Differential signaling by protease-activated receptors: implications for therapeutic targeting

Abstract

Protease-activated receptors (PARs) are a family of four G protein-coupled receptors that exhibit increasingly appreciated differences in signaling and regulation both within and between the receptor class. By nature of their proteolytic self-activation mechanism, PARs have unique processes of receptor activation, "ligand" binding, and desensitization/resensitization. These distinctive aspects have presented both challenges and opportunities in the targeting of PARs for therapeutic benefit-the most notable example of which is inhibition of PAR1 on platelets for the prevention of arterial thrombosis. However, more recent studies have uncovered further distinguishing features of PAR-mediated signaling, revealing mechanisms by which identical proteases elicit distinct effects in the same cell, as well as how distinct proteases produce different cellular consequences via the same receptor. Here we review this differential signaling by PARs, highlight how important distinctions between PAR1 and PAR4 are impacting on the progress of a new class of anti-thrombotic drugs, and discuss how these more recent insights into PAR signaling may present further opportunities for manipulating PAR activation and signaling in the development of novel therapies.

Figure 1.

Differential activation of and signaling by PAR1 and PAR4 has implications for drugs targeting thrombin-induced platelet activation. Thrombin activates both PAR1 and PAR4 on human platelets, but with several important distinctions that have important implications for the targeting of PARs as anti-platelet agents. (1) Thrombin activates PAR1 with ~30 fold greater sensitivity than PAR4, in large part due to the presence of a thrombin-binding domain (TBD; red line) in the amino terminal of PAR1 that facilitates thrombin binding and site specific cleavage and receptor activation; (2) Distinct G protein coupling between PAR1 and PAR4 facilitates different intracellular signalling events; (3) Contrasting kinetics of calcium signaling occur following PAR1 and PAR4 activation, with PAR1 activation inducing a rapid rise in intracellular calcium compared with the slower but more prolonged calcium increase induced by PAR4. As a result of these differences, PAR1 antagonists have undergone clinical development as antiplatelet drugs because they target the high affinity thrombin receptor. Whether drugs that block the divergent functions of PAR4 will provide distinct utility as anti-platelet agents remains to be determined.