TABLE 2

Time frame for discovery of the proteinase activated receptor family and its mechanism of activation

YearMilestone ObservationsCommentReferences
1967Thrombin activates platelets by di-isoflluoro-phosphate-sensitive serine proteinase actionPlatelet activation by thrombin requires its proteolytic activityDavey and Luscher, 1967
1975The thrombin catalytic step is followed by an irreversible, thrombin-independent platelet process leading to secretionThrombin cleavage is seen to precede a second independent platelet activation eventMartin et al., 1975
1980Thrombin platelet binding observed to be independent of a subsequent chymotrypsin-sensitive platelet signaling eventThrombin activation is independent of a downstream chymotrypsin-sensitive receptor activation processTam et al., 1980
1991The thrombin “receptor” is identified by expression cloning of its target from human megakaryocytes and hamster fibroblastsThe thrombin receptor is discovered to be a G protein-coupled receptorRasmussen et al., 1991; Vu et al., 1991
1991Thrombin proteolysis unmasks an N-terminal receptor-activating tethered ligand; peptides based on the revealed sequence activate the receptor directly: Proteolytically activated GPCRs (PARs) are identified.The tethered ligand mechanism distinguishes PARs from other GPCRsVu et al., 1991
1993Bioassays provide evidence for multiple members of the PAR familyPAR-activating peptides stimulate human but not rat and rabbit platelets; distinct structure-activity profiles are observed for PAR-activating peptides in different tissuesHollenberg et al., 1993; Kinlough-Rathbone et al., 1993
1994-1998Cloning of PARs 2, 3, and 4.All PARs have a target serine proteinase arginine cleavage-activation site in commonNystedt et al., 1994; Bohm et al., 1996b; Ishihara et al., 1997; Kahn et al., 1998; Xu et al., 1998
2014Adhesion G protein-coupled receptors (ADGRs) are found to be activated via a tethered ligand mechanism in common with the PARsThe tethered ligand mechanism may not apply to all of the ADGR family membersHamann et al.,. 2015; Liebscher et al., 2014b