These co-senior authors contributed equally.
Calcitonin receptor-mediated CFTR activation in human intestinal epithelial cells
Version of Record online: 28 NOV 2011
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
Journal of Cellular and Molecular Medicine
Volume 15, Issue 12, pages 2697–2705, December 2011
How to Cite
Liu, H., Singla, A., Ao, M., Gill, R. K., Venkatasubramanian, J., Rao, M. C., Alrefai, W. A. and Dudeja, P. K. (2011), Calcitonin receptor-mediated CFTR activation in human intestinal epithelial cells. Journal of Cellular and Molecular Medicine, 15: 2697–2705. doi: 10.1111/j.1582-4934.2011.01264.x
- Issue online: 28 NOV 2011
- Version of Record online: 28 NOV 2011
- Accepted manuscript online: 20 JAN 2011 11:44AM EST
- Received: August 12, 2010; Accepted: January 12, 2011
- calcitonin receptor;
- chloride secretion;
High levels of calcitonin (CT) observed in medullary thyroid carcinoma and other CT-secreting tumours cause severe diarrhoea. Previous studies have suggested that CT induces active chloride secretion. However, the involvement of CT receptor (CTR) and the molecular mechanisms underlying the modulation of intestinal electrolyte secreting intestinal epithelial cells have not been investigated. Therefore, current studies were undertaken to investigate the direct effects of CT on ion transport in intestinal epithelial cells. Real time quantitative RT-PCR and Western blot analysis demonstrated the expression of CTR in intestinal epithelial T84 cells. Exposure of T84 cells to CT from the basolateral but not from apical side significantly increased short circuit current (ISC) in a dose-dependent manner that was blocked by 1 μM of CTR antagonist, CT8–32. CT-induced ISC was blocked by replacing chloride in the bath solutions with equimolar gluconate and was significantly inhibited by the specific cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor, CFTR127inh. Further, biotinylation studies showed that CT increased CFTR levels on the apical membrane. The presence of either the Ca2+ chelator, bis(2-aminophenoxy)ethane tetraacetic acid-acetoxymethyl (BAPTA-AM) ester or the protein kinase A (PKA) inhibitor, H89, significantly inhibited ISC induced by CT (∼32–58% reduction). Response to CT was retained after permeabilization of the basolateral or the apical membranes of T84 cells with nystatin. In conclusion, the activation of CTR by CT induced chloride secretion across T84 monolayers via CFTR channel and the involvement of PKA- and Ca2+-dependent signalling pathways. These data elucidate the molecular mechanisms underlying CT-induced diarrhoea.