Propofol inhibits Piezo mechanosensitive channels.

Modulation of ion channels is a key mechanism by which anesthetics exert their effects. Propofol, a widely used anesthetic, has been shown to influence mechanosensitive ion channels, although the details of this interaction remain under investigation. In this study, we show that propofol inhibits Piezo mechanosensitive channels using electrophysiological recordings and calcium imaging in HEK293T cells overexpressing human Piezo1 (hP1) and Piezo2 (hP2) channels. At 50 μM, propofol inhibited hP1 currents across multiple configurations (outside-out, whole cell, and cell attached) with a dissociation constant of 51.6 ± 24.0 μM. The stimulus-response curve shifted to the right, with an increase in the half-maximal pressure by 14 mmHg. Propofol selectively inhibited hP1 gating by stabilizing the closed state without affecting channel conductance or slope sensitivity. It also significantly reduced Yoda1-induced calcium influx in hP1-overexpressing cells. In hP2 channels, propofol inhibited whole-cell currents by reducing channel open probability while leaving conductance unchanged. Conversely, 1 mM isoflurane did not affect hP1 or hP2 currents. These findings suggest a possible contribution of inhibition of mechanosensitive Piezo channels, providing new insights into its mechanism of action.