Rubiscolins are naturally occurring G protein-biased delta opioid receptor peptides.

ABSTRACT: The impact that ?-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 ?-arrestin. These findings have led to the development of biased opioid small molecule agonists that do not recruit ?-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 at ? opioid receptors, but with minimal ?-arrestin recruitment. Specifically, we find that rubiscolin peptides, which are produced as cleavage products of the plant protein rubisco, bind to and activate G protein signaling at ? opioid receptors. However, unlike the naturally occurring ? opioid peptides leu-enkephalin and deltorphin II, the rubiscolin peptides only very weakly recruit ?-arrestin 2 and have undetectable recruitment of ?-arrestin 1 at the ? opioid receptor.

SUBMITTER: Cassell RJ 

PROVIDER: S-EPMC6421079 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature