Ideal efficacy photoswitching for chromocontrol of TRPC4/5 channel functions in live tissues
Year: 2026
Type: article
Abstract: 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.
Source: Nature Chemical Biology
Authors: Markus Müller, Konstantin Niemeyer, Navin K. Ojha, Sebastian A. Porav, Deivanayagabarathy Vinayagam, Nicole Urban, Fanny Büchau, Katharina Oleinikov, Mazen Makke, Claudia C. Bauer, Aidan V. Johnson, Stephen P. Muench, Frank Zufall, Dieter Bruns, Yvonne Schwarz, Stefan Raunser, Trese Leinders-Zufall, Robin S. Bon, Michael Schaefer, Oliver Thorn-Seshold
Language: English
Subfield: Materials Chemistry
Field: Materials Science
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: G1171311887, G1242026511, G1579701519, Structural insights into small molecule activation of TRPC4/5 channels, Photo/photoredoxschaltbare Liganden als chemische Werkzeuge für die Optogenetik, Chemische Methoden zur Charakterisierung sowie Kontrolle des Mikrotubuliaufbaus und der Mikrotubulidynamik unter physiologischen Bedingungen, State of the art direct electron detection at the Astbury Biostructure Laboratory, SFB 894: Ca2+Signale: Molekulare Mechanismen und Integrative Funktionen, G388153354, A community based training programme for cryo-electron microscopy, G3916100709, Modern Cryo-Electron Microscopy with Direct Electron Detection at the University of Leeds., G4854761912, SFB 1032: Nanoagenzien zur raumzeitlichen Kontrolle molekularer und zellulärer Reaktionen, G6868616705, State of the art direct electron detection at the Astbury Biostructure Laboratory, TRR 152: Steuerung der Körperhomöostase durch TRPKanalModule, Modern Cryo-Electron Microscopy with Direct Electron Detection at the University of Leeds., A community based training programme for cryo-electron microscopy, Understanding potent small-molecule inhibition of TRPC1/4/5 channels, G9000245716
OpenAlex ID: W7124456076