Background: Circulating platelets roll along exposed collagen at vessel injury sites and respond with filipodia protrusion, shape change and surface area expansion. These events precede stable adhesion and wound-healing hemostatic plug formation. Various glycoproteins and integrins are considered to be both collagen responders and mediators of platelet adhesion, although the kinetics of the signaling circuits emanating from these receptors do not fully account for the rapid platelet cytoskeletal changes that occur in blood flow.

Aims: To demonstrate the role of GPR56 in hemostasis and thrombosis..

Methods: Protein biochemistry, platelet aggregometry, transgenic mice and in vivo hemostasis and thrombosis models, collagen flow chamber model with human platelets.

Results: We report that GPR56/ADGRG1 is a platelet adhesion G protein-coupled receptor (AGPCR) that transduces the signal from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change. AGPCRs are two-fragment receptors that have been proposed be activated by shear force-mediated fragment dissociation to unmask a tethered-peptide-agonist. We trapped the freed GPR56 N-terminal fragment (NTF) from human plasma using collagen-coated beads. Gpr56^-/- mice were found to have prolonged bleeding and defective platelet plug formation. Blood perfusion over collagen demonstrated that Gpr56^-/- platelets or platelets in human blood treated with recombinant GPR56 NTF adhered defectively at high shear. The GPR56 rNTF exhibited anti-coagulant properties in mouse circulation.

Conclusions: Our work updates the hemostasis model by placing GPR56 as an initial collagen-responder and shear-force transducer that fulfills platelet shape change.

[Role of GPR56 in Platelet Action During Hemostasis]

« Back to ISTH 2020 Congress

ISTH Congress Abstracts - https://abstracts.isth.org/abstract/gpr56-is-a-platelet-collagen-responsive-gpcr-and-hemostatic-sensor-of-shear-force/