PUBLICATION
TRPswitch - a step function chemo-optogenetic ligand for the vertebrate TRPA1 channel
- Authors
- Lam, P.Y., Thawani, A.R., Balderas, E., White, A.J.P., Chaudhuri, D., Fuchter, M.J., Peterson, R.
- ID
- ZDB-PUB-201002-136
- Date
- 2020
- Source
- Journal of the American Chemical Society 142(41): 17457-17468 (Journal)
- Registered Authors
- Lam, Pui Ying, Peterson, Randall
- Keywords
- none
- MeSH Terms
-
- Animals
- Azo Compounds/metabolism
- Behavior, Animal/radiation effects
- Color
- Gene Expression Regulation
- HEK293 Cells
- Heart
- Heart Conduction System/metabolism
- Humans
- Ion Channel Gating
- Ligands
- Light
- Optogenetics
- TRPA1 Cation Channel/genetics*
- TRPA1 Cation Channel/metabolism*
- Zebrafish
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism*
- PubMed
- 32966062 Full text @ J. Am. Chem. Soc.
Citation
Lam, P.Y., Thawani, A.R., Balderas, E., White, A.J.P., Chaudhuri, D., Fuchter, M.J., Peterson, R. (2020) TRPswitch - a step function chemo-optogenetic ligand for the vertebrate TRPA1 channel. Journal of the American Chemical Society. 142(41):17457-17468.
Abstract
Chemo-optogenetics has produced powerful tools for optical control of cell activity, but current tools suffer from a variety of limitations including low unitary conductance, the need to modify the target channel, or the inability to control both on and off switching. Using a zebrafish behavior-based screening strategy, we discovered "TRPswitch", a photoswitchable non-electrophilic ligand scaffold for the transient receptor potential ankyrin 1 (TRPA1) channel. TRPA1 exhibits high unitary channel conductance, making it an ideal target for chemo-optogenetic tool development. Key molecular determinants for the activity of TRPswitch were elucidated and allowed for replacement of the TRPswitch azobenzene with a next-generation azoheteroarene. The TRPswitch compounds enable reversible, repeatable, and nearly quantitative light-induced activation and deactivation of the vertebrate TRPA1 channel with violet and green light, respectively. The utility of TRPswitch compounds was demonstrated in larval zebrafish hearts exogenously expressing zebrafish Trpa1b, where heartbeat could be controlled using TRPswitch and light. Therefore, TRPA1/TRPswitch represents a novel step-function chemo-optogenetic system with a unique combination of high conductance, high efficiency, activity against an unmodified vertebrate channel, and capacity for bidirectional optical switching. This chemo-optogenetic system will be particularly applicable in systems where a large depolarization current is needed or sustained channel activation is desirable.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping