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TRPswitch-A Step-Function Chemo-optogenetic Ligand for the Vertebrate TRPA1 Channel. J Am Chem Soc 2020 Oct 14;142(41):17457-17468

Date

09/24/2020

Pubmed ID

32966062

Pubmed Central ID

PMC8011302

DOI

10.1021/jacs.0c06811

Scopus ID

2-s2.0-85092945882 (requires institutional sign-in at Scopus site)   16 Citations

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 nonelectrophilic 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 the 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.

Author List

Lam PY, Thawani AR, Balderas E, White AJP, Chaudhuri D, Fuchter MJ, Peterson RT

Author

Pui Ying Lam PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Azo Compounds
Behavior, Animal
Color
Gene Expression Regulation
HEK293 Cells
Heart
Heart Conduction System
Humans
Ion Channel Gating
Ligands
Light
Optogenetics
TRPA1 Cation Channel
Zebrafish
Zebrafish Proteins