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Role of the thrombin receptor in development and evidence for a second receptor
A J Connolly1, H Ishihara, M L Kahn
1Cardiovascular Research Institute, University of California, San Francisco, 94143-0524, USA.
Abstract:
Thrombin, a coagulation protease generated at sites of vascular injury, activates platelets, endothelial cells, leukocytes and mesenchymal cells. A G-protein-coupled receptor that is proteolytically activated by thrombin is a target for drug development aimed at blocking thrombosis, inflammation and proliferation. Here we show that although disruption of the thrombin receptor (tr) gene in mice causes about half of the tr-/- embryos to die at embryonic day 9-10, half survive to become grossly normal adult mice with no bleeding diathesis. Strikingly, tr-/- platelets respond strongly to thrombin, whereas tr-/- fibroblasts lose their ability to respond to thrombin. We conclude that the thrombin receptor plays an unexpected role in embryonic development, suggesting a possible new function for the 'coagulation' proteases themselves. Moreover, a second platelet thrombin receptor exists, and different thrombin receptors have tissue-specific roles. This may allow development of therapeutics that will selectively block thrombin's different cellular actions.
Insights
The thrombin receptor (tr) is crucial for embryonic development, with its absence causing embryonic lethality. However, a second thrombin receptor allows some survival and normal adult function.
Area of Science:
- Biochemistry
- Developmental Biology
- Pharmacology
Background:
- Thrombin is a key coagulation protease activated at vascular injury sites.
- It activates various cells, including platelets, endothelial cells, and leukocytes.
- A G-protein-coupled receptor activated by thrombin is a drug development target for thrombosis and inflammation.
Purpose of the Study:
- To investigate the role of the thrombin receptor (tr) in embryonic development.
- To explore the existence and function of additional thrombin receptors.
- To assess the potential for tissue-specific therapeutic targeting of thrombin's actions.
Main Methods:
- Gene disruption of the thrombin receptor (tr) in mice.
- Observation of embryonic lethality and adult phenotypes.
- Analysis of cellular responses to thrombin in knockout cells.
Main Results:
- Disruption of the tr gene led to embryonic lethality in approximately 50% of embryos at days 9-10.
- Surviving tr-/- mice were grossly normal adults without bleeding issues.
- tr-/- platelets retained thrombin responsiveness, but tr-/- fibroblasts lost it, indicating distinct thrombin receptor roles.
Conclusions:
- The thrombin receptor plays a critical, unexpected role in embryonic development.
- A second platelet thrombin receptor exists, and different thrombin receptors have tissue-specific functions.
- This suggests potential for developing therapeutics that selectively target specific thrombin-mediated cellular actions.