Thrombin

Table of contents 1. Thrombin: structure, functions and regulation 1.1. Introduction 1.2. Thrombin and Na+ 1.3. Thrombin structure 1.4. Kinetics of Na+ activation 1.5. Structures of E*, E and E:Na+ 1.6. Thrombin interaction with protein C 1.7. Thrombin interaction with the PARs 1.8. Dissociating procoagulant and anticoagulant activities 1.9. WE: a prototypic anticoagulant/antithrombotic thrombin 1.10. References 2. Thrombin: to PAR or not to PAR, and the regulation of inflammation 2.1. Introduction 2.2. Thrombin and the search for its receptor 2.3. Enzymes other than thrombin that are potential physiological regulators of PARs 2.3.1. Enzymes of the coagulation pathway 2.3.2. Proteinases of the gastrointestinal tract 2.3.3. PAR-regulating proteinases in the central nervous system 2.3.4. Immune cell-derived proteinases and PARs 2.3.5. Tumor-derived proteinases and a possible physiological role for kallikrein-related peptidases (KLKs) as PAR regulators 2.3.6. Pathogen-derived proteinases and PAR activation 2.4. Receptor dynamics and cell signaling: enzyme versus peptide-mediated activation 2.4.1. PAR-mediated signaling 2.4.2. PAR activation by enzyme versus peptide 2.5. PAR activation and the inflammation actions of thrombin 2.6. Non-PAR mechanisms of cell regulation mediated by thrombin and other proteinases 2.6.1. Signaling targets that are not 'classical' receptors 2.6.2. Non-catalytic mechanisms for proteinase-mediated signaling 2.6.3. Thrombin-mediated generation of agonists from fibrin and other substrates 2.7. Therapeutic implications of thrombin action via PAR and non-PAR mechanisms 2.7.1. Targeting thrombin and other serine proteinases 2.7.2. Targeting the PARs 2.8. Summary 2.9. Acknowledgements 2.10. References 3. Regulation of thrombin receptor signaling 3.1. Introduction 3.2. Cell type specific expression of thrombin receptors 3.3. Thrombin receptor activation and signaling 3.3.1. Proteolytic mechanism of thrombin receptor activation 3.3.2. Thrombin