Voltage regulates adrenergic receptor function

Abstract

The present study demonstrates that agonist-mediated activation of a2A adrenergic receptors (a2AAR) is voltage-dependent. By resolving the kinetics of conformational changes of a2AAR at defined membrane potentials, we show that negative membrane potentials in the physiological range promote agonist-mediated activation of a2AAR. We discovered that the conformational change of a2AAR 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 a2AAR were switched by voltage even under fully saturating concentrations, and the kinetics of this switch was notably faster than dissociation of clonidine from a2AAR, 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.