Johnston C, Zucca S, Grill B, Gill MS, Dao M, Wang D, Lundquist EA, Song C, Giles AC, Martemyanov KA, Orlandi C, Stoveken HM, Opperman KJ, Masuho I
[
Science,
2019]
Opioids target the -opioid receptor (MOR) to produce unrivaled pain management but their addictive properties can lead to severe abuse. We developed a whole animal behavioral platform for unbiased discovery of genes influencing opioid responsiveness. Using forward genetics in <i>C. elegans,</i> we identified a conserved orphan receptor, GPR139, with anti-opioid activity. GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds to MOR and inhibits signaling to G proteins. Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing to modulate morphine-induced analgesia, reward, and withdrawal. Thus, GPR139 could be a useful target for increasing opioid safety. These results also demonstrate the potential of <i>C. elegans</i> as a scalable platform for genetic discovery of GPCR signaling principles.
[
Front Chem,
2022]
The cellular physiochemical properties such as polarity, viscosity, and pH play a critical role in cellular homeostasis. The dynamic change of lysosomal viscosity in live cells associated with different environmental stress remains enigmatic and needs to be explored. We have developed a new class of Julolidine-based molecular viscometers with an extended π-conjugation to probe the lysosomal viscosity in live cells. High biocompatibility, pH tolerance, and the fluorogenic response with far red-emission (>600 nm) properties make these molecular viscometers suitable for live-cell fluorescence imaging in Caenorhabditis elegans. Among these probes, JIND-Mor is specifically designed to target lysosomes via simple modification. The real-time monitoring of lysosomal viscosity change under cellular stress was achieved. We believe that such a class of molecule viscometers has the potential to monitor lysosomal health in pathogenic conditions.