title: Voltage regulates adrenergic receptor function.
abstract: The present study demonstrates that agonist-mediated activation of α2A adrenergic receptors (α(2A)AR) is voltage-dependent. By resolving the kinetics of conformational changes of α(2A)AR at defined membrane potentials, we show that negative membrane potentials in the physiological range promote agonist-mediated activation of α(2A)AR. We discovered that the conformational change of α(2A)AR 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(2A)AR were switched by voltage even under fully saturating concentrations, and the kinetics of this switch was notably faster than dissociation of clonidine from α(2A)AR, 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.
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, Biochemical Pharmacological Center Marburg,  Philipps-University Marburg, 35043 Marburg,  Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rinne
authors.forename: Alexandra
authors.initials: A
authors.lastname: Birk
authors.forename: Moritz
authors.initials: M
authors.lastname: Bünemann
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D015374:Biosensing Techniques; D003000:Clonidine / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: C547769:Adra2a protein, mouse; D019390:Arrestins; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018341:Receptors, Adrenergic, alpha-2; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D000071557:beta-Arrestins; D019204:GTP-Binding Proteins; D003000:Clonidine; D009638:Norepinephrine