Fig. 7.

A model of β-Arr2–mediated eNOS activation through GIT1–eNOS signaling in SECs. In SECs, ET-1 activates its cognate G protein-coupled receptor (ET_B receptor) and causes Gα and Gβγ activation and dissociation. In normal SECs, ET_B receptor-mediated β-Arr2 recruitment of Src and activation of Erk1/2 after β-Arr2 replaces GRK2. Activated Src phosphorylates GIT1 (24). Phosphorylated GIT1 then associates with eNOS to facilitate its activating phosphorylation at Ser1177 by Akt. Receptor-activated Gβγ simultaneously stimulates Akt (at Ser473) activation through PI3-kinase and this activation may be amplified by other signaling pathways, likely through reduced GRK2/Akt interaction. In injured SECs, the reduction of β-Arr2 likely limits Src and Erk1/2-mediated GIT1 phosphorylation, with subsequent downstream effects on eNOS activity and NO production.