Figure 7.

The hypothetical model for shifting β₂-AR signaling from the canonical pathway towards the non-canonical pathway in immune cells is illustrated. We propose that signal transduction switching towards β-arrestin-mediated signaling occurs under conditions of unchecked immune cell activation or chronic or severe stress, both of which increase the firing rates of sympathetic nerves (red lightning bolts) and elevates local NE concentrations. These conditions favor the phosphorylation of the receptor by GRK 5/6 rather than GRK 2, thus promoting β-arrestin-2-mediated signaling via the MAPK, ERK1/2.