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Significance Thanks to innovative BRET-based probes, we shed light on ligand-biased ion selectivity, a difficult-to-study ion channel–related pharmacological concept, by performing the dynamic measurements of Ca2+ and K+ concentrations and… Click to show full abstract
Significance Thanks to innovative BRET-based probes, we shed light on ligand-biased ion selectivity, a difficult-to-study ion channel–related pharmacological concept, by performing the dynamic measurements of Ca2+ and K+ concentrations and ionic strength in the nanoenvironment of the TRPV1 channel during drug challenge in real-time live-cell experiments. Our results indicate that some TRPV1 antagonists display differential potencies in inhibiting CAPS-induced Ca2+ and K+ fluxes. We also detect concentration- and time-dependent ligand biases in P2X7 and P2X5 cationic selectivity. These new BRET-based probes now open up avenues for adding value to ion-channel drug discovery platforms by taking ligand bias into account, thus addressing molecular events related to ion channel activation that are intractable using either conventional fluorescent-based probes or patch-clamp techniques.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2022
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