title: 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 Ca(2+)-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.
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, United Kingdom.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Brennan
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, United Kingdom.
authors.forename: William J
authors.initials: WJ
authors.lastname: Wilkinson
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, United Kingdom.
authors.forename: Hsiu-Er
authors.initials: HE
authors.lastname: Tseng
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, United Kingdom.
authors.forename: Brenda
authors.initials: B
authors.lastname: Finney
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, United Kingdom.
authors.forename: Bethan
authors.initials: B
authors.lastname: Monk
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, United Kingdom.
authors.forename: Holly
authors.initials: H
authors.lastname: Dibble
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, United Kingdom.
authors.forename: Samantha
authors.initials: S
authors.lastname: Quilliam
authors.affiliation: The Saban Research Institute, Children Hospital Los Angeles, 4650 Sunset Blvd # 83, Los Angeles, CA 90027, +1 323-362-5422, USA.
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.affiliation: Laboratory of Molecular Genetics, Giannina Gaslini Institute, Genoa, Italy.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Galietta
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, United Kingdom.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kemp
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, United Kingdom.
authors.forename: Daniela
authors.initials: D
authors.lastname: Riccardi
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000075369:Anoctamin-1; D000075002:Bestrophins; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D005110:Extracellular Space; D005136:Eye Proteins / Q000378:metabolism; D005325:Fetal Organ Maturity; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism; D008168:Lung / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D038081:Organogenesis; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*
chemical_list: C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; C491856:Best1 protein, mouse; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins; D007473:Ion Channels; D044169:Receptors, Calcium-Sensing; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000262:Adenylyl Cyclases