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(based on a 12/6/2010 OHSU School of Medicine release) The OHSU School of Medicine’s featured paper for December 2010 is from the Proceedings of the National Academy of Sciences, and is titled “Kinetics of G-protein-coupled receptor endosomal trafficking pathways revealed by single quantum dots.” The research was conducted by an investigative collaboration that included Tania Q. Vu, PhD, Assistant Professor, and Katye M. Fichter, PhD, postdoctoral researcher from the Department of Biomedical Engineering and colleagues from The Rockefeller University, Marc Flajolet, PhD, and Paul Greengard, PhD.
G-protein-coupled receptors (GPCRs) are the largest protein superfamily in the human genome; they comprise 30 percent of current drug targets and regulate diverse cellular signaling responses. Previous studies have linked many GPCR neurotransmitter receptors - especially serotonin and dopamine to psychiatric disease, and as such, they are major targets of drug development.
The role of endosomal trafficking in GPCR signaling regulation remains difficult to study due to the inability to distinguish among many individual receptors, simultaneously trafficking within multiple endosomal pathways. Previous research has been limited to observing bulk measurements of hundreds of proteins at a time. Because receptor internalization and recycling are made of the simultaneous kinetics of many individual receptor trafficking events, it is complicated. Without proper technology to access molecular-level phenomena, researchers have been left with an incomplete picture of the mechanisms underlying receptor regulation.
Research in this paper demonstrates that it is possible to tag single, or small groups of receptor proteins inside cells using nanocrystal quantum dots. Tagging individual receptors offers a more complete picture of the percentage of receptor molecules on the cellular membrane that are capable of transducing extracellular chemical signals (neurotransmitters, for example). Furthermore, scientists can look at the recycling pathways responsible for carrying internalized receptors back to the cellular membrane. Using quantum dots to do this, researchers found that the serotonin receptor subtype 1A, a target of many anti-anxiety medications, uses two different recycling pathways simultaneously - a fast recycling pathway and a short recycling pathway. These results demonstrate how complex the internal machinery of the cell is in receptor recycling and ultimately signal regulation.
Looking forward, single-molecule imaging of endosomal trafficking will significantly impact the understanding of cellular signaling and provide powerful tools to elucidate the actions of GPCR-targeted therapeutics. “We are very interested in investigating the effect of anti-depressant and anti-anxiety therapeutics on the regulation of neurotransmitter receptors such as serotonin receptors,” said Dr. Vu. “Using the quantum dots to investigate the affect of these therapeutics on the regulation of serotonin receptors will allow for the development of better therapeutics for affective disorders.” Read the full paper (.pdf)at on the PNAS website