Integrin β(3) directly inhibits the Gα(13)-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis

The integrins and G protein-coupled receptors are both fundamental in cell biology. The cross talk between these two, however, is unclear. Here we show that β(3) integrins negatively regulate G protein-coupled signaling by directly inhibiting the Gα(13)-p115RhoGEF interaction. Furthermore, whereas β(3) deficiency or integrin antagonists inhibit integrin-dependent platelet aggregation and exocytosis (granule secretion), they enhance G protein-coupled RhoA activation and integrin-independent secretion. In contrast, a β(3)-derived Gα(13)-binding peptide or Gα(13) knockout inhibits G protein-coupled RhoA activation and both integrin-independent and dependent platelet secretion without affecting primary platelet aggregation. In a mouse model of myocardial ischemia/reperfusion injury in vivo, the β(3)-derived Gα(13)-binding peptide inhibits platelet secretion of granule constituents, which exacerbates inflammation and ischemia/reperfusion injury. These data establish crucial integrin-G protein crosstalk, providing a rationale for therapeutic approaches that inhibit exocytosis in platelets and possibly other cells without adverse effects associated with loss of cell adhesion.