Characterization of Compartmentalized GPCR Signaling in Neurons

More than a third of all G protein-coupled receptors (GPCRs) are expressed in the brain, where they modulate synaptic plasticity, memory and behavior, and also contribute to the pathophysiology of neuropsychiatric disorders. Therefore, improved understanding of how GPCRs several neurological and operate in neurons is fundamentally important to neuroscience, and will enable mechanism-based discovery of more selective and efficient therapies for memory disorders and mental illness. In this proposal, we build on our transformative finding that receptor activation on endosomal compartments underlies unique cellular responses. We propose to explore the molecular consequences of endosomal receptor signaling in neurons, and to investigate how neurons discriminate between distinct sites of local activation. We focus on the prototypical β2-adrenoceptor (β2-AR), a recognized mediator of neuronal function, to test the hypothesis that the molecular composition of signaling complexes present at endosomes is distinct from the plasma membrane resulting in unique neuronal outcomes upon β2-AR activation. We will employ an interdisciplinary approach in human iPSC-derived neurons to 1) delineate the consequences of compartmentalized β2-AR signaling on transcriptional reprogramming, 2) elucidate the role of plasma membrane- and endosomal β2-ARs in translational regulation of gene expression, and 3) determine how the endosome induces spatially biased GPCR responses. Successful completion of these studies will illuminate how spatial GPCR regulation is established, and how it shapes critical neuronal outputs of this pathway.