Functional and Mechanistic Dissection of GPCR Endosomal Signaling Dynamics

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Abstract G protein-coupled receptors (GPCRs), which compose the largest class of drug targets, are critical signaling proteins that translate extracellular stimuli to mediate human physiology. As such, understanding GPCR signaling cascades will provide insight into the molecular mechanisms underlying these complex physiological processes, their perturbation in disease, and inform our ability to design more efficient therapeutics. In recent years, my lab and others have made a paradigm-shifting discovery that GPCRs can be activated after drug- induced internalization from the plasma membrane into endosomal compartments. However, one essential variable that remains unexplored is how the temporal dynamics of GPCR endosomal cAMP activity impact downstream signaling. In the current proposal, I will dissect the influence of the duration of GPCR activation in endosomes on downstream signaling, identify novel protein complexes that regulate receptor spatiotemporal signaling dynamics, and apply this knowledge to a physiologically relevant system—hippocampal neurons. By combining functional genomics, proteomics, and optogenetics, this proposal aims to provide a comprehensive understanding of how the temporal dynamics of GPCR signaling in endosomes regulates biological functions. This work is essential to comprehending the mechanisms of GPCR signaling and identifying novel signaling pathways, providing new targets for pharmacologic therapies.