GPR56/ADGRG1 is a platelet collagen-responsive GPCR and hemostatic sensor of shear force
| Autor: | Maiya Yu, Xianhua Piao, Emily N Stringham, Rong Luo, Jennifer Yeung, Gregory G. Tall, Hannah M. Stoveken, Luciana K. Rosselli-Murai, Alexander Vizurraga, Reheman Adili, Michael Holinstat |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
collagen
Blood Platelets CD36 Antigens 0301 basic medicine Integrins Medical Sciences Receptors Collagen Platelet Aggregation 030204 cardiovascular system & hematology Receptors G-Protein-Coupled Mice 03 medical and health sciences Platelet Adhesiveness 0302 clinical medicine Animals Humans Platelet Pseudopodia Cytoskeleton Receptor G protein-coupled receptor Mice Knockout Multidisciplinary Chemistry Thrombosis Adhesion Biological Sciences adhesion GPCR Love Cell biology 030104 developmental biology GPR56 Hemostasis platelets hemostasis Signal transduction Transcriptome signal transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2008921117 |
| Popis: | 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. Circulating platelets roll along exposed collagen at vessel injury sites and respond with filipodia protrusion, shape change, and surface area expansion to facilitate platelet adhesion and plug formation. Various glycoproteins were considered to be both collagen responders and mediators of platelet adhesion, yet the signaling kinetics emanating from these receptors do not fully account for the rapid platelet cytoskeletal changes that occur in blood flow. We found the free N-terminal fragment of the adhesion G protein-coupled receptor (GPCR) GPR56 in human plasma and report that GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change. Gpr56−/− mice have prolonged bleeding, defective platelet plug formation, and delayed thrombotic occlusion. Human and mouse blood perfusion studies demonstrated GPR56 and shear-force dependence of platelet adhesion to immobilized collagen. Our work places GPR56 as an initial collagen responder and shear-force transducer that is essential for platelet shape change during hemostasis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|