Opioids are highly potent analgesics but develop tolerance. Previous studies have focused on phosphorylation of the μ-opioid receptor as it is involved in maintaining cellular sensitivity via desensitization, recycling, and degradation of the activated receptor. Recently, ubiquitination, another form of posttranslational modification has attracted attention in terms of triggering intracellular signaling and regulation of the activated receptor. Here, we generated a ubiquitination-deficient mutant of the μ-opioid receptor to investigate whether ubiquitination is involved in driving Gi/o-mediated analgesic signaling, receptor desensitization or subsequent receptor internalization. Our study shows that the Gi/o pathway and receptor phosphorylation do not require ubiquitination. Instead, ubiquitination regulates the internalization efficiency and might help in promoting internalization of the desensitized MOP.
Keywords: Phosphorylation; Posttranslational modification; Tolerance; Ubiquitination; μ-opioid receptor.
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