Molecular Mechanism of Active Ca2+ Reabsorption in the Distal Nephron

▪ Abstract The identification of the epithelial Ca 2+ channel (ECaC) complements the group of Ca 2+ transport proteins including calbindin-D 28K , Na + /Ca 2+ exchanger and plasma membrane Ca 2+ -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 Ca 2+ transport and belongs to a superfamily of Ca 2+ channels that includes the vanilloid receptor and transient receptor potential channels. This new Ca 2+ 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 Ca 2+ permeability, a high selectivity for Ca 2+ , hyperpolarization-stimulated and Ca 2+ -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 Ca 2+ -selective channel and highlights the implications for active transcellular Ca 2+ reabsorption in health and disease.