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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Bünemann, Moritz Rinne, Andreas Birk, Alexandra |
| Description | Author Affiliation: Rinne A ( Institute of Pharmacology and Clinical Pharmacy, Biochemical Pharmacological Center Marburg, Philipps-University Marburg, 35043 Marburg, Germany.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 4 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Receptors, Adrenergic, Alpha-2 Metabolism Animals Arrestins Biosensing Techniques Clonidine Pharmacology Fluorescence Resonance Energy Transfer G Protein-Coupled Inwardly-Rectifying Potassium Channels GTP-Binding Proteins HEK293 Cells Kinetics Membrane Potentials Mice Norepinephrine Protein Conformation Chemistry Genetics Receptors, G-Protein-Coupled Recombinant Proteins Signal Transduction Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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