Human TRPV4 engineering yields an ultrasound-sensitive actuator for sonogenetics.

Sonogenetics offers non-invasive and cell-type specific modulation of cells genetically engineered to express ultrasound-sensitive actuators. Finding an ion channel to serve as sonogenetic actuator it critical for advancing this promising technique. Here, we show that ultrasound can activate human TRP channel hTRPV4. By screening different hTRPV4 variants, we identify a mutation F617L that increases mechano-sensitivity of this channel to ultrasound, while reduces its sensitivity to hypo-osmolarity, elevated temperature, and agonist. This altered sensitivity profile correlates with structural differences in hTRPV4-F617L compared to wild-type channels revealed by our cryo-electron microscopy analysis. We also show that hTRPV4-F617L can serve as a sonogenetic actuator for neuromodulation in freely moving mice. Our findings demonstrate the use of structure-guided mutagenesis to engineer ion channels with tailored properties of ideal sonogenetic actuators.