Membrane Potential Controls the Efficacy of Catecholamine-induced β1-Adrenoceptor Activity

Background: The activity of several G(q)- and G(1)-coupled receptors is modulated by the membrane potential. Results: Voltage modulates catecholamine-mediated activation of G(s)-coupled beta(1)- and beta(2)-adrenoceptors. Conclusion: Voltage-dependence of beta(1)-AR is due to alterations in the efficacy of catecholamines. Significance: By modulating catecholamine efficacy on beta(1)-ARs, voltage can modify receptor activity on a very fast time scale. G protein-coupled receptors (GPCRs) are membrane-located proteins and, therefore, are exposed to changes in membrane potential (V-M) in excitable tissues. These changes have been shown to alter receptor activation of certain G(i)-and G(q)-coupled GPCRs. By means of a combination of whole-cell patch-clamp and Forster resonance energy transfer (FRET) in single cells, we demonstrate that the activation of the G(s)-coupled (1)-adrenoreceptor (beta(1)-AR) by the catecholamines isoprenaline (Iso) and adrenaline (Adr) is regulated by V-M. This voltage-dependence is also transmitted to G protein and arrestin 3 signaling. Voltage-dependence of beta(2)-AR activation, however, was weak compared with beta(1)-AR voltage-dependence. Drug efficacy is a major target of beta(1)-AR voltage-dependence as depolarization attenuated receptor activation, even under saturating concentrations of agonists, with significantly faster kinetics than the deactivation upon agonist withdrawal. Also the efficacy of the endogenous full agonist adrenaline was reduced by depolarization. This is a unique finding since reports of natural full agonists at other voltage-dependent GPCRs only show alterations in affinity during depolarization. Based on a Boltzmann function fit to the relationship of V-M and receptor-arrestin 3 interaction we determined the voltage-dependence with highest sensitivity in the physiological range of membrane potential. Our data suggest that under physiological conditions voltage regulates the activity of agonist-occupied beta(1)-adrenoceptors on a very fast time scale.