The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

Abstract

The mammalian Slc4 (Solute carrier 4) family of transporters is a functionally diverse group of 10 multi-spanning membrane proteins that includes three Cl-HCO3 exchangers (AE1-3), five Na(+)-coupled HCO3(-) transporters (NCBTs), and two other unusual members (AE4, BTR1). In this review, we mainly focus on the five mammalian NCBTs-NBCe1, NBCe2, NBCn1, NDCBE, and NBCn2. Each plays a specialized role in maintaining intracellular pH and, by contributing to the movement of HCO3(-) across epithelia, in maintaining whole-body pH and otherwise contributing to epithelial transport. Disruptions involving NCBT genes are linked to blindness, deafness, proximal renal tubular acidosis, mental retardation, and epilepsy. We also review AE1-3, AE4, and BTR1, addressing their relevance to the study of NCBTs. This review draws together recent advances in our understanding of the phylogenetic origins and physiological relevance of NCBTs and their progenitors. Underlying these advances is progress in such diverse disciplines as physiology, molecular biology, genetics, immunocytochemistry, proteomics, and structural biology. This review highlights the key similarities and differences between individual NCBTs and the genes that encode them and also clarifies the sometimes confusing NCBT nomenclature.

Interplay between Disulfide Bonding and N-Glycosylation Defines SLC4 Na+-coupled Transporter Extracellular Topography

“…The rapid influx of CO 2 quickly lowered the intracellular pH (pH i ). Once pH i had stabilized, the cells were bathed in Na ϩ -containing HCO 3 Ϫ -buffered solution to drive NBCe1-A transport. Fig.…”

“…SLC4 transporters represent a family of membrane proteins that transport HCO 3 Ϫ in various cell types (1)(2)(3). These transporters are widely expressed in the brain, heart, kidney, pancreas, intestine, muscle, teeth, and eye where they play critical roles in intracellular pH regulation, transepithelial transport, and systemic acid-base balance.…”

“…These transporters are widely expressed in the brain, heart, kidney, pancreas, intestine, muscle, teeth, and eye where they play critical roles in intracellular pH regulation, transepithelial transport, and systemic acid-base balance. SLC4 transporters have high amino acid sequence homology but vary in their Na ϩ and Cl Ϫ dependence, stoichiometry (electroneutral/electrogenic), and mechanisms of ion transport (exchanger/cotransporter) (1)(2)(3). Of all the SLC4 Na ϩ -coupled transporters, the electrogenic Na ϩ -base cotransporter NBCe1 has been studied extensively because of its essential role in mediating HCO 3 Ϫ transport in multiple organs including kidney, brain, eye, and tooth ameloblasts (1)(2)(3).…”

“…SLC4 transporters have high amino acid sequence homology but vary in their Na ϩ and Cl Ϫ dependence, stoichiometry (electroneutral/electrogenic), and mechanisms of ion transport (exchanger/cotransporter) (1)(2)(3). Of all the SLC4 Na ϩ -coupled transporters, the electrogenic Na ϩ -base cotransporter NBCe1 has been studied extensively because of its essential role in mediating HCO 3 Ϫ transport in multiple organs including kidney, brain, eye, and tooth ameloblasts (1)(2)(3). Eight missense mutations in NBCe1 have thus far been reported to cause a severe form of human proximal renal tubular acidosis with extrarenal manifestations (1,4).…”

Deficient acid handling with distal RTA in the NBCe2 knockout mouse

“…The electrogenic Na ϩ -HCO 3 Ϫ cotransporter (NBCe2, also referred as NBC4) is encoded by the SLC4A5 gene. It is notable that members of the SLC4 family, as recently reviewed (9,10,32,34), are involved in dRTA. Recent studies have suggested that NBCe2 expresses in the distal nephron and is involved in acid/base regulation in the renal distal tubule (11,15).…”