New understanding of the mu receptor with implications for pain treatment
June 26, 2015
June’s featured paper is "Agonist Binding and Desensitization of the Mu-Opioid Receptor Is Modulated By Phosphorylation of the C-Terminal Tail Domain,” published in Molecular Pharmacology. The paper is published by a team led by Drs. Birdsong and Williams.
“Although this class of drugs provides significant relief for severe pain, they also have significant drawbacks, from constipation to addiction,” said Mary Heinricher, Ph.D., associate dean for basic research in the OHSU School of Medicine. “I selected this month’s featured paper from Will Birdsong and colleagues because it makes significant contributions to this field of research.”
One of the major problems with opioid treatment occurs when prolonged exposure to high concentrations of drugs cause the receptor to rapidly decrease its function, a process known as receptor-mediated desensitization.
“It was thought that desensitization may be the first step in the development of tolerance to opioids, where increasing doses of opioids are required to maintain equivalent pain relief,” said Will Birdsong, Ph.D., research assistant scientist at the Vollum Institute.
“The exact mechanisms involved in the process of desensitization are unknown,” added John Williams, Ph.D., senior scientist at the Vollum Institute. “We wanted to investigate the role of receptor phosphorylation in desensitization.”
Phosphorylation is the process by which a phosphate is added to a protein, a kind of molecular tag commonly used to modify receptors. It was originally hypothesized that phosphorylation of the mu opioid receptor (MOPr) led to binding of the arrestin protein which subsequently facilitated internalization of the MOPr.
“With fewer receptors on the surface of cells, it was thought that there would be less signaling in response to opioid drugs, thus the response was desensitized,” said Dr. Williams. “Previous work from our lab and others had demonstrated that inhibiting the enzyme that phosphorylated the receptor, elimination of the arrestin protein, or inhibition of receptor internalization did not prevent receptor desensitization. This suggested that either the canonical model of desensitization was incorrect or incomplete.”
This month’s highlighted paper, “Agonist Binding and Desensitization of the Mu-Opioid Receptor Is Modulated By Phosphorylation of the C-Terminal Tail Domain,” published in the journal Molecular Pharmacology, found an alternative mechanism that could explain MOPr desensitization.
“We found that conditions that are known to cause receptor desensitization also cause a change in the binding of opioid drugs to the receptor,” said Dr. Birdsong. “Thus, the receptor had a "memory" of being previously exposed to drugs.”
The Williams lab further investigated the protein by making mutations in the phosphorylation clusters to prevent receptor phosphorylation. They replaced the endogenous MOPr with mutant receptors to study the effect of these phosphorylation sites on receptor desensitization.
“We found that only when both phosphorylation clusters were mutated was there a significant attenuation of desensitization of the receptor,” said Dr. Birdsong.
“Since loss of multiple phosphorylation sites was required to eliminate opioid-induced receptor desensitization, our work suggests that there are multiple parallel phosphorylation pathways that can lead to receptor desensitization including pathways that have not yet been identified,” said Dr. Birdsong. “There may not be a single target that will prevent tolerance, rather multiple targets that could be differentially utilized depending on the opioid drug used.”For example it is known that morphine induces relatively little receptor phosphorylation compared to fentanyl. “Our future work will include investigating the role of these phosphorylation sites in the process of opioid tolerance, said Dr. Williams.
“Researchers in the Williams lab have shown that different steps in the activation and inactivation of the mu receptor can be independently regulated,” said Dr. Heinricher. “This work gives us hope that specific steps in the process could be novel targets for new drugs to treat pain.”
Resources• Read the paper
• Learn about the Williams Lab
CitationAgonist Binding and Desensitization of the Mu-Opioid Receptor Is Modulated By Phosphorylation of the C-Terminal Tail Domain
Mol Pharmacol. 2015 May 1. pii: mol.114.097527
Will Birdsong, Seksiri Arttamangkul, James R Bunzow, and John T. Williams
Pictured above: Dr. Will Birdsong
More Published Papers• OHSU School of Medicine Papers of the Month
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About the School of Medicine Paper of the Month
The OHSU School of Medicine spotlights a recently published faculty research paper each month. The goals are to describe to the public the exceptional research happening at OHSU as well as inform our faculty of the innovative work underway across the school’s departments, institutes and disciplines. The monthly paper is selected by Associate Dean for Basic Research Mary Heinricher, Ph.D.