JOURNAL ARTICLE
REVIEW

[Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis]

Yo-ichi Nabeshima
Clinical Calcium 2008, 18 (7): 923-34
18591743
Recent advances that have given rise to marked progress in clarifying actions of alpha-Klotho (alpha-Kl) and FGf23 can be summarized as follows ; (i) alpha-Kl binds to Na(+), K(+)-ATPase, and Na(+), K(+)-ATPase is recruited to the plasma membrane by a novelalpha-Kl dependent pathway in correlation with cleavage and secretion ofalpha-Kl in response to extracellular Ca(2+) fluctuation. (ii) The increased Na(+) gradient created by Na(+), K(+)-ATPase activity drives the transepithelial transport of Ca(2+) in the choroid plexus and the kidney, this is defective in alpha-kl(-/-) mice. (iii) The regulated PTH secretion in the parathyroid glands is triggered via recruitment of Na(+), K(+)-ATPase to the cell surface in response to extracellular Ca(2+) concentrations. (iv) alpha-Kl, in combination with FGF23, regulates the production of 1,25 (OH) (2)D in the kidney. In this pathway, alpha-Kl binds to FGF23, andalpha-Kl converts the canonical FGF receptor 1c to a specific receptor for FGF23, enabling the high affinity binding of FGF23 to the cell surface of the distal convoluted tubule where alpha-Kl is expressed. (v) FGF23 signal down-regulates serum phosphate levels, due to decreased NaPi-IIa abundance in the apical membrane of the kidney proximal tubule cells. (vi) alpha-Kl in urine increases TRPV5 channel abundance at the luminal cell surface by hydrolyzing the N-linked extracellular sugar residues of TRPV5, resulting in increased Ca(2+) influx from the lumen. These findings revealed a comprehensive regulatory scheme of mineral homeostasis that is illustrated by the mutually regulated positive/negative feedback actions of alpha-Kl, FGF23, PTH and 1,25 (OH) (2)D. In this regard, alpha-Kl and FGF23 might play pivotal roles in mineral metabolism as regulators that integrate calcium and phosphate homeostasis, although this concept requires further verification in the light of related findings. Here, the unveiling of the molecular functions of alpha-Klotho and FGF23 has recently given new insight into the field of calcium and phosphate homeostasis. Unveiled molecular functions of alpha-Kl and FGF23 provided answers for several important questions regarding the mechanisms of calcium and phosphate homeostasis that remained to be solved, such as : (i) what is the non-hormonal regulatory system that directly responds to the fluctuation of extracellular Ca(2+), (ii) how is Na(+), K(+)-ATPase activity enhanced in response to low calcium stimuli in the parathyroid glands, (iii) what is the exact role of FGF23 in calcium and phosphorus metabolism, (iv) how is Ca(2+) influx through TRPV5 controlled in the DCT nephron, and finally (v) how is calcium homeostasis regulated in cerebrospinal fluid. However, several critical questions still remain to be solved. So far reported,alpha-Kl binds to Na(+), K(+)-ATPase, FGF receptors and FGF23, and alpha-Kl hydrolyzes the sugar moieties of TRPV5. Does alpha-Kl recognize these proteins directly or indirectly?Is there any common mechanism?How can we reconcile such diverse functions of alpha-Kl?What is the Ca(2+) sensor machinery and how can we isolate it?How do hypervitaminosis D and the subsequently altered mineral-ion balance lead to the multiple phenotypes?What is the phosphate sensor machinery and how can we isolate it? How does the Fgf23/alpha-Kl system regulate phosphorus homeostasis?How are serum concentrations of Ca(2 + ) and phosphate mutually regulated?

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