A schematic of crosstalk between the (G protein-coupled receptor) GPCR-coupled G 13 pathway and integrin IIb 3 in regulating RhoA activation and platelet granule secretion. Left panel: GPCR agonists such as thrombin induce G 13 -p115RhoGEF-dependent activation of RhoA, which mediates integrin-independent granule secretion. Center panel: following integrin ligation, G 13 interacts with the 3 cytoplasmic domain ExE motif, which inhibits G 13 binding to p115RhoGEF, resulting in inhibition of p115RhoGEF-mediated RhoA activation and integrin-independent granule secretion. G 13 binding to 3 , however, also mediates integrin outside-in signaling leading to Src activation and integrin-dependent granule secretion. Right Panel: The 3 -derived mP6 peptide binds to G 13 to inhibit G 13 interacting with both p115-RhoGEF and 3 . Thus, mP6 potently inhibits both integrin-independent and integrin-dependent secretion without affecting integrin ligation and primary platelet adhesion/aggregation necessary for normal hemostasis. Source data are provided as a Source Data file.
