Investigation of a Newly Discovered Organelle-Based Signaling Paradigm

Project summary/Abstract My research program investigates cellular architecture as a key factor in signal transduction. A long-held tenet of molecular pharmacology is that receptors at the cell surface are the sole site of action of external, plasma membrane impermeable ligands such as peptide/protein-derived hormones and biogenic amines. Therefore, understanding of the immediate consequences of signaling has largely been confined to events that happen proximal to the plasma membrane. The work from my lab suggests that these are narrow views of how signaling receptors function. By developing novel tools to visualize signaling in intact cells and focusing on a class of G protein coupled receptors (GPCRs), we have shown that 1) receptor activation and subsequent G protein- mediated signaling occurs not only at the plasma membrane but also at previously unappreciated subcellular compartments such as the endosomes and the Golgi membranes, 2) signaling from these internal compartments constitutes a critical aspect of cellular responses to external cues, 3) transport mechanisms allow membrane impermeable ligands to access compartments within the cell, 4) efficacies of certain clinically used drugs may be driven from their serendipitous capacity to cross the plasma membrane and act on internal receptor pools, and that 5) receptor activation at each subcellular membrane compartment recruits a unique set of effectors/proteins via distinct lipid environment at each location. Subcellular, compartmentalized signaling by GPCRs is a new and largely unappreciated facet of cellular signaling with major implications for physiology and pathophysiology. My goal is to investigate spatially distinct subcellular compartments as signaling hubs. We will decipher the factors that initiate signaling at each signaling hub and determine how each compartment achieves specialized molecular and cellular outcomes, and how this knowledge can provide a framework for developing therapeutics that selectively act on compartment specific aspects of signaling.