| First Author | Rinne A | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 4 | Pages | 1536-41 |
| PubMed ID | 23297214 | Mgi Jnum | J:193713 |
| Mgi Id | MGI:5469245 | Doi | 10.1073/pnas.1212656110 |
| Citation | Rinne A, et al. (2013) Voltage regulates adrenergic receptor function. Proc Natl Acad Sci U S A 110(4):1536-41 |
| abstractText | The present study demonstrates that agonist-mediated activation of alpha2A adrenergic receptors (alpha(2A)AR) is voltage-dependent. By resolving the kinetics of conformational changes of alpha(2A)AR at defined membrane potentials, we show that negative membrane potentials in the physiological range promote agonist-mediated activation of alpha(2A)AR. We discovered that the conformational change of alpha(2A)AR by voltage is independent from receptor-G protein docking and regulates receptor signaling, including beta-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 alpha(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 alpha(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. |
