The multiple layers of signaling selectivity at protease-activated receptors

The Protease-Activated Receptors (PARs) are G-protein-coupled receptors (GPCRs) characterized by a unique mechanism of activation. They carry built in their extended N-terminal structure their own activating agonist, in the form of a cryptic tethered ligand, unmasked by an irreversible proteolytic cleavage. Besides, PARs display several other particular properties, that converge and create interacting and intertwined layers of molecular processes regulating receptor's selective signaling with important biological and pharmacological consequences. These include the operation of multiple proteases, co-factors and protease inhibitors expressed in many types of cells and tissues, creating a dynamic balance between activators and inhibitors of PAR function in a tissue specific way. Membrane microdomain compartmentalization and allosteric modulation through intermolecular interactions between PARs adds further complexity to the receptor signaling and desensitization. Furthermore, molecular components interacting with thrombin and PARs take on new roles. In particular, activated protein C (APC) forms a significant negative feedback loop for thrombin with anticoagulant properties. In addition, APC exerts anti-inflammatory and direct neuroprotective effects in vivo and in vitro. This has informed the pharmacological dissection of anticoagulant from the anti-inflammatory and neuroprotective actions of APC and the generation of engineered APC mutations with diminished risk of serious bleeding, while preserving the cytoprotective effects of APC on cells. Even more important, these advances have made possible a paradigm shift, away from a "neurocentric" and towards a "vasculo-neuronal-inflammatory model of action", which supports novel pharmacological strategies targeting multiple disease mechanisms.