BTDAzo - a photoswitchable TRPC5 channel activator

Abstract

Photoswitchable reagents to modulate protein activity are powerful tools for high-spatiotemporal-precision control over endogenous biological functions. TRPC5 is a Ca2+-permeable cation channel with distinct tissue-specific roles, ranging from synaptic function to hormone regulation. Achieving spatially-resolved control over TRPC5 activity in particular cells or tissues, and temporal regulation in targeted cells, are therefore crucial milestones towards understanding and harnessing the biology of TRPC5. Here we develop the first photoswitchable TRPC5-modulating reagent, BTDAzo, towards reaching this goal. BTDAzo can photocontrol TRPC5 currents in cell culture, as well as controlling endogenous TRPC5-based neuronal Ca2+ responses in mouse brain slices. BTDAzos are also the first reported azo-benzothiadiazines, an accessible and conveniently derivatised azoheteroarene that features excellent two-colour photoswitching. BTDAzo's TRPC5 control across relevant channel biology settings makes it appropriate for a range of dynamically reversible photoswitching studies in TRP channel biology, aiming to decipher the various biological roles of this centrally important ion channel.

Self-reporting styrylthiazolium photopharmaceuticals: mitochondrial localisation as well as SAR drive biological activity

“…However, partitioning of photoswitches out of the cytosol (e.g. into lipid environments) is known to substantially impact their cellular performance 16,34,35 ; such partitioning might shield StyBtz from GSH, enabling StyBtz2 to exert Z-specific bioactivity.…”