Yoda 1 is a selective activator of mouse and human mechanosensitive channel piezo1. In HEK cells, Yoda 1 slows the inactivation phase of transient currents, sensitizes Piezo1 to activation by pressure, and partially activates channels in the absence of external pressure. In MDCK cells, Yoda 1 induces Ca2+-dependent chromatin hypercondensation and alters Ca2+-dependent myosin contractility, leading to nuclear shrinkage in cells. In red blood cells from sickle cell anemia (SCA) patients, Yoda 1 increases intracellular Ca2+ and phosphatidylserine exposure, which leads to KCa3.1 channel mediated Ca2+ influx and K+ and water efflux, causing shrinkage of the cells.