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Figure 1


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 ({alpha}-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{alpha}q, G{alpha}12/13, G{alpha}i and Gbeta{gamma} to activate a variety of signalling cascades and cellular responses. The G{alpha}12/13 subunits bind RhoGEFs, which activate small G-proteins such as Rho. G{alpha}q activates phospholipase Cbeta, 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. Gbeta{gamma} 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.





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