Role of the Ubiquitin System in Chronic Pain

Abstract

As a significant public health issue, chronic pain, mainly neuropathic pain (NP) and inflammatory pain, has a severe impact. The underlying mechanisms of chronic pain are enigmatic at present. The roles of ubiquitin have been demonstrated in various physiological and pathological conditions and underscore its potential as therapeutic targets. The dysfunction of the component of the ubiquitin system that occurs during chronic pain is rapidly being discovered. These results provide insight into potential molecular mechanisms of chronic pain. Chronic pain is regulated by ubiquitination, SUMOylation, ubiquitin ligase, and deubiquitinating enzyme (DUB), etc. Insight into the mechanism of the ubiquitin system regulating chronic pain might contribute to relevant therapeutic targets and the development of novel analgesics.

Keywords: SUMOylation; chronic pain; deubiquitinases; ubiquitin ligase; ubiquitination.

FIGURE 1

Neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) family of E3 ubiquitin ligase can effectively regulate Nav channels. Sodium channels play an important role in neuropathic pain. When nociceptors are activated, Nav1.7 and Nav1.8 are upregulated, leading to pain. The NEDD4 family of E3 ubiquitin ligase can react on sodium ion channels to ubiquitinate them and promote the channel endocytosis. Specifically, NEDD4 ubiquitin ligase can react with the PY motif at the end of the C subunit of each Nav subtype, thereby regulating the expression of the Nav channel, as well as the current density and neuronal excitability. Therefore, the pain signal of sensory neurons can be reduced indirectly by regulating the activity of NEDD4-2.

FIGURE 2

Cav3.2 channel ubiquitination status is regulated by the interaction of E3 ligase and ubiquitin-specific protease 5 (USP5). The ubiquitination state of Cav3.2 channel in the pain pathway is regulated by the interaction of USP5 and HECT E3 ligase HECT E3 ligase E3 ubiquitin-protein ligase 1 (WWP1), which can regulate the stability of the calcium channel protein in the plasma membrane. When pain occurs, USP5 is upregulated and its cUBP domain interacts with the III–IV junction of Cav3.2 T-type calcium channels. This can reduce the ubiquitination of Cav3.2 channels and upregulate Cav3.2 channels, making them more stable on the cell surface. WWP1 also binds to intracellular regions III–IV in the Cav3.2 t-channel junction region and modifies specific lysine residues in this region.

FIGURE 3

Ubiquitin system. Ubiquitin molecules can be covalently linked to other substrates to form ubiquitin chains. A chain of four or more ubiquitin units constitutes proteasome 26S. Ubiquitin is an ATP-dependent process catalyzed by three enzymes (E1, E2, and E3), which also confer specificity to the process. The first reaction catalyzed by E1 is responsible for the activation of ubiquitin. E1 transfers ubiquitin on cysteine to E2. Through the activity of transferase, E2 transfers the ubiquitin to E3 ligase (two groups of protein ubiquitin ligase, HECT E3 enzymes and ring E3s, the way they transfer ubiquitin is exactly different), which binds ubiquitin to the Lys residue of the target protein. Polyubiquitinated protein can be degraded by 26S proteasome, and ubiquitin can be recovered under the action of the deubiquitinating enzyme.