Abstract
Calcium-mediated agonists have long been known to stimulate transepithelial ion and fluid transport across a wide array of epithelial tissues. A key component of this response are the Ca2+-activated K+ channels, whose activation results in a hyperpolarization of the basolateral and apical membranes, thereby maintaining the electrochemical driving force for ion transport. In 1997, the intermediate conductance, Ca2+-activated K+ channel, KCa3.1 was cloned and subsequently shown to be localized to both the basolateral and apical membranes of secretory epithelia where it is activated by Ca2+-mediated agonists. Herein, we review the data confirming the critical role that KCa3.1 plays in transepithelial ion transport as well as the regulation, gating, trafficking of this channel, and this channel’s role in cell proliferation. Very recently, the cryo-EM structure of human KCa3.1 was solved in both the closed and activated states; providing novel insight into the Ca2+-dependent gating of this family of channels. Finally, KCa3.1 has been recently linked to two separate diseases. That is, the rare anemia, hereditary xerocytosis, was recently shown to be caused by mutations in KCa3.1 that result in a shift in the Ca2+-dependent gating of the channel. In addition, KCa3.1 was very recently shown to be a modifier gene for cystic fibrosis (CF). Thus, we summarize the evidence for the role of KCa3.1 in both hereditary xerocytosis and epithelial diseases.