Protease-Activated Receptors in Inflammation and Vascular Biology
Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors that play critical roles in thrombosis, inflammation, and vascular biologyThe PARs are cleaved by thrombin and other proteases at a specific peptide bond to expose a new N-terminus that binds to the body of the receptor in an unusual intramolecular mode. A major interest of our research group is to study the molecular mechanism of protease activation of the PARs and the subsequent signaling in vascular cells and in cancer.
Figure 1. Interest in PARs and their role in physiology and disease has heightened in recent years.
PARs and Thrombosis
Thrombosis associated with the pathophysiological activation of platelets and vascular cells has brought thrombin and its receptors to the forefront of cardiovascular medicine. Protease signaling through the protease-activated receptors (PARs) has been shown to influence a wide range of physiological responses including platelet activation, intimal hyperplasia, inflammation, and maintenance of vascular tone and barrier function.
Figure 2. The figure illustrates interactions with PARs and several of the physiological responses to the interaction.
Pepducins as Novel Cell-Penetrating Intracellular Agonists and Antagonists of G Protein-Coupled Receptors
We have established a new technology based on cell-penetrating peptides known as pepducins as a novel approach of activating or inhibiting signaling between selected receptors and G proteins. These cell-penetrating pepducins are powerful tools to evaluate PARs, chemokines, and other receptors as potential therapeutic targets in both in vitro and mouse model systems.
Figure 3. A model of pepducin-mediated effects is shown.