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Establishing the Framework to Evaluate Negative Modulators of Mu Opioid Receptor Signaling in Cells
Author(s) -
Stoveken Hannah M,
Wang Dandan,
Masuho Ikuo,
Grill Brock,
Martemyanov Kirill A
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.503.18
Subject(s) - heterotrimeric g protein , g protein , g protein coupled receptor , g protein coupled inwardly rectifying potassium channel , regulator of g protein signaling , signal transduction , microbiology and biotechnology , gtpase activating protein , gtpase , opioid receptor , opioid , pharmacology , biology , chemistry , receptor , biochemistry
Opioid addiction and accidental overdose have arisen as critical health issues as the prevalence and availability of this addicting class of drugs have dramatically increased. The mu opioid receptor (MOR) is the primary analgesic mediator in the brain and is activated by the class of drugs known as opioids. MOR is a G protein coupled receptor (GPCR) that signals through the heterotrimeric G protein class Gi/o. Once activated, the heterotrimeric G proteins transduce the opioid signal to other effectors including adenylate cyclase, voltage‐gated calcium channels, and G protein‐coupled inward‐rectifying potassium (GIRK) channels, among others. Together, this signaling renders the cell less excitable and blocks transmission of pain responses but also elicits unwanted side effects. Endogenously, MOR signaling is regulated to terminate or tune signaling and hence to alter the duration or intensity of the opioid response. Regulators of G protein signaling (RGS) proteins, for example, serve as GTPase‐activating proteins to inactivate Gi/o and terminate MOR signaling. We hypothesized that there may be undiscovered negative MOR regulators that could modulate MOR signaling to lessen opioid side effects. We are currently developing an unbiased forward genetic screen in c. elegans to uncover potential new cell‐autonomous MOR modulators. While the screen is an ongoing effort, we are working to establish the framework for evaluating potential hits in cell‐based assays of MOR signaling. As proof of concept, we examined the effect of the known negative MOR regulator R7BP‐RGS7‐Gb5 complex in cellular assays of MOR function and/or trafficking. Overall, this project is aimed at uncovering and determining the molecular mechanisms of potential new anti‐opioid signaling pathways that could be pharmacologically modulated to mitigate negative opioid‐related side effects. Support or Funding Information National Institutes of Health R01 to KM This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .