Dataset Information
Voltage modulates the effect of μ-receptor activation in a ligand-dependent manner.
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ABSTRACT: Background and purpose
Various GPCRs have been described as being modulated in a voltage-dependent manner. Opioid analgesics act via activation of μ receptors in various neurons. As neurons are exposed to large changes in membrane potential, we were interested in studying the effects of depolarization on μ receptor signalling.Experimental approach
We investigated potential voltage sensitivity of μ receptors 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 μ receptor 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 GPCR kinases and arrestin3 to μ receptors by a robust increase in signalling upon membrane depolarization. The pronounced voltage sensitivity of morphine-induced μ receptor activation was also observed at the level of Kir 3.X currents in rat locus coeruleus neurons. The efficacy of peptide ligands to activate μ receptors was not (Met-enkephalin) or only moderately ([D-Ala2 , N-Me-Phe4 , Gly5 -ol]-enkephalin) enhanced upon depolarization. In contrast, depolarization reduced the ability of the analgesic fentanyl to activate μ receptors.Conclusion and implications
Our results indicate a strong ligand-dependent modulation of μ receptor activity by the membrane potential, suggesting preferential activity of morphine in neurons with high neuronal activity.
SUBMITTER: Ruland JG
PROVIDER: S-EPMC7348086 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Voltage modulates the effect of μ-receptor activation in a ligand-dependent manner.
British journal of pharmacology 20200519 15
<h4>Background and purpose</h4>Various GPCRs have been described as being modulated in a voltage-dependent manner. Opioid analgesics act via activation of μ receptors in various neurons. As neurons are exposed to large changes in membrane potential, we were interested in studying the effects of depolarization on μ receptor signalling.<h4>Experimental approach</h4>We investigated potential voltage sensitivity of μ receptors in heterologous expression systems (HEK293T cells) using electrophysiolog ...[more]
