressed by chelation of intracellular Ca(2+), whereas caspase inhibition completely abolished ABT737-induced PS exposure in both Scott and control platelets. On the other hand, high PS exposure induced by the Ca(2+)-mobilizing agonists convulxin/thrombin fully relied on mitochondrial depolarization and was virtually absent in Scott platelets. Finally, PS exposure induced by collagen/thrombin was partly affected in Scott platelets, and the residual PS positive fraction was insensitive to inhibition of caspases or mitochondrial depolarization. In conclusion, TMEM16F is not required for, but enhances, caspase-dependent PS exposure; convulxin-/thrombin-induced PS exposure is entirely dependent on TMEM16F, whereas collagen/thrombin-induced PS exposure results from 2 distinct pathways, one of which involves mitochondrial depolarization and is mediated by TMEM16F. |
| Databáze: | OpenAIRE |
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