Rubsicolins are naturally occurring G-protein-biased delta opioid receptor peptides

Abstract

The impact that {beta}-arrestin proteins have on G-protein-coupled receptor trafficking, signaling and physiological behavior has gained much appreciation over the past decade. A number of studies have attributed the side effects associated with the use of naturally occurring and synthetic opioids, such as respiratory depression and constipation, to excessive recruitment of {beta}-arrestin. These findings have led to the development of biased opioid small molecule agonists that do not recruit {beta}-arrestin, activating only the canonical G-protein pathway. Similar G-protein biased small molecule opioids have been found to occur in nature, particularly within kratom, and opioids within salvia have served as a template for the synthesis of other G-protein-biased opioids. Here, we present the first report of naturally occurring peptides that selectively activate G-protein signaling pathways with minimal {beta}-arrestin recruitment. We find that rubiscolin peptides, which are produced as cleavage products of the plant protein rubisco, bind to and activate G-protein signaling at {delta} opioid receptors. However, unlike the naturally occurring {delta} opioid peptides leu-enkephalin and deltorphin II, the rubiscolin peptides only very weakly recruit {beta}-arrestin 2 and have undectable recruitment of {beta}-arrestin 1 at the {delta} opioid receptor.