Voltage-sensor conformational microenvironments encode isoform-selective ion channel activation

Abstract

Significance Developing drugs that selectively target closely related ion channel isoforms remains a major challenge because these proteins often share highly conserved drug-binding sites. Here, we show that selective activation of Kv7 potassium channel isoforms by the rosemary-derived metabolite carnosic acid (CA) arises not from unique binding residues, but from subtle conformational and electrostatic differences within the channel voltage sensor. We further show that CA unexpectedly enhances the activity of the anticonvulsant retigabine despite exhibiting minimal activity on its own at therapeutically important Kv7.2/3 channels. These findings establish a general mechanism for isoform-selective ion channel modulation and identify the voltage sensor as a tunable target for developing safer and more selective therapeutics.