Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Mar 21;20(6):1441.
doi: 10.3390/ijms20061441.

Interplay between the Endogenous Opioid System and Proteasome Complex: Beyond Signaling

Francesca Felicia Caputi  1 , Laura Rullo  2 , Serena Stamatakos  3 , Sanzio Candeletti  4 , Patrizia Romualdi  5
Affiliations
Review

Interplay between the Endogenous Opioid System and Proteasome Complex: Beyond Signaling

Francesca Felicia Caputi et al. Int J Mol Sci. .

Abstract

Intracellular signaling mechanisms underlying the opioid system regulation of nociception, neurotransmitters release, stress responses, depression, and the modulation of reward circuitry have been investigated from different points of view. The presence of the ubiquitin proteasome system (UPS) in the synaptic terminations suggest a potential role of ubiquitin-dependent mechanisms in the control of the membrane occupancy by G protein-coupled receptors (GPCRs), including those belonging to the opioid family. In this review, we focused our attention on the role played by the ubiquitination processes and by UPS in the modulation of opioid receptor signaling and in pathological conditions involving the endogenous opioid system. The collective evidence here reported highlights the potential usefulness of proteasome inhibitors in neuropathic pain, addictive behavior, and analgesia since these molecules can reduce pain behavioral signs, heroin self-administration, and the development of morphine analgesic tolerance. Moreover, the complex mechanisms involved in the effects induced by opioid agonists binding to their receptors include the ubiquitination process as a post-translational modification which plays a relevant role in receptor trafficking and degradation. Hence, UPS modulation may offer novel opportunities to control the balance between therapeutic versus adverse effects evoked by opioid receptor activation, thus, representing a promising druggable target.

Keywords: 26S proteasome; GPCRs; UPS; opioid receptors; opioid system; ubiquitination.

PubMed Disclaimer

Conflict of interest statement

All Authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of the ubiquitin conjugation pathway. Ubiquitination is a three step process involving specific groups of enzymes, which are: (1) E1, ubiquitin (Ubq) activating enzyme; (2) E2, Ubq conjugating enzyme and (3) E3, Ubq ligase enzyme. Ubq is known to form covalent bonds with protein substrates (4) which, once modified, are subjected to different fates. De-ubiquitinating enzymes (DUBs) remove ubiquitins from substrate proteins.
Figure 2
Figure 2
The ubiquitin post-translational modifications, either mono- or poly-ubiquitination, direct the conjugated substrates to different cellular fates which depend from the length and the type of ubiquitin chain.
Figure 3
Figure 3
Schematic representation of the 26S Protesome complex.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Akil H., Watson S.J., Young E., Lewis M.E., Khachaturian H., Walker J.M. Endogenous opioids: Biology and function. Annu. Rev. Neurosci. 1984;7:223–255. doi: 10.1146/annurev.ne.07.030184.001255. - DOI - PubMed
    1. Mansour A., Fox C.A., Akil H., Watson S.J. Opioid-receptor mRNA expression in the rat CNS: Anatomical and functional implications. Trends Neurosci. 1995;18:22–29. doi: 10.1016/0166-2236(95)93946-U. - DOI - PubMed
    1. Toll L., Bruchas M.R., Calo’ G., Cox B.M., Zaveri N.T. Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharmacol. Rev. 2016;68:419–457. doi: 10.1124/pr.114.009209. - DOI - PMC - PubMed
    1. Kieffer B.L. Recent advances in molecular recognition and signal transduction of active peptides: Receptors for opioid peptides. Cell Mol. Neurobiol. 1995;15:615–635. doi: 10.1007/BF02071128. - DOI - PMC - PubMed
    1. Kieffer B.L., Evans C.J. Opioid receptors: From binding sites to visible molecules in vivo. Neuropharmacology. 2009;56(Suppl. 1):205–212. doi: 10.1016/j.neuropharm.2008.07.033. - DOI - PMC - PubMed

LinkOut - more resources