Mol Pharmacol. 2025 Nov;107(11):100076. doi: 10.1016/j.molpha.2025.100076. Epub 2025 Sep 25.
ABSTRACT
In cardiomyocytes, Kv7.1 associates with the regulatory subunit KCNE1 to generate the delayed rectifier potassium current I, which plays a crucial role in cardiac repolarization at elevated heart rates. Gain-of-function mutations in either of these subunits are associated with short QT syndrome, a condition that increases the risk of cardiac arrhythmias including atrial fibrillation, syncope, and sudden death. Therefore, the study of pharmacological inhibitors of Kv7.1 and I is of significant therapeutic interest. In this work, we used whole-cell patch clamp recordings to characterize the electrophysiological effects of the Kv7.1 blocker 3-(triphenylmethylaminomethyl)pyridine (UCL2077) in both Kv7.1 and I (Kv7.1 + KCNE1) channels. We found that UCL2077 inhibited both Kv7.1 and I channels with high affinity (IC in the picomolar range) and mild voltage dependence. The drug induced a biphasic time-dependent current decay and reduced current reactivation of Kv7.1, whereas the kinetics of I were unaffected. We examined state dependence using mutations that functionally stabilize Kv7.1/I in either the intermediate-open (E160R/R231E) or in the activated-open (E160R/R237E) state. In both channels, UCL2077 potency correlated with the strength of the electromechanical coupling. Our results are further supported by a kinetic Markov model simulating UCL2077 binding that closely resembles the experimental currents. Overall, our work provides an in-depth characterization of UCL2077's action on Kv7.1 and I channels, offering valuable insights for the development of Kv7.1/I inhibitors in the context of short QT syndrome and other cardiac arrhythmias. SIGNIFICANCE STATEMENT: This study characterizes UCL2077: a highly specific, high-affinity inhibitor of Kv7.1 and I channels with therapeutic implications for cardiac arrhythmia. Our work reveals a picomolar affinity, mild voltage dependence, and a kinetic modulation consistent with state-dependent open-channel block.
PMID:41175503 | PMC:PMC12799529 | DOI:10.1016/j.molpha.2025.100076