Voltage regulates adrenergic receptor function

The present study demonstrates that agonist-mediated activation of α2A adrenergic receptors (α ₂AAR) is voltage-dependent. By resolving the kinetics of conformational changes of α ₂AAR at defined membrane potentials, we show that negative membrane potentials in the physiological range promote agonist-mediated activation of α ₂AAR. We discovered that the conformational change of α ₂AAR by voltage is independent from receptor-G protein docking and regulates receptor signaling, including β-arrestin binding, activation of G proteins, and G protein-activated inwardly rectifying K ⁺ currents. Comparison of the dynamics of voltage-dependence of clonidine- vs. norepinephrine-activated receptors uncovers interesting mechanistic insights. For norepinephrine, the time course of voltage-dependent deactivation reflected the deactivation kinetics of the receptor after agonist withdrawal and was strongly attenuated at saturating concentrations. In contrast, clonidine-activated α ₂AAR were switched by voltage even under fully saturating concentrations, and the kinetics of this switch was notably faster than dissociation of clonidine from α ₂AAR, indicating voltage-dependent regulation of the efficacy. We conclude that adrenergic receptors exhibit a unique, agonist-dependent mechanism of voltage-sensitivity that modulates downstream receptor signaling.