Mechanisms and function of spatially encoded GPCR signaling

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Mechanisms and function of spatially encoded GPCR signaling PROJECT SUMMARY: G protein-coupled receptors (GPCRs), a critical class of signal transducers, are ubiquitously expressed in the human body and can detect virtually all types of stimuli. As such, these transmembrane receptors control all essential human physiology, and account for almost half of current therapeutic targets. All of the known drugs acting on GPCRs were developed on the assumption that signals initiated at the cell surface were the primary process that needed to be regulated. However, recent work by us and others has upended this `classical' model of GPCR signal transduction by demonstrating that receptors can be active inside the cell. Furthermore, we have established that localization of the active GPCR can specify functionally distinct cellular responses and could shape how cells interpret different drugs acting through the same receptor. Leveraging the insights from these findings, we aim to provide a comprehensive dissection of the cellular functions and molecular underpinnings of compartmentalized GPCR signaling. Specifically, in this proposal we will dissect how spatially encoded responses are established across multiple levels, from molecular determinants within the GPCR itself, to downstream effectors, and cell-type specific mechanisms. Further, we will carry out comprehensive analysis of the downstream responses triggered by known compartments of receptor activity to determine the consequences of localized signaling. This proposal is anchored in our strengths in high-throughput quantitative methods, imaging, pharmacology, and cell biology. These studies will elucidate fundamental principles governing cellular signal transduction, and allow us to re- explore the molecular determinants of GPCR pharmacology in order to effectively target these pathways in disease.