Optical control of G protein-coupled receptor function - Project Summary The overarching goals of my lab are to (i) develop molecular tools to control and map how subcellular signaling influences physiology and pathology and (ii) learn from and use biological photon reception to advance molecular pharmacology. Due to their unprecedented physiological and pathological footprint in many diseases, including cardiovascular, metabolic, neurological, and oncological, we focus on G protein-coupled receptors (GPCRs). Although GPCRs in individual cells in the body are controlled by spatially and temporally fluctuating ligands with various cell membrane permeabilities, limited tools to interrogate their signaling with native fidelity have been an obstacle to understanding their signaling regulations in health and disease. With the R01 funding support, promising published and preliminary data we generated show the feasibility of optical control of endogenous GPCRs and G proteins to overcome this challenge. This MIRA proposal will deliver innovative optical tools to control endogenous GPCRs in unmodified cells and in vivo (Goal 1) and GPCRs and endogenous G proteins at exclusive subcellular locations such as Golgi and nuclear membranes (Goal 2). It also focuses on finding molecular links between environmental light conditions, cell signaling, and animal behavior mediated by the melanopsin photopigment (Goal 3). Given the immense challenges in controlling deep-tissue GPCRs to understand diseases such as neurodegeneration, the likely pathological outcomes of GPCR-G protein signaling from endomembranes, including heart failure and addiction, and the significance of the link between environmental light conditions with mood and behavior disorders, such as seasonal affective disorders and depression, we anticipate that the project deliverables will be significant in deciphering pathological mechanisms and finding disease intervention points.
