Transient receptor potential (TRP) channels play significant roles in human physiology and facilitate essential ions' (Na+, Ca2+) permeation through the plasma membrane. The focus of this proposal is on the transient receptor potential vanilloid 2 (TRPV2), which plays an essential role in cardiac function and immunity, and has been placed on the list of important anti-tumor drug targets. Nevertheless, it remains the least studied TRPV channel at the cellular and molecular levels. We propose to use the combination of cryo-EM, electrophysiological analysis, site-directed mutagenesis, and computational methods to establish a detailed structural understanding of the mechanisms of TRPV2 channel gating. In this current proposal we will focus on understanding TRPV2 regulation by phosphoinositides, determine the mechanism of TRPV2 gating by diverse ligands and dissect the molecular mechanism of TRPV2 interaction with cytoskeleton. Information obtained upon completion of these studies will be potentially used for future design of TRPV2 specific therapeutics.

Public Health Relevance

The transient pathophysiological receptor potential vanilloid events in human body, 2 (TRPV2) yet remains contributes to a the least studied broad range of TRPV channel physiological at the cellular and and molecular levels. This proposal focuses on establishing a detailed structural understanding of the mechanisms of TRPV2 channel ligand activation , inhibition and lipid modulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM103899-07
Application #
9917459
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Flicker, Paula F
Project Start
2013-08-01
Project End
2023-06-30
Budget Start
2019-09-24
Budget End
2020-06-30
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hughes, Taylor E T; Lodowski, David T; Huynh, Kevin W et al. (2018) Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM. Nat Struct Mol Biol 25:53-60
Hughes, Taylor E T; Pumroy, Ruth A; Yazici, Aysenur Torun et al. (2018) Structural insights on TRPV5 gating by endogenous modulators. Nat Commun 9:4198
Samanta, Amrita; Hughes, Taylor E T; Moiseenkova-Bell, Vera Y (2018) Transient Receptor Potential (TRP) Channels. Subcell Biochem 87:141-165
Samanta, Amrita; Kiselar, Janna; Pumroy, Ruth A et al. (2018) Structural insights into the molecular mechanism of mouse TRPA1 activation and inhibition. J Gen Physiol 150:751-762
Basak, Sandip; Gicheru, Yvonne; Samanta, Amrita et al. (2018) Cryo-EM structure of 5-HT3A receptor in its resting conformation. Nat Commun 9:514
Arne, Jason M; Widjaja-Adhi, Made Airanthi K; Hughes, Taylor et al. (2017) Allosteric modulation of the substrate specificity of acyl-CoA wax alcohol acyltransferase 2. J Lipid Res 58:719-730
Huynh, Kevin W; Cohen, Matthew R; Jiang, Jiansen et al. (2016) Structure of the full-length TRPV2 channel by cryo-EM. Nat Commun 7:11130
Cohen, Matthew R; Johnson, William M; Pilat, Jennifer M et al. (2015) Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons. Mol Cell Biol 35:4238-52
Cohen, Matthew R; Moiseenkova-Bell, Vera Y (2014) Structure of thermally activated TRP channels. Curr Top Membr 74:181-211
Huynh, Kevin W; Cohen, Matthew R; Moiseenkova-Bell, Vera Y (2014) Application of amphipols for structure-functional analysis of TRP channels. J Membr Biol 247:843-51

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