Protease-activated receptor 4 (PAR-4) belongs to a family of four G protein-coupled receptors (PAR1-4) that are activated as a result of proteolytic cleavage by certain serine proteases, hence their name. In this novel modality of activation, a specific protease cleaves the PAR receptor within a defined sequence in its extracellular N-terminal domain. This results in the creation of a new N-terminal tethered ligand, which subsequently binds to a site in the second extracellular loop of the same receptor. This binding results in the coupling of the receptor to G proteins and in the activation of several signal transduction pathways.^1-3

Different PARs are activated by different proteases. Hence, PAR-4 is activated by both thrombin and trypsin whereas PAR-1 and PAR-3 are activated only by thrombin and PAR-2 is activated only by trypsin.^1-3 PAR-4 can be also cleaved and activated by other proteases such as cathepsin G.

The intracellular signaling mechanisms mediated by PAR-4 activation are not completely elucidated but they involve calcium mobilization downstream of phospholipase Cβ through the G_αq pathway.^1-3

Tissue distribution of PAR-4 is very broad with the highest expression levels found in lung, testis, pancreas and small intestine. In addition, PAR-4 expression was observed in platelets, megakaryocytes and leukocytes. Studies with platelets derived from PAR-4 knockout mice have established an essential role for PAR-4 in thrombin-induced platelet activation.
PAR-4 is likely involved in other physiological functions such as regulation of gastrointestinal motility and regulation of vascular endothelial cell function.^1-3