Fig. 6.

Membrane charge is a tunable modulator of β₂AR−G protein interaction. Models depict epinephrine-bound β₂AR. Left: In negatively charged lipids, β₂AR−G_s coupling is efficient, but β₂AR−G_i3 coupling is relatively inefficient, in part because β₂AR−G_i3 attraction is countered by membrane-G_i3 repulsion. Specifically, negatively charged lipids repel the negatively charged EDGE motif found on the amino terminal helix of G_i3 (shown in red), a region that is positively charged in G_s (shown in blue). Right: Two mechanisms that neutralize membrane charge facilitate β₂AR coupling to G_i3. These mechanisms may play a role in G_s-to-G_i switching in cardiac myocytes. Top right: Ca²⁺ and Mg²⁺ stabilize a like-charge interaction between the membrane and the EDGE motif. (Note that the effect of Ca²⁺ and Mg²⁺ may extend beyond an effect on αN positioning.) Bottom right: Epinephrine-stimulated β₂AR traffics to membrane without negatively charged lipids