Br J Pharmacol 2026 Jun 10; doi: 10.1111/bph.70531.

Functional screen for subtype specificity of voltage sensor-targeted Kv7 potentiators.

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BACKGROUND AND PURPOSE: Voltage-gated Kv7 (potassium channel subfamily Q [KCNQ]) potassium channels are powerful modulators of neuronal excitability. ICA-069673 is a N-aryl benzamide drug that targets the voltage-sensing domain (VSD) of Kv7.2 with strong selectivity over Kv7.3 or Kv7.5, but the molecular basis of this selectivity remains poorly understood. Our objective was to identify novel sequence determinants of subtype specificity of ICA-069673. EXPERIMENTAL APPROACH: We generated a library of Kv7.2 mutants based on sequence differences between Kv7.2 (ICA-069673 sensitive) and Kv7.3 or Kv7.5 subtypes (ICA-069673 insensitive). Xenopus oocytes and/or HEK293 cells were used for electrophysiological characterisation of mutants and identification of residues that influence ICA-069673 sensitivity. KEY RESULTS: We identified several substitutions that markedly reduce ICA-069673 sensitivity in Kv7.2. While the S2-S3 region is particularly important, ICA-069673 modulation of Kv7.2 is influenced by residues throughout the VSD. Kv7.2[I173T] had the most prominent effect on ICA-069673 sensitivity, including accelerated channel closure upon rapid ICA-069673 wash-off. Interestingly, different residues contribute to ICA-069673 resistance in Kv7.3 versus Kv7.5. CONCLUSION AND IMPLICATIONS: The sensitivity of Kv7 subtypes to VSD-targeted potentiators varies markedly, arising from amino acid differences across the VSD. Resistance in Kv7.3 and Kv7.5 appears to arise from distinct sequence differences.

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