Format

Send to

Choose Destination
Br J Pharmacol. 2019 May 9. doi: 10.1111/bph.14702. [Epub ahead of print]

The G protein-biased agents PZM21 and TRV130 are partial agonists of μ-opioid receptor-mediated signaling to ion channels.

Author information

1
Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, Newark, NJ, 07103, USA.

Abstract

BACKGROUND AND PURPOSE:

Opioids remain the most efficient medications against severe pain; they act on receptors that couple to heterotrimeric G-proteins in the Gαi/o family. Opioids exert many of their acute effects through modulating ion channels via Gβγ subunits. Many of their side effects are attributed to β-arrestin recruitment. Several biased agonists that do not recruit β-arrestins, but activate G-protein dependent pathways have been developed recently. While these compounds have been proposed to be full agonists of G-protein signaling in several high throughput pharmacological assays, their effects were not studied on ion channel targets.

EXPERIMENTAL APPROACH:

Here we used patch clamp electrophysiology and Ca2+ imaging to test the effects of TRV130, PZM21 and herkinorin, three G-protein biased agonists of μ-opioid receptors (μOR), on ion channel targets of Gαi/o /Gβγ signaling. We also studied G-protein dissociation using a fluorescence resonance energy transfer (FRET)-based assay.

KEY RESULTS:

All three biased agonists induced smaller activation of G protein-coupled inwardly rectifying potassium channels (GIRK2), and smaller inhibition of Transient Receptor Potential Melastatin (TRPM3) than the full μOR agonist DAMGO. Co-application of TRV130 or PZM21, but not herkinorin alleviated the effects of DAMGO on both channels. PZM21 and TRV130 also decreased the effect of morphine on GIRK2 channels. CaV 2.2 was also inhibited less by PZM21 and TRV130 than by DAMGO. We also found that TRV130, PZM21 and herkinorin were less effective than DAMGO in inducing dissociation of the Gαi /Gβγ complex.

CONCLUSION AND IMPLICATIONS:

TRV130, PZM21 and potentially herkinorin are partial agonists of μOR.

PMID:
31074038
DOI:
10.1111/bph.14702

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center