Klotho is a transmembrane protein expressed primarily in kidney, parathyroid 
gland, and choroid plexus. The extracellular domain could be cleaved off and 
released into the systemic circulation. Klotho is in part effective as 
β-glucuronidase regulating protein stability in the cell membrane. Klotho is a 
major determinant of aging and life span.Overexpression of Klotho increases and 
Klotho deficiency decreases life span. Klotho deficiency may further result in 
hearing loss and cardiac arrhythmia. The present study explored whether Klotho 
modifies activity and protein abundance of KCNQ1/KCNE1, a K(+) channel required 
for proper hearing and cardiac repolarization. To this end, cRNA encoding 
KCNQ1/KCNE1 was injected in Xenopus oocytes with or without additional injection 
of cRNA encoding Klotho. KCNQ1/KCNE1 expressing oocytes were treated with human 
recombinant Klotho protein (30 ng/mL) for 24 h. Moreover, oocytes which express 
both KCNQ1/KCNE1 and Klotho were treated with 10 μM DSA L (D-saccharic 
acid-1,4-lactone), a β-glucuronidase inhibitor. The KCNQ1/KCNE1 
depolarization-induced current (I(Ks)) was determined utilizing dual electrode 
voltage clamp, while KCNQ1/KCNE1 protein abundance in the cell membrane was 
visualized utilizing specific antibody binding and quantified by 
chemiluminescence. KCNQ1/KCNE1 channel activity and KCNQ1/KCNE1 protein 
abundance were upregulated by coexpression of Klotho. The effect was mimicked by 
treatment with human recombinant Klotho protein (30 ng/mL) and inhibited by DSA 
L (10 μM). In conclusion, Klotho upregulates KCNQ1/KCNE1 channel activity by 
“mainly” enhancing channel protein abundance in the plasma cell membrane, an 
effect at least partially mediated through the β-glucuronidase activity of 
Klotho protein.