Soluble αKlotho downregulates Orai1-mediated store-operated Ca2+ entry via PI3K-dependent signaling

Ji Hee Kim, Eun Young Park, Kyu Hee Hwang, Kyu Sang Park, Seong Jin Choi, Seung Kuy Cha

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Abstract

αKlotho is a type 1 transmembrane anti-aging protein. αKlotho-deficient mice have premature aging phenotypes and an imbalance of ion homeostasis including Ca2+ and phosphate. Soluble αKlotho is known to regulate multiple ion channels and growth factor-mediated phosphoinositide-3-kinase (PI3K) signaling. Store-operated Ca2+ entry (SOCE) mediated by pore-forming subunit Orai1 and ER Ca2+ sensor STIM1 is a ubiquitous Ca2+ influx mechanism and has been implicated in multiple diseases. However, it is currently unknown whether soluble αKlotho regulates Orai1-mediated SOCE via PI3K-dependent signaling. Among the Klotho family, αKlotho downregulates SOCE while βKlotho or γKlotho does not affect SOCE. Soluble αKlotho suppresses serum-stimulated SOCE and Ca2+ release-activated Ca2+ (CRAC) channel currents. Serum increases the cell-surface abundance of Orai1 via stimulating vesicular exocytosis of the channel. The serum-stimulated SOCE and cell-surface abundance of Orai1 are inhibited by the preincubation of αKlotho protein or PI3K inhibitors. Moreover, the inhibition of SOCE and cell-surface abundance of Orai1 by pretreatment of brefeldin A or tetanus toxin or PI3K inhibitors prevents further inhibition by αKlotho. Functionally, we further show that soluble αKlotho ameliorates serum-stimulated SOCE and cell migration in breast and lung cancer cells. These results demonstrate that soluble αKlotho downregulates SOCE by inhibiting PI3K-driven vesicular exocytosis of the Orai1 channel and contributes to the suppression of SOCE-mediated tumor cell migration.

Original languageEnglish
Pages (from-to)647-658
Number of pages12
JournalPflugers Archiv European Journal of Physiology
Volume473
Issue number4
DOIs
Publication statusPublished - 2021 Apr

Bibliographical note

Funding Information:
We thank Professors; Makoto Kuro-O (Jichi Medical University, Japan), Joseph Yuan (University of North Texas), Chan Young Park (UNIST, Korea), and Yangsik Jeong (Yonsei University, Korea) for providing materials. We also thank Bao Dang to proofread the manuscript.

Funding Information:
This study was supported by the Medical Research Center Program (2017R1A5A2015369) and the Basic Science Research Program (2019R1A2C1084880, 2017R1D1A3B03031760, and 2015R1D1A1A01060454) through the National Research Foundation of Korea.

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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