Optical Activation of Photoswitchable TRPC Ligands in the Mammalian Olfactory System Using Laser Scanning Confocal...

The transient receptor potential canonical (TRPC) ion channels play important biological roles, but their activation mechanisms are incompletely understood. Here, we describe recent methodological advances using small molecular probes designed for photopharmacology of TRPC channels by focusing on results obtained from the mouse olfactory system. These studies developed and used photoswitchable diacylglycerol (DAG) analogs for ultrarapid activation of native TRPC2 channels in vomeronasal sensory neurons and type B cells of the main olfactory epithelium. Further studies investigated the role of TRPC5 channels in prolactin regulation of dopamine neurons in the arcuate nucleus of the hypothalamus. Here, the first photoswitchable TRPC5 modulator, BTDAzo, was developed and shown to control endogenous TRPC5-based neuronal Ca²⁺ responses in mouse brain slices. Thus, photoswitchable reagents are rapidly gaining widespread recognition for investigating various types of TRPC channels including TRPC2, TRPC3, TRPC5, and TRPC6, enabling to gain new insights into the gating mechanisms and functions of these channels.