G protein-coupled receptors (GPCRs) constitute the largest class of membrane proteins that transduce signals across the plasma membrane, and have emerged as major drug targets in the development of therapeutics in all clinical areas.  In fact, ~40% of all prescribed drugs target GPCRs.  We study interactions of membrane lipids (such as cholesterol and sphingolipids) with GPCRs and its implications in health and disease.  We are one of the first groups to work in this important area.  We employ a judicious combination of biophysical, biochemical, cell biological and molecular dynamics simulation approaches to explore this area.  In our work, we have shown that GPCR-cholesterol interaction is important for ligand binding, G-protein  coupling, downstream signaling, oligomerization, and endocytosis of GPCRs. The choice of GPCR in our laboratory is the serotonin_1A receptor, a neurotransmitter GPCR, which is implicated in anxiety and depression and serves as a  popular drug target.  We have recently identified certain regions of the serotonin_1A receptor that are crucial for sensing altered membrane cholesterol levels. 

    GPCRs orchestrate a multitude of physiological processes within cells, which are maintained within stringent spatiotemporal regimes utilizing several regulatory mechanisms.  Endocytosis is an important regulatory feature of GPCR signaling that involves the internalization and sequestration of receptors from the plasma membrane into intracellular vesicular structures (endosomes). The detailed mechanism of endocytosis and trafficking of GPCRs is not well understood. Importantly, dysregulated GPCR trafficking has been associated with several pathophysiological conditions, and exploring the mechanistic details of endocytosis and trafficking of GPCRs therefore assumes relevance. In our current work, we use innovative advanced microscopy and flow cytometry techniques to study the role of membrane lipids in GPCR endocytosis and trafficking in real time in living cells.  We explore the effects of altered membrane lipid composition and actin cytoskeleton on GPCR endocytosis and trafficking.  We believe that this novel and transformative approach would empower us to explore GPCR endocytosis and its (mis)regulation under healthy and disease conditions, and eventually could translate into the development of novel drugs.