The G protein-biased PZM21 and TRV130 act as partial agonists of μ-opioid receptors signaling to ion channel targets

Abstract

Opioids exert many of their acute effects through modulating ion channels via G βγ subunits. Some of their side effects are attributed to β-arrestin recruitment, and several biased agonists that do not activate this pathway have been developed recently. Here we tested the effects of TRV130, PZM21 and herkinorin, three G-protein biased agonists of μ-opioid receptors (μOR), on ion channel targets. Compared to the full μOR agonist DAMGO, all three biased agonists induced smaller activation of G proteincoupled inwardly rectifying potassium channels (GIRK2), and smaller inhibition of Transient Receptor Potential Melastatin (TRPM3) channels. Furthermore, co-application of TRV130 or PZM21, but not herkinorin reduced the effects of DAMGO on both ion channels. Ca V 2.2 was also inhibited less by PZM21 and TRV130 than by DAMGO.TRV130, PZM21 and herkinorin were also less effective than DAMGO in inducing dissociation of the G αi /G βγ complex. We conclude that TRV130, PZM21 are partial agonists of μOR.