Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D-3-responsive epithelia

In mammals, the extracellular calcium concentration is maintained within a narrow range despite large variations in daily dietary input and body deman d. The small intestine and kidney constitute the influx pathways into the e xtracellular Ca2+ pool and, therefore, play a primary role in Ca2+ homeosta sis, We identified an apical Ca2+ influx channel, which is expressed in pro ximal small intestine, the distal part of the nephron and placenta. This no vel epithelial Ca2+ channel (ECaC) of 730 amino acids contains six putative membrane-spanning domains with an additional hydrophobic stretch predicted to be the pore region. ECaC resembles the recently cloned capsaicin recept or and the transient receptor potential-related ion channels with respect t o its predicted topology but shares less than 30% sequence homology with th ese channels. In kidney, ECaC is abundantly present in the apical membrane of Ca2+ transporting cells and colocalizes with 1,25-dihydroxyvitamin D-3-d ependent calbindin-D-28K. ECaC expression in Xenopus oocytes confers Ca2+ i nflux with properties identical to those observed in distal renal cells. Th us, ECaC has the expected properties for being the gatekeeper of 1,25-dihyd roxyvitamin D-3-dependent active transepithelial Ca2+ transport.