TRPA1 is a Ca2+-permeable, non-selective cation channel and one of the key pain sensors in mammals. It has emerged as a novel target for analgesics and anti-inflammatory agents. Pain sensation mediated by TRPA1 involves modification of N-terminal cysteine residues on the channel by thiol-reactive compounds and inflammatory mediators. Binding of thiol-reactive compounds to the channel in the resting state leads to channel activation followed rapidly by desensitization. While channel activity has been studied extensively by electrophysiological methods, little is known about the structural mechanisms of channel activation and desensitization. Additionally, two compounds that directly inhibit TRPA1 are in pre-clinical trials, and understanding the mechanism of TRPA1 inhibition by these compounds will be important for advancing our knowledge of the structural differences between functionally relevant TRPA1 conformations. Using cryo-EM, site-directed mutagenesis, limited proteolysis, and mass spectrometry, in this grant we aim to establish a detailed structural understanding of the mechanisms of TRPA1 channel activation, desensitization and inhibition, which will help facilitate rational design of novel analgesics.
Pain, while serving the beneficial function of provoking our attention to dangerous situations, is an unpleasant sensory and emotional experience. TRPA1 is a Ca2+-permeable, non-selective cation channel and one of the key pain sensors in mammals. This proposal focuses on establishing a detailed structural understanding of the mechanisms of TRPA1 channel activation, desensitization and inhibition, which will help facilitate rational design of novel analgesics.
| 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 |
Showing the most recent 10 out of 12 publications
