alpha-Klotho: a regulator that integrates calcium homeostasis

Abstract

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 alpha-Klotho has recently given new insight into this field. alpha-Klotho is a unique molecule that plays pivotal roles in: (i) the rapid tuning of extracellular Ca(2+) concentration through transepithelial Ca(2+) transport; (ii) parathyroid hormone secretion and subsequent Ca(2+) increase in the serum, and (iii) the signal transduction of FGF23 that adjusts the calcium concentration by downregulating the production of 1,25(OH)(2)D(3). Through these pathways, alpha-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, alpha-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.