Heterotrimeric G proteins (???) are well known for their function in linking G protein-coupled receptors (GPCRs) to a variety of intracellular responses, and thereby playing essential roles in transmitting a wide variety of extracellular signals into regulation of countless physiological process. In the textbook view, G proteins carry out their function while associated with the cytoplasmic surface of a cell's plasma membrane. In contrast to the classical view of plasma membrane limited G protein signaling, it is becoming increasingly recognized that G protein localization is dynamic and regulated, such that they can reversibly traffic from the plasma membrane to intracellular locations, and that G proteins can have important cellular functions at intracellular sites. The research in this proposal focuses on one such non-canonical G protein function: Golgi-localized G??-mediated regulation of a signaling pathway on the cytoplasmic surface of Golgi membranes that controls the Golgi exit of select protein cargo destined for the plasma membrane. This research will not only provide new insight into heterotrimeric G protein signaling functions, but will also further our understanding f mechanisms that regulate protein transport, a complex process for which a great deal remains to be understood. This essential cellular process involves protein synthesis at and translocation into the endoplasmic reticulum, transit through the endoplasmic reticulum and Golgi, sorting into distinct cargo-containing domains at the trans Golgi network, and finally exit from the Golgi in vesicles or transport carriers and movement to the plasma membrane or intracellular organelle destinations. This application will focus on the role of G?? in regulating the step of Golgi exit o select cargo proteins. To address this non-canonical function of G??, the major objectives are 1) Investigate the role of Golgi-localized G?? in the Golgi-to-PM transport of select cargo;2) Investigate the role of RKTG in G??-dependent regulation of Golgi-to-PM traffic;and 3) Investigate the role of GPCRs and the trafficking of G?? in the regulation of Golgi-to-PM transport. These objectives will be pursued by a variety of experimental approaches, including cultured cells, immunofluorescence microscopy, fluorescence microscopy of live cells, subcellular fractionation, pharmacological inhibitors, mutational analysis, biochemical assays, and the development of novel approaches for spatial and temporal inhibition of GPCRs and G proteins.

Public Health Relevance

G protein-mediated signaling pathways regulate numerous physiological responses, including neuron development, neurotransmitter responses, cardiovascular function, cell differentiation, cell migration, immune cell function, and smell, tase, and vision. Dysregulation of G protein-mediated signaling pathways contribute to numerous disease states, including neurological diseases, heart disease, hypertension, cancer, metastasis, endocrine disorders, and blindness. Understanding novel G protein signaling pathways at novel intracellular locations will provide new knowledge and opportunities to therapeutically target unwanted G protein responses while leaving intact beneficial G protein signaling pathways.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Dunsmore, Sarah
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Thomas Jefferson University
Schools of Medicine
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