The importance of receptor location in signaling

G-protein coupled receptors (GPCRs) are involved in all aspects of how we perceive our world, from the ability to detect light, touch, to our sensation of taste and smell. Since GPCRs are involved in so many pathways, GPCRs are key targets for therapeutics. The majority of newly developed drugs target GPCR signaling.

We once thought that GPCRs worked as simple switches sitting on cell membranes that only relayed a signal and then were discarded. Due to this limited view of GPCR function, we designed drugs to target GPCR signaling on the plasma membrane. We are now discovering that GPCRs can form signaling complexes, not just on the plasma membrane of cells, but from different intra-cellular sites and that this intra-cellular signaling is very important in the development of many disease states like pain, itch, and inflammation.

Our research focuses on the importance of GPCR signaling from these intracellular sites and the impact that the endosomal signaling of GPCRs have on neuron activation. We are also developing new strategies to deliver drugs to these intracellular sites where they can be more effective in altering GPCR signaling and in treating diseases.


Human cells expressing the Gastrin Releasing Peptide Receptor (GRPR)

Human cells expressing the Gastrin Releasing Peptide Receptor (GRPR), a GPCR that is important in itch sensation. These cells also express a marker for endosomes (Green) a compartment in cells that is important in GPCR trafficking and signaling. Here we activate GRPR with a fluorescent agonist (Red) and we can see GRPR and the agonist internalize and co-localize with the endosomal marker. The merging of the receptor with the endosomes can be seen by the yellow dots and some regions are highlighted by the yellow circles.


HEK cells with a fluorescent nanoparticle (Magenta)

Here we pretreat the HEK cells with a fluorescent nanoparticle (Magenta) that carries an inhibitor for GRPR. The nanoparticles are internalized into the cells where they await the activated GRPR (Red) to specifically inhibit endosomal mediated signaling. Yellow circles highlight regions where the nanoparticles and receptors are joining in endosomes.