The extracellular calcium-sensing receptor regulates human fetal lung development via CFTR

Sarah C. Brennan, William J. Wilkinson, Hsiu Er Tseng, Brenda Finney, Bethan Monk, Holly Dibble, Samantha Quilliam, David Warburton, Luis J. Galietta, Paul J. Kemp, Daniela Riccardi

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Abstract

Optimal fetal lung growth requires anion-driven fluid secretion into the lumen of the developing organ. The fetus is hypercalcemic compared to the mother and here we show that in the developing human lung this hypercalcaemia acts on the extracellular calcium-sensing receptor, CaSR, to promote fluid-driven lung expansion through activation of the cystic fibrosis transmembrane conductance regulator, CFTR. Several chloride channels including TMEM16, bestrophin, CFTR, CLCN2 and CLCA1, are also expressed in the developing human fetal lung at gestational stages when CaSR expression is maximal. Measurements of Cl- -driven fluid secretion in organ explant cultures show that pharmacological CaSR activation by calcimimetics stimulates lung fluid secretion through CFTR, an effect which in humans, but not mice, was also mimicked by fetal hypercalcemic conditions, demonstrating that the physiological relevance of such a mechanism appears to be species-specific. Calcimimetics promote CFTR opening by activating adenylate cyclase and we show that Ca2+ -stimulated type I adenylate cyclase is expressed in the developing human lung. Together, these observations suggest that physiological fetal hypercalcemia, acting on the CaSR, promotes human fetal lung development via cAMP-dependent opening of CFTR. Disturbances in this process would be expected to permanently impact lung structure and might predispose to certain postnatal respiratory diseases.

Original languageEnglish
Article number21975
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Feb 25 2016

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Brennan, S. C., Wilkinson, W. J., Tseng, H. E., Finney, B., Monk, B., Dibble, H., Quilliam, S., Warburton, D., Galietta, L. J., Kemp, P. J., & Riccardi, D. (2016). The extracellular calcium-sensing receptor regulates human fetal lung development via CFTR. Scientific Reports, 6, [21975]. https://doi.org/10.1038/srep21975