Abstract
The transport of chloride and bicarbonate across epithelia controls the pH and volume of the intracellular and luminal fluids, as well as the systemic pH and vascular volume. The anion exchanger pendrin (SLC26A4) and the cystic fibrosis transmembrane conductance regulator (CFTR) channel are expressed in the apical membrane of epithelial cells of various organs and tissues, including the airways, kidney, thyroid, and inner ear. While pendrin drives chloride reabsorption and bicarbonate, thiocyanate or iodide secretion within the apical compartment, CFTR represents a pathway for the apical efflux of chloride, bicarbonate, and possibly iodide. In the airways, pendrin and CFTR seems to be involved in alkalinization of the apical fluid via bicarbonate secretion, especially during inflammation, while CFTR also controls the volume of the apical fluid via a cAMP-dependent chloride secretion, which is stimulated by pendrin. In the kidney, pendrin is expressed in the cortical collecting duct and connecting tubule and co-localizes with CFTR in the apical membrane of β intercalated cells. Bicarbonate secretion occurs via pendrin, which also drives chloride reabsorption. A functional CFTR is required for pendrin activity. Whether CFTR stimulates pendrin via a direct molecular interaction or other mechanisms, or simply provides a pathway for chloride recycling across the apical membrane remains to be established. In the thyroid, CFTR and pendrin might have overlapping functions in driving the apical flux of iodide within the follicular lumen. In other organs, including the inner ear, the possible functional interplay between pendrin and CFTR needs to be explored.
Highlights
Transcellular Cl− and HCO3− transport plays a crucial role in cell physiology
We focus on the functional interaction between the anion exchanger pendrin and the CFTR channel in orchestrating the anion transport as well as the control of the pH and volume of the luminal fluids in epithelia of various organs
In IL13-treated airway epithelial cells isolated from healthy subjects or patients with cystic fibrosis, selective inhibition of pendrin significantly increased airway surface liquid (ASL) volume, which might result from an impaired pendrin-dependent Cl−/HCO3− exchange [57] accompanied by a downregulation of ENaC function in response to IL13
Summary
Transcellular Cl− and HCO3− transport plays a crucial role in cell physiology. In several tissues, the anion transport through the epithelium is due to the coordinated function of the cystic fibrosis transmembrane conductance regulator (CFTR) channel (OMIM *602421) and members of the solute carrier SLC26 family of transporters, which share similar tissue expression patterns. Sequence alterations in the SLC26A4 gene, encoding pathogenic pendrin protein variants, cause Pendred syndrome [14] and non-syndromic sensorineural deafness DFNB4 [15]. Additional putative phosphorylation sites for other kinases including PKC can be predicted by bioinformatics (https://services.healthtech.dtu.dk/service.php?NetPhos -3.1; NCBI Reference Sequence: NP_000432.1) In this respect, additional studies would be needed to clarify the possible role of phosphorylation on pendrin function and subcellular distribution. Tissue-specific pendrin expression and function is reviewed; for information concerning the structure, expression, and function of CFTR in different organs as well as clinical aspects of cystic fibrosis (CF; OMIM #219700) we refer to recent excellent reviews [28,29,30] and other publications of this same Special Issue
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