Question:

Klotho, a transmembrane protein, protease and hormone, contributes to inhibition of 1,25(OH)₂D₃ formation and participates in the regulation of epithelial Ca²⁺, phosphate and electrolyte transport. Klotho deficiency leads to early appearance of age related disorders and premature death. Sequelae of Klotho deficiency include cardiac arrhythmia and sudden cardiac death, pointing to deranged cardiac excitation. The disorder may be in large part due to excessive formation of 1,25(OH)₂D₃, but may involve in addition direct regulation of cardiac ion channels by Klotho. The present study thus explored the possibility that Klotho influences the cardiac K⁺ channels KCNQ1/KCNE1 and/or HERG.

Methods:

cRNA encoding KCNQ1/KCNE1 or HERG was injected into Xenopus oocytes with and without additional injection of cRNA encoding Klotho, K⁺ channels activity was determined by two-electrode voltage-clamp and channel protein abundance in the cell membrane by chemiluminescence. Moreover, dual electrode voltage clamp was performed in oocytes treated with recombinant human Klotho protein or DSAL (D-saccharic acid-1,4-lactone), a β-glucuronidase inhibitor.

Results:

Coexpression of Klotho significantly increased KCNE1/KCNQ1 and HERG mediated currents. Klotho was at least partially effective by increasing channel protein abundance in the cell membrane. Treatment of KCNE1/KCNQ1 or HERG expressing oocytes with Klotho was similarly followed by a gradual increase of channel activity and of protein abundance in the cell membrane. The effect of klotho protein was reversed by β-glucuronidase-inhibitor d-saccharic acid-1,4-lactone (DSAL).

Conclusions:

Klotho is a powerful regulator of cardiac K⁺ channels KCNE1/KCNQ1 and HERG.