Division of Endocrinology, Diabetes & Metabolic Diseases
The Luttrell laboratory is investigating how signals transmitted by seven membrane-spanning G protein-coupled receptors (GPCRs) contribute to the development of cardiac hypertrophy and fibrosis, diabetic vascular and renal disease, and metabolic bone diseases like osteoporosis. Their most significant research discoveries to date include: 1) Discovery of molecular mechanisms through which GPCRs regulate the activity of receptor tyrosine kinases, and vice versa; 2) The original discovery that arrestins, proteins first characterized for their role in GPCR desensitization, functional as signal transducers that link GPCRs to a number of signaling pathways independent of heterotrimeric G proteins; 3) Discovery that G protein-dependent and arrestin-dependent GPCR signaling are pharmacologically dissociable using ‘biased’ orthosteric agonists, synthetic or natural ligands that elicit only a subset of the possible responses arising from receptor activation; 4) Demonstrating that arrestin pathway-selective biased agonists can produce biological effects in vivo that cannot be attained through conventional agonism or antagonism; and, 5) Elucidation of molecular mechanisms by which ‘unbalanced’ GPCR activation by biased agonists can engender novel and unpredictable cell/tissue responses in vitro and in vivo.
Their current focus is on how receptors like the AT1A angiotensin and PTH1 parathyroid hormone receptors integrate G protein-dependent and G protein-independent signals arising from arrestin-dependent ‘signalsomes’, to produce temporally, spatially and functionally distinct signals and how these signals are coordinated to control gene expression, cell proliferation, survival, migration and apoptosis. The finding that ‘biased’ GPCR ligands can selectively activate or block only a subset of the full response profile of the receptor, creates the potential to design drugs that modify only the deleterious aspects of signaling or that target critical points of signal convergence.
Recent work has focused on understanding the roles of arrestin-dependent signaling in a number of physiologically and pathologically relevant contexts. The laboratory routinely employs systems level techniques, including functional genomic and phosphoproteomic analyses of large datasets from in vivo and in vitro models, to understand complex signal transduction networks. At the molecular level, they employ FRET- and BRET-based assay techniques, protein fragment complementation, and luciferase-based sensors to monitor protein-protein interactions in live cells and real time. Another area is interest is in defining pathophysiologic processes involved in the development of microvascular and macrovascular disease in patients with diabetes mellitus. In addition to in vitro work, these studies employ clinical samples from the longitudinal DCCT/EDIC cohort of patients with type I diabetes and the VA Diabetes Trial cohort of patients with type II diabetes and employ systems level techniques such as plasma proteomics to elucidate the signaling networks driving different aspects of diabetic complications.