Apical Entry Channels in Calcium-Transporting

alcium is the fifth most abundant element in the earth’s crust and the most abundant cation in the human body. A 70-kg person possesses roughly 1 kg of calcium. Of this, 99% is in the mineral phase of the bones and teeth and 1% is in the extracellular and intracellular fluids. The ionic form of calcium serves as a universal intracellular messenger to modulate many processes, such as neurotransmission, muscle contraction, and secretion. Since all of the calcium in our bodies is ultimately absorbed from the diet, intestinal calcium absorption is an important determinant of calcium homeostasis. Two pathways are responsible for calcium entry into the body: the paracellular and the transcellular pathways. In the paracellular pathway, calcium enters through tight junctions located between the epithelial cells, whereas in the transcellular pathway, calcium enters across the apical and basolateral membranes of a cell, a process that requires an apical calcium entry channel, an intracellular calcium binding protein called calbindin (calbindin D 9k ), and calcium pump [plasma membrane calcium ATPase (PMCA 1b )]. Similar mechanisms of transcellular calcium transport exist in the renal distal tubules and the syncytium of the placenta. Recently, our understanding of the paracellular and transcellular pathways has been advanced by the identification of the channels for both pathways. With respect to the paracellular pathway, claudins are thought to form part of a paracellular channel-like structure. In the present review, we will focus on two recently identified apical calcium channels, calcium transport protein subtype 1 (CaT1) and epithelial calcium channel (ECaC), in the transcellular pathway. (Basic information about these two channels is available in Table 1.) CaT1 was first identified in the rat intestine (12) and ECaC in the rabbit kidney (4). Several other names (CaT-L/ECaC2 and CaT2/ECaC1) were also used for CaT1 and ECaC, respectively (Table 1). Recently, a human gene nomenclature was introduced for cation channels related to the Drosophila transient receptor potential (TRP) channels. Since CaT1 and ECaC are distally related to the TRPs, the human genes for CaT1 and ECaC were termed TRPV6 and TRPV5, respectively [“V” denotes “vanilloid receptor (VR1)-related”]. The human CaT1 and ECaC share 75% amino acid sequence identity. They are encoded by two genes juxtaposed on human chromosome 7q3335. One is likely duplicated from the other during the course of evolution. CaT1 and ECaC are calcium-selective members of a cation channel subfamily consisting of six members (10). The other four members of the family encode nonselective cation channels that serve as sensors. Three of them (VR1, VRL-1, and TRPV3) are heat sensors that are expressed in sensory neurons and skin, and another one (OTRPC4/VR-OAC/VRL-2/TRP12) is an osmoreceptor expressed in the central nervous system and the kidney. In contrast, CaT1 and ECaC, which share ~30% amino acid identity with the other channels of the family, serve as apical transporters in calcium-transporting epithelia.