PIEZO proteins form a unique family of mechanosensitive ion channels encompassing two vertebrate members called PIEZO1 and PIEZO2. In the absence of mechanical stimulus, PIEZO1 can be chemically activated by the Yoda1, a synthetic small molecule that is thought to exert no modulatory effects on the PIEZO2 homolog. Here, using electrophysiological recordings in transfected mammalian cells, we show that Yoda1 also modulates PIEZO2 by slowing down the rate of inactivation of poking-evoked currents, decreasing the mechanical threshold of pressure-evoked currents, and increasing single channel open probability under steady-state pressure conditions. In addition, Yoda1 significantly increased calcium influx in hypo-osmotic, but not isotonic, conditions. Although the Yoda1 analog Yoda2 is a more potent PIEZO1 activator, this was not the case for PIEZO2. Dooku1, another Yoda1 analog which lacks modulatory effect on PIEZO1, acts as a positive modulator of PIEZO2. We next deploy all-atom molecular dynamics simulations to shed light on the differential modulation by Yoda1 and its analogs on PIEZO1 and PIEZO2. This work challenges the common view that Yoda1 acts as a selective activator of PIEZO1 and should prompt the community to exert caution when using this molecule as a probe to untangle the biological contributions of mammalian PIEZO channels.
Wijerathne et al. (Sun,) studied this question.