Abstract 130: The Integrin β 3 Subunit Directly Inhibits The Galpha 13 -p115RhoGEF Interaction To Regulate G Protein Signaling And Platelet Exocytosis

The integrin family of adhesion receptors and G protein-coupled receptors (GPCRs) are both fundamental to a cell’s responses to extracellular stimuli. For example, GPCR- or integrin-regulated exocytosis mediates platelet granule secretion, neurotransmission, and endocrine secretion, and is important in thrombosis and inflammation. GPCRs are known to stimulate integrin activation and signaling. However, it is unclear whether integrins regulate G protein signaling and if there is crosstalk between integrins and GPCRs in regulating exocytosis. Here we show that β 3 integrins negatively regulate GPCR signaling by directly inhibiting the Gα 13 -p115RhoGEF interaction. Furthermore, whereas β 3 deficiency or integrin antagonist RGDS inhibited integrin-dependent platelet aggregation and exocytosis (granule secretion), they enhanced GPCR-stimulated RhoA activation and integrin-independent secretion. In contrast, a β 3 -derived Gα 13 -binding peptide or Gα 13 knockout inhibited GPCR-stimulated RhoA activation and both integrin-independent and dependent platelet secretion without affecting primary platelet aggregation important for hemostasis. In a mouse model of myocardial ischemia/reperfusion injury (MI/RI) i n vivo , the β 3 -derived Gα 13 -binding M3mP6 peptide nanoparticle inhibited secretion of serotonin, a platelet granule constituent that exacerbates inflammation and MI/RI. These data establish crucial integrin-GPCR crosstalk that provides a rationale for developing therapeutic agents that strongly inhibit exocytosis in platelets and possibly other cells without adverse effects associated with loss of cell adhesion.