Tiapko Oleksandra, Shrestha Niroj, Lindinger Sonja, Guedes de la Cruz Gema, Graziani Annarita, Klec Christiane, Butorac Carmen, Graier Wolfgang F, Kubista Helmut, Freichel Marc, Birnbaumer Lutz, Romanin Christoph, Glasnov Toma, Groschner Klaus
Gottfried Schatz Research Center - Biophysics , Medical University of Graz , Neue Stiftingtalstraße 6/D/04 , 8010 Graz , Austria . Email:
Institute of Biophysics , University of Linz , Gruberstrasse 40/1 , 4020 Linz , Austria.
Chem Sci. 2019 Jan 15;10(9):2837-2842. doi: 10.1039/c8sc05536j. eCollection 2019 Mar 7.
Lipid-gated TRPC channels are highly expressed in cardiovascular and neuronal tissues. Exerting precise pharmacological control over their activity in native cells is expected to serve as a basis for the development of novel therapies. Here we report on a new photopharmacological tool that enables manipulation of TRPC3 channels by light, in a manner independent of lipid metabolism and with higher temporal precision than lipid photopharmacology. Using the azobenzene photoswitch moiety, we modified GSK1702934A to generate light-controlled TRPC agonists. We obtained one light-sensitive molecule (OptoBI-1) that allows us to exert efficient, light-mediated control over TRPC3 activity and the associated cellular Ca signaling. OptoBI-1 enabled high-precision, temporal control of TRPC3-linked cell functions such as neuronal firing and endothelial Ca transients. With these findings, we introduce a novel photopharmacological strategy to control native TRPC conductances.
脂质门控的瞬时受体电位通道C型（TRPC）在心血管和神经组织中高度表达。对其在天然细胞中的活性进行精确的药理学控制有望成为开发新疗法的基础。在此，我们报告一种新的光药理学工具，它能够以独立于脂质代谢的方式，通过光来操纵TRPC3通道，且具有比脂质光药理学更高的时间精度。我们利用偶氮苯光开关部分修饰了GSK1702934A，以生成光控TRPC激动剂。我们获得了一种光敏感分子（OptoBI-1），它使我们能够对TRPC3活性及相关的细胞钙信号传导施加有效的光介导控制。OptoBI-1能够对与TRPC3相关的细胞功能进行高精度的时间控制，如神经元放电和内皮细胞钙瞬变。基于这些发现，我们引入了一种控制天然TRPC电导的新型光药理学策略。
