(Left) Opening the Piezo1 ion channel (green) by mechanical stress or by the synthetic small molecule Yoda1 promotes an influx of calcium ions that stimulates the opening of the KCa3.1 Gardos channel (blue). The resulting efflux of potassium ions through the KCa3.1 Gardos channel leads to a loss of water from the red blood cell, which causes it to shrink. Mutations in the Piezo1 gene reduce the ability of the Piezo1 ion channel to close, which causes red blood cells to shrink in the disease xerocytosis. Excessive opening of the Piezo1 ion channel might also be involved in sickle cell disease. (Right) When the gene for Piezo1 is deleted, there is no influx of calcium ions, so the KCa3.1 Gardos channel remains closed and the cell becomes overhydrated. Red blood cells that lack the KCa3.1 Gardos channel also become overhydrated (not shown; Grgic et al., 2009).