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Science 316 (5831): 1615-1618

Copyright © 2007 by the American Association for the Advancement of Science

{alpha}-Klotho as a Regulator of Calcium Homeostasis

Akihiro Imura,1,2,8* Yoshihito Tsuji,1,5* Miyahiko Murata,1,3* Ryota Maeda,1,2 Koji Kubota,1,2 Akiko Iwano,1,8 Chikashi Obuse,9 Kazuya Togashi,10 Makoto Tominaga,10 Naoko Kita,1 Ken-ichi Tomiyama,1 Junko Iijima,1 Yoko Nabeshima,1 Makio Fujioka,7 Ryo Asato,4 Shinzo Tanaka,4 Ken Kojima,4 Juichi Ito,4 Kazuhiko Nozaki,5 Nobuo Hashimoto,5 Tetsufumi Ito,11 Takeshi Nishio,3 Takashi Uchiyama,6 Toshihiko Fujimori,1,8 Yo-ichi Nabeshima1,8{dagger}

Abstract: {alpha}-klotho was identified as a gene associated with premature aging–like phenotypes characterized by short lifespan. In mice, we found the molecular association of {alpha}-Klotho ({alpha}-Kl) and Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) and provide evidence for an increase of abundance of Na+,K+-ATPase at the plasma membrane. Low concentrations of extracellular free calcium ([Ca2+]e) rapidly induce regulated parathyroid hormone (PTH) secretion in an {alpha}-Kl- and Na+,K+-ATPase–dependent manner. The increased Na+ gradient created by Na+,K+-ATPase activity might drive the transepithelial transport of Ca2+ in cooperation with ion channels and transporters in the choroid plexus and the kidney. Our findings reveal fundamental roles of {alpha}-Kl in the regulation of calcium metabolism.

1 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
2 Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
3 Integrative Brain Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
4 Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
5 Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
6 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
7 Electron Microscopy Center, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
8 Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan.
9 Laboratory of Functional Networks for Chromosome Inheritance, Graduate School of Life Science, Hokkaido University, Sapporo 001-0021, Japan.
10 Section of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Aichi 444-8787, Japan.
11 Department of Anatomy, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: nabemr{at}

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