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Density-Dependent Mu Opioid Receptor Function Revealed by Single-Molecule Microscopy

Holsey, Michael David

The Mu Opioid Receptor (MOR) is a G protein-coupled receptor (GPCR) important for pain regulation. Opioid agonists have long been the most effective treatment for most types of pain; however, this class of drugs is highly problematic due to the combination of several dangerous side effects like addiction, tolerance, and respiratory depression. Recently, a dramatic rise in opioid prescriptions has led to a nationwide opioid epidemic. Efforts to develop novel opioids with improved therapeutic profiles have led to work suggesting that MOR signaling through G proteins leads to analgesia while signaling through arrestin leads to respiratory depression and tolerance. However, more recent work has raised questions about which aspects of arrestin signaling and function contribute to these side effects. Additionally, the overall complexity of arrestin function especially with regard to trafficking at the cell membrane has recently come in to clearer view. Here, we use single-molecule tracking to describe membrane diffusion behavior of single MORs before and after agonist treatment in heterologous cells. By tracking individual MORs, we have revealed cell-context specific rules for MOR immobilization and endocytosis and shown that these processes depend on receptor density as well as the local availability of arrestin molecules.

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More About This Work

Academic Units
Cellular Physiology and Biophysics
Thesis Advisors
Javitch, Jonathan A.
Degree
Ph.D., Columbia University
Published Here
September 23, 2019
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