Integrin & beta;(3) directly inhibits the G & alpha;(13)-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis

Zhang et al. show that the adhesion receptor integrin & beta;3 directly inhibits G protein mediated RhoA activation and granule secretion. A peptide mimicking this effect selectively inhibits platelet secretion but not integrin-mediated platelet adhesion. 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 & beta;(3) integrins negatively regulate G protein-coupled signaling by directly inhibiting the G & alpha;(13)-p115RhoGEF interaction. Furthermore, whereas & beta;(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 & beta;(3)-derived G & alpha;(13)-binding peptide or G & alpha;(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 & beta;(3)-derived G & alpha;(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.

Automated summary

Zhang et al. demonstrate that integrin β3 receptor inhibits G protein-mediated RhoA activation and granule secretion. A peptide mimicking this effect selectively inhibits platelet secretion without affecting integrin-mediated adhesion. The cross-talk between integrins and G protein-coupled receptors is crucial and has implications for therapeutic approaches in platelet and cell adhesion-related diseases.