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

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.

Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland

“…At E16, NKCC1 was detected in both the epithelial and mesenchymal compartments (Fig. 3U), similar to what has been reported in the fetal lung (Brennan et al, 2016). By P1, NKCC1 expression became (U-Y) NKCC1 was broadly expressed at E16, but switched between ductal and acinar compartments between P1 and P7.…”

Role of iodide metabolism in physiology and cancer

“…Accordingly, NIS expression has been localized to ciliated columnar cells of the bronchial mucosa, although its precise localization remains controversial (Kang et al 2009). Moreover, ANO1, CFTR, PENDRIN and DUOX2/ DUOX1 are expressed in the Ap membrane of bronchial epithelial cells (Lee et al 2015, Brennan et al 2016, and LPO is secreted primarily in tracheal and bronchial submucosal glands (Wijkstrom-Frei et al 2003). This situation…”

Activating Calcium-Sensing Receptor Mutations: Prospects for Future Treatment with Calcilytics

“…In clinical trials with healthy individuals the most common adverse effects of [ 5 1 _ T D $ D I F F ] calcilytics were mild disorders of the gastrointestinal tract and nervous system, such as fatigue, headache, constipation, diarrhea, nausea, and dyspepsia [76,81], which might be related to CaSR expressed in gut [82] and brain [83]. CaSR is also present in skin, lung, heart, mammary glands, and numerous other tissues [18,[84][85][86], but the physiological and pharmacological significance of CaSR expression in these tissues has been disputed [87]. Potential short-and long-term adverse effects of calcilytics cannot be ruled out, and will need to be evaluated in clinical studies before calcilytics can be used for routine medical treatment of ADH and BS5 patients.…”