Pharmacology/Drug action
GPCRs are a major class of drug targets; in fact, current estimates suggest that close to half of all pharmaceutical drugs on the market act on these receptors and their associated pathways. We study how drug specificity is encoded at the cellular level by asking how activation of the same receptor by different ligands can lead to distinct cellular responses (Figure).
Figure- Ligand discrimination. Different ligands binding the same GPCR vary in their endocytic efficacy. Does ligand-induced internalization underlie drug specificity? Genes encoding receptors and other signaling components are polymorphic in the human population (red star denotes a SNP in the GPCR gene). How do variants affect GPCR trafficking and ligand-dependent signaling?
We are currently focusing on:
Evaluating how the spatial and biochemical regulation of GPCRs shapes divergent drug actions.
Evaluating how genetic variation in receptors and components of their signaling networks affect cellular responses to different drugs.
For reference, see:
Tsvetanova NG, Trester-Zedlitz M, Newton BW, Riordan DP, Sundaram AB, Johnson JR, Krogan NJ, von Zastrow M. (2017). GPCR endocytosis confers uniformity in responses to chemically distinct ligands. Molecular Pharmacology 91:145-156.