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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM125351-02
Application #
9608759
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Nie, Zhongzhen
Project Start
2018-01-01
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Physiology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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: