Intensive study on calcium homeostasis regulation over the past several decades has established a systematized construal of its role in living phenomena, leaving us with the impression that this field is fairly defined and understood. However, the unveiling of the molecular function of α-Klotho has recently given new insight into this field. α-Klotho is a unique molecule that plays pivotal roles in: (i) the rapid tuning of extracellular Ca2+ concentration through transepithelial Ca2+ transport; (ii) parathyroid hormone secretion and subsequent Ca2+ increase in the serum, and (iii) the signal transduction of FGF23 that adjusts the calcium concentration by downregulating the production of 1,25(OH)2D3. Through these pathways, α-Klotho participates in the regulation of calcium homeostasis of the CSF and blood/body fluids by its actions in the choroid plexus, parathyroid glands and DCT nephrons. In this regard, α-Klotho is a key player that integrates ‘a multi-step regulatory system of calcium homeostasis’ that rapidly adjusts the extracellular calcium concentration and continuously maintains its concentration within a narrow physiological range.

Keywords:
α-Klotho, Calcium homeostasis, FGF23, Vitamin D, Parathyroid hormone, N+,K+-ATPase
1.
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsuki T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima Y: Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45–51.
2.
Henrissat B, Davies G: Structural and sequence-based classification of glycoside hydrolases. Curr Opin Struct Biol 1997;7:637–644.
3.
Takeshita K, Fujimori T, Kurotaki Y, Honjo H, Tsujikawa H, Yasui K, Lee JK, Kamiya K, Kitaichi K, Yamamoto K, Ito M, Kondo T, Iino S, Inden Y, Hirai M, Murohara T, Kodama I, Nabeshima Y: Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation 2004;109:1776–1782.
4.
Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Herbert SC: Cloning and characterization of an extracellular Ca2+ sensing receptor from bovine parathyroid. Nature 1993;366:575–580.
5.
Brown EM, MacLead RJ: Extracellular calcium sensing and extra cellular calcium signaling. Physiol Rev 2001;81:239–297.
6.
Bilezikian JP, Marcus R, Levine MA: Section II: Physiological aspects of the parathyroid; in Bilezikian JP, Marcus R, Levine MA (eds): The Parathyroids: Basic and Clinical Concepts, ed 2. New York, Academic Press, 2003, pp 167–291.
7.
Hoenderop JG, Leeuwen JP, Eerden BC, Kersten FF, Emp AW, Merillat AM, Waarsing JH, Rossier BC, Vallon V, Hummler E, Bindels RJ: Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. J Clin Invest 2003;112:1906–1914.
8.
Strange K: Regulation of solute and water balance and cell volume in the central nervous system.J Am Soc Nephrol 1992;3:12–27.
9.
Somjen GG: Ion regulation in the brain: implications for pathophysiology. Neuroscientist 2002;8:254–267.
10.
Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y: α-Klotho as a regulator of calcium homeostasis. Science 2007;316:1615–1618.
11.
Wilson JD, Foster DW, Kronenberg HM, Larsen PR: Hormones and disorders of mineral metabolism; in Bringhurst FR, Demay MB, Kronenberg HM (eds): Williams Textbook of Endocrinology. Philadelphia, Saunders, 2003, pp 1303–1371.
12.
Imura A, Iwano A, Kita N, Thoyama O, Fujimori T, Nabeshima Y: Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 2004;565:143–147.
13.
Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG: The β-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 2005;310:490–493.
14.
Skou JC: The Na+,K+-pump. Methods Enzymol 1988;156:1–25.
15.
Skou JC, Esmann M: The Na+,K+-ATPase. J Bioenerg Biomembr 1992;24:249–261.
16.
Kaplan JH: Biochemistry of Na+,K+-ATPase. Annu Rev Biochem 2002;71:511–535.
17.
Scheiner-Bobis G: The sodium pump. Its molecular properties and mechanisms of ion transport. Eur J Biochem 2002;269:2424–2433.
18.
Lassiter WC, Gottschalk CW, Mylle M: Micropuncture study of renal tubular reabsorption of calcium in normal rodents. Am J Physiol 1963;204:771–775.
19.
Rocha AS, Magaldi JB, Kokko JP: Calcium and phosphate transport in isolated segments of rabbit Henle’s loop. J Clin Invest 1977;59:975–983.
20.
Suki WN: Calcium transport in the nephron. Am J Physiol 1979;237:F1–F6.
21.
Kinne-Saffran E, Kinne R: Localization of a calcium stimulated ATPase in the basal-lateral plasma membranes of the proximal tubule of rat kidney cortex. J Membr Biol 1974;17:263–274.
22.
Ullrich KJ, Rumrich JG, Klöss S: Active Ca2+ reabsorption in the proximal tubule of the rat kidney. Pfugers Arch 1976;364:223–228.
23.
Shareghi GR, Stoner LC: Calcium transport across segments of the rabbit distal nephron in vitro. Am J Physiol 1978;235:F367–F375.
24.
Quamme GA: Effect of calcitonin on calcium and magnesium transport in rat nephron. Am J Physiol 1980;238:E573–E578.
25.
Quamme GA: Effect of hypercalcemia on renal tubular handling of calcium and magnesium. Can J Physiol Pharmacol 1982;60:1275–1280.
26.
Sutton RA, Wong NL, Quamme GA, Dirks JH: Renal tubular calcium transport: effects of changes in filtered calcium load. Am J Physiol 1983;245:F515–F520.
27.
Ho C, Conner DA, Pollack MR, Ladd DJ, Kifor O, Warren HB. Brown EM, Seidman JG, Seidman CE: A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 1995;11:389–394.
28.
Tsuruoka S, Nishiki K, Ioka T, Ando H, Saito Y, Kurabayashi M, Nagai R, Fujimura A: Defect in parathyroid-hormone-induced luminal calcium absorption in connecting tubules of Klotho mice. Nephrol Dial Transplant 2006;21:2762–2767.
29.
Brown EM, Watson EJ, Thatcher JG, Koletsky R, Dawson-Hughes BF, Posillico JT, Shoback DM: Ouabain and low extracellular potassium inhibit PTH secretion from bovine parathyroid cells by a mechanism that does not involve increases in the cytosolic calcium concentration. Metabolism 1987;36:36–42.
30.
Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y: Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 2003;17:2393–2403.
31.
Shimada T, Mizutani S, Muto T, Yoneda T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T: Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001;98:6500–6505.
32.
Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T: Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004;113:561–568.
33.
Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T: Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;444:770–774.
34.
Tohyama O, Imura A, Iwano A, Freund JN, Henrissat B, Fujimori T, Nabeshima Y: Klotho is a novel β-glucuronidase capable of hydrolyzing steroid β-glucuronides. J Biol Chem 2004;273:9777–9784.
35.
Garrett JE, Tamir H, Kifor O, Simin RT, Rogers KV, Mithal A, Gagel RF, Brown EM: Calcitonin-secreting cells of the thyroid express an extracellular calcium receptor gene. Endocrinology 1995;136:5202–5211.
36.
Riccardi D, Park J, Lee WS, Gamba G, Brown EM, Hebert SC: Cloning and functional expression of a rat kidney extracellular calcium-sensing receptor. Proc Natl Acad Sci USA 1995;92:131–135.
37.
Ruat M, Molliver ME, Snowman AM, Snyder SH: Calcium sensing receptor: molecular cloning in rata and localization to nerve terminals. Proc Natl Acad Sci USA 1995;92:3161–3165.
38.
Freichel M, Zink-Lorentz A, Holloschi A, Hafner M, Flockerzi V, Raue F: Expression of a calcium-sensing receptor in a human medullary carcinoma cell line and its contribution to calcitonin secretion. Endocrinology 1996;137:3842–3848.
39.
Razzaque MS, Lanske B: Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice. Trends Mol Med 2006;12:298–305.
40.
Razzaque MS, Sutara D, Taguchi T, St-Arnaud R, Lanske B: Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 2006;20:720–722.
41.
Nabeshima Y: Toward a better understanding of Klotho. Sci Aging Knowledge Environ 2006;8:pe11.
42.
Kurosu H, Yamamoto M, Clark AJD, Pastor JV, Nandi A, Grunani P, McGuiness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takawaya Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M: Suppression of aging in mice by the hormone Klotho. Science 2005;309:1829–1833.
43.
Ichikawa S, Imel EA, Kreiter ML, Xijie Yu, Donald S, Mackenzie BS, Sorenson AH, Goetz R, Mohammadi M, White KE, Econs MJ: A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 2007;117:2684–2691.
44.
Lanske B, Razzaque MS: Mineral metabolism and aging: the fibroblast growth factor 23 enigma. Curr Opin Nephrol Hypertens 2007;16:311–318.
45.
Lanske B, Razzaque MS: Premature aging in klotho mutant mice: cause or consequence? Ageing Res Rev 2007;6:73–79.
46.
Razzaque MS, Lanske B: The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. J Endocrinol 2007;194:1–10.
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2007
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