Allyson F. O'Donnell, Ph.D.

Nearly half of all prescription drugs alter G-protein coupled receptor (GPCR) signaling, including treatments for asthma, hypertension, neurodegenerative disorders and depression. β-arrestins are critical regulators of GPCRs: they act as trafficking adaptors to control GPCR endocytosis and impede G-protein signaling. β-arrestins are themselves therapeutic targets, highlighting the clinical importance of understanding arrestin function. However, β-arrestins are only a small branch of the larger arrestin family that includes the widely conserved but functionally uncharacterized α-arrestins, which are the primary focus of my research. My work has shown that α-arrestins, like β-arrestins, regulate GPCR signaling, but also operate in unexpected trafficking pathways, including endosomal recycling and clathrin-independent endocytosis. Using Saccharomyces cerevisiae as a model, I have identified α-arrestin interactions with signaling regulators, cargos and vesicle coat proteins, and have begun to define the molecular mechanisms underlying α-arrestin-mediated trafficking. Notably, all of the α-arrestin-interacting partners identified in yeast are conserved. My research applies insights gained in yeast to direct parallel studies on the relatively unstudied mammalian α-arrestins.

Our main objectives in the lab are to define the protein trafficking functions associated for a-arrestins, determine which signaling mechanisms controlling the function of these adaptors, and identify the membrane cargo proteins regulated by the a-arrestins. Our most recent work defines a role for a-arrestins in regulating intracellular sorting of membrane cargo, in addition to the well-defined roles for these adaptors in endocytosis. We recently demonstrated that trafficking of the mammalian Kir2.1 potassium channel, which regulates potassium homeostasis in the heart and when defective results in cardiac arrhythmias, is controlled by three specific a-arrestins. Our studies have identified ubiquitination and phosphorylation as key regulators of a-arrestins-mediated trafficking of Kir2.1. Our research leverages yeast, HEK293T cells and primary cardiomyocytes as model systems to define how Kir2.1 trafficking is regulated by these relatively understudied trafficking adaptors. The power of this multi-systems approach is that it permits fast mutational analyses and identification of novel regulators of Kir2.1 trafficking in the yeast system and then supports validation of these findings in physiologically relevant in mammalian models. We use a broad range of cell biological, genetic, high-throughput and computational approaches to achieve our research objectives.