GPR56/ADGRG1 is a platelet collagen-responsive GPCR and hemostatic sensor of shear force

Significance We identified the known collagen receptor GPR56/ADGRG1 on platelets. GPR56 is an adhesion G protein-coupled receptor that becomes activated following forced dissociation of its N-terminal fragment and C-terminal fragment or seven-transmembrane spanning domain (7TM). Fragment dissociation reveals the cryptic stalk of the 7TM, which acts as a tethered peptide agonist, and for GPR56, this activates platelet G13 signaling. GPR56 pharmacological probes activated platelets to undergo shape change and aggregation, which are critical for the formation of hemostatic plugs. Gpr56 −/− mice exhibit prolonged bleeding, defective platelet plug formation in vessel injury assays, and delayed thrombotic vessel occlusion. Shear-force dependency of platelet adhesion to immobilized collagen was found to be GPR56 dependent.