Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants.

Anna Abrimian,Ying-Xian Pan,Tamar Kraft

doi:10.3390/ijms22073779

Anna Abrimian, Ying-Xian Pan + Show 1 more

Open Access

https://doi.org/10.3390/ijms22073779

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Abstract

There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), and play important roles not only in analgesia, but also many other biological processes such as reward, stress response, feeding and emotion. The MOR gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, generating multiple splice variants or isoforms. One type of these splice variants, the full-length 7 transmembrane (TM) Carboxyl (C)-terminal variants, has the same receptor structures but contains different intracellular C-terminal tails. The pharmacological functions of several endogenous opioid peptides through the mouse, rat and human OPRM1 7TM C-terminal variants have been considerably investigated together with various mu opioid ligands. The current review focuses on the studies of these endogenous opioid peptides and summarizes the results from early pharmacological studies, including receptor binding affinity and G protein activation, and recent studies of β-arrestin2 recruitment and biased signaling, aiming to provide new insights into the mechanisms and functions of endogenous opioid peptides, which are mediated through the OPRM1 7TM C-terminal splice variants.

Highlights

Discovery of the three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin in the 1970s [1,2,3,4] with help by early established opioid receptor binding assays [5,6,7] revolutionized the opioid field and further advanced our understanding of opioid receptor subtypes
We mainly focus on the pharmacological functions of several endogenous opioid peptides, including β-endorphin, dynorphin A and
The C-terminal tail of mMOR-1A contains four amino acids as VCAF, encoded by exon 3a, instead of the 12 aa, LENLEAETAPLP, encoded by exon 4 in mMOR-1. These results suggest that the C-terminal sequences can differentially influence the efficacy and potency in β-arrestin2 recruitment by these endogenous opioid peptides

Summary

Introduction

Discovery of the three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin in the 1970s [1,2,3,4] with help by early established opioid receptor binding assays [5,6,7] revolutionized the opioid field and further advanced our understanding of opioid receptor subtypes. 1992 [8,9] quickly led to isolate the mu opioid receptor (MOR) [10,11,12,13] and kappa opioid receptor (KOR-1) [14,15,16] These discoveries validated the pharmacologically defined opioid receptor subtypes, and provided essential tools to investigate the mechanisms and functions of the endogenous opioid peptides. The MOR gene (OPRM1) undergoes extensive alternative pre-mRNA splicing, producing multiple splice variants or receptor isoforms The relationships between endogenous opioid peptides and originally cloned opioid receptors, including MOR-1, DOR-1 and KOR-1, have been extensively studied in many different systems. We include the data from endomorphin-1 and endomorphin-2 despite the fact that their precursors and genes have not been identified

The Opioid Receptors and Endogenous Opioid Peptides

Binding Affinities of Endogenous Opioid Peptides in the Full-Length 7TM

G Protein Coupling Induced by Endogenous Opioid Peptides in the Full-Length

Biased Signaling of Endogenous Opioid Peptides in the Full-Length 7TM

Findings

Conclusions