Active Ca2+ reabsorption in the connecting tubule

The kidney plays a crucial role in the maintenance of the body calcium (Ca2+) balance. Ca2+ is an essential ion in all organisms and participates in a large variety of structural and functional processes. In mammals, active tubular Ca2+ reabsorption is restricted to the distal part of the nephron, i.e., the late distal convoluted (DCT2) and the connecting tubules (CNT), where approximately 10-15% of the total Ca2+ is reabsorbed. This active transcellular transport is hallmarked by the transient receptor potential vanilloid 5 (TRPV5) epithelial Ca2+ channel, regulated by an array of events, and mediated by hormones, including 1,25-dihydroxyvitamin D-3, parathyroid hormone, and estrogen. Novel molecular mechanisms have been identified, such as the direct regulatory effects of klotho and tissue kallikrein on the abundance of TRPV5 at the apical membrane. The newly discovered mechanisms could provide potential pharmacological targets in the therapy of renal Ca2+ wasting. This review discusses the three basic molecular steps of active Ca2+ reabsorption in the DCT/CNT segments of the nephron, including apical entry, cytoplasmic transport, and basolateral extrusion of Ca2+. In addition, an overview of the recently identified mechanisms governing this active Ca2+ transport through the DCT2/CNT epithelial cells will be presented.