Fig. 1. PAR1 activation and signalling. PAR1 is a seven-transmembrane-span G-protein-coupled receptor that is activated by a unique proteolytic mechanism. Thrombin (-Th), a serine protease, binds to and cleaves the N-terminal exodomain of PAR1. The newly unmasked N-terminus of PAR1 then acts as a tethered ligand and binds intramolecularly to the receptor to trigger transmembrane signalling. Synthetic peptides that mimic the tethered ligand domain can activate PAR1 independently of proteolysis. PAR1 couples to G_q, G_12/13, G_i and G to activate a variety of signalling cascades and cellular responses. The G_12/13 subunits bind RhoGEFs, which activate small G-proteins such as Rho. G_q activates phospholipase C, triggering phosphoinositide hydrolysis, resulting in inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃] and diacylglycerol (DAG) production and Ca²⁺ mobilization, protein kinase C (PKC) and MAP kinase activation. G can activate PI-3-kinase, G-protein-coupled receptor kinases (GRKs) and other effectors. PAR1 is uncoupled from G-protein signalling by rapid phosphorylation and arrestin binding.