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GPR56, a novel platelet collagen receptor that loves stress

Platelets interact with the injured vasculature and/or ruptured atherosclerotic plaque through adhesion receptors. Upon vascular injury, the underlying extracellular matrix, of which collagen type III is a major component, becomes exposed to the blood circulation and allows platelets to adhere and become activated. At arterial shear rate, this process is mediated through the interaction of platelet GPIb with collagenbound von Willebrand factor (VWF), allowing platelets to be recruited from the blood stream. Subsequent activation by collagen results in shape change, cell spreading, release of secondary mediators such as adenosine diphosphate (ADP) and thromboxane A2 (TxA2), and integrin αIIbβ3 activation. The latter allows fibrinogen binding and bridging of platelets together to form a thrombus. The first positive identification of a platelet collagen receptor came from a patient deficient in glycoprotein (GP)Ia, whose platelets failed to respond to collagen.1 GPIa, as part of the GPIa/IIa complex (integrin α2β1), was subsequently confirmed to be a collagen receptor2, and deficiency resulted in a complete loss of collageninduced aggregation. GPIa deficiency, however, only delayed in vivo thrombus formation and had no effect on bleeding time.3 Integrin α2β1 was shown to support firm adhesion to collagen under flow.4 Multiple groups suggested the existence of an additional GP collagen receptor with a molecular weight of around 60– 65 kDa,57 which was later identified as GPVI.8 Subsequent cloning of the GP6 gene for GPVI showed it encoded an immunoreceptor tyrosinebased activation motif (ITAM)containing transmembrane receptor.911 The importance of GPVI was confirmed by antibodymediated GPVI depletion and GPVI deficiency in mice, which resulted in impaired in vivo thrombosis with very little effect on tail bleeding.12,13 Furthermore, acquired and inherited loss of GPVI, though the latter being rare, resulted in a mild bleeding disorder14 and left adhesion to collagen intact.15 Due to this differential role of GPVI in thrombosis and hemostasis, GPVI has been proposed as a promising antithrombotic target.16,17 However, the lack of a severe bleeding phenotype has puzzled platelet scientists. Proposed explanations include redundancy with alternative collagen receptors (integrin α2β1), other platelet receptors (CLEC2), and different subendothelial ligands for platelets (laminin, fibronectin, podoplanin).1821 However, these interactions struggle to fully explain how platelets are activated upon vascular injury in the absence of GPVI and raised the question whether an additional signaling collagen receptor exists. A more recent addition to the adhesion receptors family is the adhesion G proteincoupled receptors (aGPCRs).22 These receptors share many commonalities that unite GPCRs, for example, possessing 7 transmembrane (TM) domains and coupling to G proteins. However, they have several atypical characteristics, such as the presence of a GPCR autoproteolysisinducing domain proximal to the start of the first transmembrane span (TM1).23 A proposed physiological mechanism of aGPCR activation is through shear forcemediated interactions with proteins in the extracellular matrix, including collagen.23 In this instance, the Nterminal domain becomes immobilized to its protein ligand, and the force created by cell movement drives a dissociation event to expose a tethered ligand that can activate aGPCR signaling. Interestingly, proteomic and transcriptomic studies showed that human platelets express GPR56,24,25 an aGPCR whose ligand is collagen type III.26 This raised the exciting possibility that platelet GPR56 may contribute to plateletmediated hemostasis and/or thrombosis, possibly providing an explanation for