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{beta}{gamma} subunits. Some of their side effects are attributed to {beta}-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 -opioid receptors (OR), on ion channel targets. Compared to the full OR agonist DAMGO, 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) channels. Furthermore, co-application of TRV130 or PZM21, but not herkinorin reduced the effects of DAMGO on both ion channels. CaV2.2 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 Gi /G{beta}{gamma} complex. We conclude that TRV130, PZM21 are partial agonists of OR.