Photoswitchable TRPC6 channel activators evoke distinct channel kinetics reflecting different gating behaviors

Keck, Maximilian; Hermann, Christian; Lützel, Kyra; Gudermann, Thomas; Konrad, David B.; Mederos y Schnitzler, Michael; Storch, Ursula (2024): Photoswitchable TRPC6 channel activators evoke distinct channel kinetics reflecting different gating behaviors. iScience, 27 (10): 111008. ISSN 2589-0042

Abstract

The non-selective transient receptor potential canonical 6 (TRPC6) cation channels have several physiological and pathophysiological effects. They are activated by the lipid second messenger diacylglycerol (DAG) and by non-lipidic compounds such as GSK 1702934A (GSK). Advances in photopharmacology led to the development of photoswitchable activators such as PhoDAG, OptoDArG, and OptoBI-1 that can be switched ON and OFF with the spatiotemporal precision of light. We aimed to elucidate whether these photopharmaceuticals allow for a reliable determination of the ion channel current kinetics. We performed electrophysiological whole-cell measurements in the overexpression system and analyzed TRPC6 currents induced by photoswitching. We observed distinct activation, deactivation and inactivation current kinetics suggesting that each photoswitchable activator elicits a distinct active channel state. Notably, the current kinetics strongly depended on the intensity of the light source. Altogether, photopharmaceuticals are advantageous for an extended biophysical characterization of whole-cell currents and provide insight into their gating mechanism.

• Dokumententyp: Artikel (LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Walther-Straub-Institut für Pharmakologie und Toxikologie
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 239283807
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 503157935