Calcium-Selective Ion Channel, CaT1, Is Apically Localized in Gastrointestinal Tract Epithelia and Is Aberrantly Expressed in Human Malignancies

Abstract

SUMMARY:CaT1 is a highly selective calcium entry channel that has been proposed to be responsible for apical calcium entry in the vitamin D-regulated transcellular pathway of Ca 2ϩ absorption; however, the lack of a CaT1 antibody suitable for immunohistochemistry has prevented the direct testing of this hypothesis by the localization of CaT1 protein in the gastrointestinal tract and other tissues. In this study, we developed two CaT1 antibodies and have used them to establish for the first time that CaT1 localizes to the apical membrane of intestinal absorptive cells, thereby providing the first direct evidence that this protein is in fact an apical entry channel in the gastrointestinal tract. In addition, we found that CaT1 protein is highly expressed in a number of exocrine organs including pancreas, prostate, and mammary gland, suggesting an, as yet, unrecognized role in secretory epithelia. Finally, we found CaT1 protein to be present at elevated levels in comparison with normal tissues in a series of prostate, breast, thyroid, colon, and ovarian carcinomas, consistent with previous reports of up-regulation of CaT1 mRNA in prostate cancer tissues. Our findings indicate that CaT1 is likely to serve as a component of transcellular calcium transport mechanisms in many tissues and epithelial cancers. (Lab Invest 2002, 82:1755-1764.

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

“…The Na+/H+ exchange protein (NHE-3) has been shown by immunochemistry to be located on the apex of villus enterocytes [41]. The vitamin D regulated calcium transport protein CaT1 has been similarly localized [42]. An extensive study of the cystic fibrosis transmembrane conductance regulator (CFTR) in intestinal cells by electron microscopy and immunofluorescence showed no evidence of an extracellular component [43].…”

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

“…Moreover, TRPV6 was shown to be strongly upregulated in prostate cancer (Peng et al 2001b;Wissenbach et al 2001Wissenbach et al , 2004. Also in carcinomas of other tissues, such as breast, thyroid, colon and ovary, TRPV6 expression is increased (Zhuang et al 2002). Thus, TRPV6 might be a new marker for tumor progression.…”

“…In human, both channels are coexpressed in organs that mediate transcellular Ca 2+ transport such as duodenum, jejunum, colon, and kidney, but also in pancreas, prostate, mammary, sweat and salivary gland (Hirnet et al 2003;Hoenderop et al 1999Hoenderop et al , 2000aJanssen et al 2002;Muller et al 2000a;Peng et al 1999Peng et al , 2000Peng et al , 2001aWeber et al 2001;Wissenbach et al 2001;Zhuang et al 2002). In general, TRPV5 seems to be the major isoform in kidney, whereas TRPV6 is more ubiquitously expressed with the highest concentrations in the prostate, stomach, brain, lung and small intestine.…”

Vitamin D Deficiency

“…According to B. Hollis, vitamin D intoxication develops if the level of blood calcidiol [25(OH)-D] > 250 nmol/l (100 ng/ml) [8]. There have been studies demonstrating that the level of 25(OH)-D may exceed 250 nmol/l without signs of intoxication in sunbathers; clinical symptoms of hypervitaminosis D are not observed at this level of calcidiol and oral intake of vitamin D drugs as well [9]. There are hard copy proofs that vitamin D intake in the single dose of 200,000 IU does not cause vitamin D intoxication in neonates, infants and older children [5].…”

“…In an epithelial cell, a calcium ion binds with a calcium-binding protein (calbindin), the synthesis of which is stimulated by interaction of calcitriol with vitamin D receptor (VDR). After that, calcium ions with calciumbinding protein move to the basolateral cell membrane and enter the extracellular space with the help of the plasma membrane's Ca 2+ -ATPase (PMCA1b) [9]. Homologous calcium channel TRPV6 can be found in renal tubules [11].…”