Voltage modulates the effect of μ receptor activation in a ligand-dependent manner

Julia G Ruland, Sina B Kirchhofer, Sebastian Klindert, Chris P Bailey, Moritz Bünemann

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BACKGROUND AND PURPOSE: Various GPCRs (G-protein coupled receptors) have been described as being modulated in a voltage-dependent manner. Opioid analgesics act via activation of μ-receptors (MOP) in various neurons. As neurons are exposed to large changes in membrane potential, we were interested in studying the effects of depolarization on MOP signalling.

EXPERIMENTAL APPROACH: We investigated potential voltage-sensitivity of MOP in heterologous expression systems (HEK293T cells) using electrophysiology in combination with Förster resonance energy transfer-based assays. Depolarization-induced changes in signalling were also tested in physiological rat tissue containing locus coeruleus neurons. We applied depolarization steps across the physiological range of membrane potentials.

KEY RESULTS: Studying MOP function and signalling in cells we discovered that morphine-induced signalling was strongly dependent on the membrane potential (VM ). This became apparent at the level of G-protein activation, G-protein coupled inwardly rectifying potassium channel (Kir 3.X) currents and binding of G-protein coupled receptor kinases and Arrestin3 to MOP by a robust increase in signalling upon membrane depolarization. The pronounced voltage-sensitivity of morphine-induced MOP activation was also observed at the level of Kir 3.X currents in rat locus coeruleus neurons. The efficacy of peptidergic ligands to activate MOP was not (Met-enkephalin) or only moderately (DAMGO) enhanced upon depolarization. In contrast, depolarization reduced the ability of the analgesic fentanyl to activate MOP.

CONCLUSION AND IMPLICATIONS: Our results indicate a strong ligand-dependent modulation of MOP activity by the membrane potential, suggesting preferential activity of morphine in neurons with high neuronal activity.

Original languageEnglish
JournalBritish Journal of Pharmacology
Early online date16 Apr 2020
Publication statusE-pub ahead of print - 16 Apr 2020

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