BRET-Based Approaches for Ion Channels: Emerging Applications and Future Directions

Bioluminescence resonance energy transfer (BRET) is a technique based on energy transfer between a luminescent enzyme and a fluorescent acceptor. Since its first description in 1999, BRET has been widely applied in chemical biology research and drug discovery. Today, it is regarded as one of the most versatile methods for investigating the dynamics of ligand-protein and protein-protein interactions, both in cell-free systems and living cells. Owing to several advantages, including compatibility with high-throughput screening, suitability for cellular target engagement studies, and the ability to monitor real-time kinetics, BRET-based binding assays have become indispensable tools, particularly in early-stage drug discovery. Consequently, over the past decade these approaches have been extensively used for major drug target classes such as G protein-coupled receptors (GPCRs), kinases, and proteases. Despite the high relevance of ion channels as drug targets-approximately one-fifth of all approved drugs act on them-BRET-based assays have so far played only a limited role in this field. Here, we summarize recent applications of BRET-based methods for ion channels with a particular focus on approaches for studying ligand-ion channel interactions, highlighting current challenges and, more importantly, the significant potential of this technology to advance ion channel-focused drug discovery.