Molecular mechanism of active Ca2+ reabsorption in the distal nephron

The identification of the epithelial Ca2+ channel (ECaC) complements the group of Ca2+ transport proteins including calbindin-D-28K, Na+/Ca2+ exchanger and plasma membrane Ca2+-ATPase, which are co-expressed in 1,25(OH)(2)D-3-responsive nephron segments. ECaC constitutes the rate-limiting apical entry step in the process of active transcellular Ca2+ transport and belongs to a superfamily of Ca2+ channels that includes the vanilloid receptor and transient receptor potential channels. This new Ca2+ channel consists of six transmembrane-spanning domains, including a pore-forming hydrophobic stretch between domain 5 and 6. The C- and N-terminal tails contain several conserved regulatory sites, implying that the channel function is modulated by regulatory proteins. The distinctive functional properties of ECaC include a constitutively activated Ca2+ permeability, a high selectivity for Ca2+, hyperpolarization-stimulated and Ca2+-dependent feedback regulation of channel activity, and 1,25(OH)(2)D-3-induced gene activation. This review covers the distinctive properties of this new highly Ca2+-selective channel and highlights the implications for active transcellular Ca2+ reabsorption in health and disease.