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

Cassell, Robert J. and Mores, Kendall L. and Zerfas, Breanna L. and Mahmoud, Amr H. and Lill, Markus A. and Trader, Darci J. and van Rijn, Richard M.. (2019) Rubiscolins are naturally occurring G protein-biased delta opioid receptor peptides. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 29 (3). pp. 450-456.

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The impact that β-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 β-arrestin. These findings have led to the development of biased opioid small molecule agonists that do not recruit β-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 δ opioid receptors, but with minimal β-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 δ opioid receptors. However, unlike the naturally occurring δ opioid peptides leu-enkephalin and deltorphin II, the rubiscolin peptides only very weakly recruit β-arrestin 2 and have undetectable recruitment of β-arrestin 1 at the δ opioid receptor.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Computational Pharmacy (Lill)
UniBasel Contributors:Lill, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Jul 2020 15:12
Deposited On:03 Jul 2020 15:12

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