Photoswitchable reagents can be powerful tools for high-precision biological control. TRPC5 is a Ca 2 + -permeable cation channel with distinct tissuespecific roles, from synaptic function to hormone regulation. Reagents giving spatiotemporally-resolved control over TRPC5 activity may be key to understanding and harnessing its biology. Here we develop the first photoswitchable TRPC5-modulator, BTDAzo, to address this goal. BTDAzo can photocontrol TRPC5 currents in cell culture, as well as controlling endogenous TRPC5-based neuronal Ca 2 + responses in mouse brain slices. BTDAzos are also the first reported azobenzothiadiazines, an accessible and conveniently derivatised azoheteroarene with strong two-colour photoswitching. BTDAzo's ability to control TRPC5 across relevant channel biology settings makes it suitable for a range of dynamically reversible photoswitching studies in TRP channel biology, with the aim to decipher the various biological roles of this centrally important ion channel.

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.

Photoswitchable reagents can be powerful tools for high-precision biological control. TRPC5 is a Ca 2 + -permeable cation channel with distinct tissuespecific roles, from synaptic function to hormone regulation. Reagents giving spatiotemporally-resolved control over TRPC5 activity may be key to understanding and harnessing its biology. Here we develop the first photoswitchable TRPC5-modulator, BTDAzo, to address this goal. BTDAzo can photocontrol TRPC5 currents in cell culture, as well as controlling endogenous TRPC5-based neuronal Ca 2 + responses in mouse brain slices. BTDAzos are also the first reported azobenzothiadiazines, an accessible and conveniently derivatised azoheteroarene with strong two-colour photoswitching. BTDAzo's ability to control TRPC5 across relevant channel biology settings makes it suitable for a range of dynamically reversible photoswitching studies in TRP channel biology, with the aim to decipher the various biological roles of this centrally important ion channel.