Slc26 Family of Anion Transporters in the Gastrointestinal Tract: Expression, Function, Regulation, and Role in Disease

Abstract

SLC26 family members are multifunctional transporters of small anions, including Cl − , HCO 3 − , sulfate, oxalate, and formate. Most SLC26 isoforms act as secondary (coupled) anion transporters, while others mediate uncoupled electrogenic transport resembling Cl − channels. Of the 11 described SLC26 isoforms, the SLC26A1,2,3,6,7,9,11 are expressed in the gastrointestinal tract, where they participate in salt and water transport, surface pH‐microclimate regulation, affect the microbiome composition, the absorption, and secretion of oxalate and sulfate, and other functions that require further study. Several intestinal or extra‐intestinal diseases are related to SLC26A mutations. Patients with congenital chloride diarrhea (CLD) suffer from Cl − ‐rich acidic diarrhea and systemic alkalosis due to SLC26A3 mutations. Patients with osteochondrodysplastic syndromes experience skeletal defects due to SLC26A2 mutations, resulting in defective sulfate absorption in enterocytes and sulfate uptake in chondrocytes. Because of functional interactions between SLC26 and other proteins, such as the Cl − channel CFTR, some of the intestinal cystic fibrosis manifestations may be attributed to impaired SLC26 isoform localization and function. The altered expression of SLC26 members due to inflammation or operative procedures have important consequences on intestinal transport and barrier function in common diseases as inflammatory bowel disease or bariatric surgery. The present review gives an overview on the current state of knowledge of the intestinally expressed SLC26A isoforms (SLC26A1,2,3,6,7,9,11) from the history of their functional identification, cloning and expression, the insights into their function, interaction partners and regulation gained in heterologous expression systems and Slc26a‐deficient mice, to information about their transcriptional regulation and roles in gastrointestinal disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:839‐872, 2019.

Importance of SLC26 Transmembrane Anion Exchangers in Sperm Post-testicular Maturation and Fertilization Potential

“…SLC26 proteins constitute one of the main classes of transporters that are involved in HCO 3 – and pH homeostasis regulation; the other being SLC4, and HCO 3 – transporters (see review Bernardino et al, 2019). In humans, their importance in maintaining correct ionic equilibrium and pH in various tissues and differentiation processes is demonstrated by the identification of SLC26 “loss of function” mutations in several hereditary genetic diseases: nephrolithiasis (SLC26A1), diastrophic dysplasia (SLC26A2), chloride loosing diarrhea (SLC26A3), Pendred syndrome -deafness and goiter- (SLC26A4), non-syndromic deafness (SLC26A5) and in men with reduced fertility and asthenozoospermia (SLC26A3, SLC26A8) (Everett and Green, 1999; Dawson and Markovich, 2005; El Khouri and Toure, 2014; Seidler and Nikolovska, 2019; Table 1). All the above phenotypes are in line with the nearly restricted tissue expression profiles observed for most of SLC26 genes.…”

Slc26a3 deletion alters pH‐microclimate, mucin biosynthesis, microbiome composition and increases the TNFα expression in murine colon

“…8 SLC26A3 may be the CFTRdependent HCO 3 − export system in the mid-distal colon, an intestinal segment which expresses no other apical Cl − / HCO 3 − exchanger gene with significant expression levels. 9 Other functions of SLC26A3, for example its role in HCO 3 − secretion, mucus synthesis and secretion, the maintenance of pH-microclimate, microbiome composition and epithelial barrier properties are not well studied. The composition, physical properties and function of intestinal mucus has become a major area of research, because a disturbed intestinal mucus layer has proven to be an important causative factor in human intestinal diseases such as inflammatory bowel disease and cystic fibrosis.…”

Looking into the genetic bases of OCD dimensions: a pilot genome-wide association study

“…Most of the hoarding dimension genes involved are members of the solute-carrier 26 family A (SLC26A). These transporters have been observed to influence, among other functions, microbiome composition, pH regulation, and anion transport 82 , which in turn have been related with the pathophysiology of different psychiatric disorders 83 . More specifically, anion transport and pH regulation in the brain play a role in intra-and inter-signaling and plasticity processes 84 .…”