Fig. 3.

Production of NO after E2 binding. A functional signaling complex containing c-Src, PI3K and ER46 co-localized with Caveolin-1 in ECs. Membrane localization requires palmitoylation of ER46 at Cys⁴⁴⁷ and also lipid modification of c-Src. ERα membrane localization also requires palmitoylation at Cys⁴¹⁵. Gβγ activation of phospholipase C generates IP₃ and diacylglycerol from membrane PIP2. IP₃ causes Ca²⁺ release from the endoplasmic reticulum which binds to calmodulin (Cam) which then binds to eNOS and causes eNOS to dissociate from caveolin 1 and come off the membrane. Activation of PI3K leads to the conversion of PIP2 to PIP3 which activates PDK1 and Akt. Along with MAPK (Erk1/2) activation this phosphorylates eNOS on Ser¹¹⁷⁷ and translocates it back to the plasma membrane following myristylation, where it catalyzes the formation of NO and L-citrulline from L-arginine. NO release induces VSMC relaxation. Adapted from (Orshal and Khalil, 2004).