Figure 9

Model for PAR ₂ regulation of AMPK activity. PAR₂ can activate G-protein pathways leading to Ca2+ mobilization and CAMKKβ activation, which then lead to phosphorylation and activation of AMPK. LKB1 also contributes to PAR_2-stimulated AMPK activation, either through activation of the enzyme itself or by inducing a conformational change in AMPK that renders it more sensitive to phosphorylation by LKB1. At later time points, we predict that PAR2 may inhibit the activity of a phosphatase or protect AMPK from dephosphorylation, thus leading to the observed prolonged activation. Simultaneously, PAR₂ can recruit β-arrestin-2 which binds both AMPK and CAMKKβ and prevents phosphorylation of AMPK. The resulting shift in the balance of phosphorylation and dephosphorylation of AMPK can lead to an observed decrease in overall AMPK phosphorylation in the presence of β-arrestin-2.