Regulation of ion channels by secreted Klotho: mechanisms and implications

Klotho is an anti-aging protein predominantly expressed in the kidney, parathyroid glands, and choroid plexus of the brain. It is a single-pass transmembrane protein with a large extracellular domain. The extracellular domain of Klotho is cleaved and released into extracellular fluid, including blood, urine, and cerebrospinal fluid. The membrane-bound full-length Klotho and secreted extracellular domain of Klotho have distinct functions. Membrane Klotho interacts with fibroblast growth factor (FGF) receptors to form high-affinity receptors for FGF23. Secreted Klotho functions as a humoral factor that regulates several ion channels and transporters, and other processes, including insulin and insulin-like growth factor signaling. This mini-review focuses on the mechanisms of regulation of cell-surface abundance of ion channels by secreted Klotho and the importance of these effects of Klotho in physiology and pathological conditions.