PAR1 couples to multiple G-proteins, which leads to a wide array of cellular events. Thrombin activation of PAR1 results in proinflammatory pathways, whereas APC activation of PAR1 leads to cytoprotective signaling. (A) The orthosteric inhibitor vorapaxar interacts at the ligand-binding site and blocks all signaling from PAR1. (B) The new compounds, parmodulins, selectively block Gα_q signaling, sparing the cytoprotective pathways induced by APC. The specific effects on α_i- and β-arrestin have not been directly tested. EPCR, endothelial protein C receptor. Professional illustration by Luk Cox, Somersault18:24.