The goal of this proposal is to determine the molecular mechanisms underlying multi-modal gating of the pain-receptor ion channel TRPV1 by interrogating the structural mechanisms for activation by capsaicin, heat, protons, savory compounds, and signaling lipids. We will use tmFRET and computational methods to determine the conformational change induced by each modality and the coupling between modalities.
Although chronic pain is a major problem for our economy and the quality of life, current treatments are not very effective and have unwanted side effects. In this project, we will elucidate the fundamental biological mechanisms by which the pain receptor ion channel TRPV1 detects and integrates multiple types of painful stimuli, which will provide a new basis for the development of novel pain therapies.
|Gordon, Sharona E; Munari, Mika; Zagotta, William N (2018) Visualizing conformational dynamics of proteins in solution and at the cell membrane. Elife 7:|
|Stratiievska, Anastasiia; Nelson, Sara; Senning, Eric N et al. (2018) Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor. Elife 7:|