Ideal efficacy photoswitching for chromocontrol of TRPC4/5 channel functions in live tissues
Precisely probing the endogenous roles of target proteins is crucial for biological research. Photochemical tools can be photoactuated with high spatiotemporal resolution but often they are unreliable in vivo because spatiotemporal variations of reagent concentration result in inhomogeneous bioactivity. We now describe ideal efficacy photoswitching, a paradigm that internally compensates for reagent concentration by self-competitive binding, allowing purely wavelength-dependent chromocontrol over bioactivity that is consistent from cell culture to deep tissues. We demonstrate this with photoswitches for endogenous transient receptor potential (TRP) C4 and C5 ion channels, reproducibly delivering strong agonism under 360-nm illumination, weak agonism under 385-nm illumination and strong antagonism under 440-nm illumination. These ligands unlock a range of high-precision investigations in TRP biology, from neuronal activity to exocytosis, reproductive signaling and smooth muscle contractility. The ideal efficacy photoswitching paradigm should also unlock high-performance chromocontrol over a wide range of sensory or signaling channels and receptors even in vivo.
Authors
- Deivanayagabarathy Vinayagam (ORCID: https://orcid.org/0000-0001-7862-9499)
- Fanny Büchau (ORCID: https://orcid.org/0000-0002-6630-3325)
- Stefan Raunser (ORCID: https://orcid.org/0000-0001-9373-3016)
- Claudia Bauer (ORCID: https://orcid.org/0000-0003-4278-4803)
- Robin S. Bon (ORCID: https://orcid.org/0000-0003-1733-3680)
- Trese Leinders‐Zufall (ORCID: https://orcid.org/0000-0002-0678-362X)
- Katharina Oleinikov
- Michael Schaefer (ORCID: https://orcid.org/0000-0003-3662-4387)
- Dieter Bruns (ORCID: https://orcid.org/0000-0002-2497-1878)
- Navin K. Ojha (ORCID: https://orcid.org/0000-0001-9225-4267)
- Konstantin Niemeyer
- Yvonne Schwarz
- Mazen Makke
- Aidan V. Johnson (ORCID: https://orcid.org/0000-0003-0303-9106)
- Stephen P. Muench (ORCID: https://orcid.org/0000-0001-6869-4414)
- Sebastian Porav
- Nicole Urban
- Frank Zufall
- Markus Müller
Institutions
- University of Leeds (GB)
- University Hospital Leipzig (DE)
- Max Planck Institute of Molecular Physiology (DE)
- Institute of Structural and Molecular Biology (GB)
- Hochschule für Technik und Wirtschaft Dresden – University of Applied Sciences (DE)
- Technische Universität Dresden (DE)
- Ludwig-Maximilians-Universität München (DE)
- Saarland University (DE)
- Leipzig University (DE)
Publication Details
- Journal
- Nature Chemical Biology
- Published
- 2026-01-16
- DOI
- https://doi.org/10.1038/s41589-025-02085-x
- Citations
- 1
- Primary Topic
- Photochromic and Fluorescence Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 16.08