Structure, function, and regulation of the SLC4 NBCe1 transporter and its role in causing proximal renal tubular acidosis

Abstract

Purpose of review: There has been significant progress in our understanding of the structural and functional properties and regulation of the electrogenic sodium bicarbonate cotansporter NBCe1, a membrane transporter that plays a key role in renal acid-base physiology. The NBCe1 variant NBCe1-A mediates basolateral electrogenic sodium-base transport in the proximal tubule and is critically required for transepithelial bicarbonate absorption. Mutations in NBCe1 cause autosomal recessive proximal renal tubular acidosis (pRTA). The review summarizes recent advances in this area.

Recent findings: A topological model of NBCe1 has been established that provides a foundation for future structure-functional studies of the transporter. Critical residues and regions have been identified in NBCe1 that play key roles in its structure, function (substrate transport, electrogenicity) and regulation. The mechanisms of how NBCe1 mutations cause pRTA have also recently been elucidated.

Summary: Given the important role of proximal tubule transepithelial bicarbonate absorption in systemic acid-base balance, a clear understanding of the structure-functional properties of NBCe1 is a prerequisite for elucidating the mechanisms of defective transepithelial bicarbonate transport in pRTA.

Figure 1

Dendrogram of SLC4 transporters: Depicted are the protein names of each transporter in the SLC4 family except for SLC4A9 (“AE4”) and SLC4A11 (“BTR or NaBC1”) whose function is currently unclear and therefore the gene name is depicted. SLC4 proteins with similar function tend to more homologous at the amino acid level i.e. function follows structure. AE1-3 are Na⁺-independent Cl⁻-HCO₃⁻ exchangers; NBCe1 and NBCe2 are electrogenic Na⁺-CO₃²⁻(HCO₃⁻) transporters; NDCBE is Na⁺-driven Cl⁻-HCO₃⁻ exchanger; NBCn1 and NBCn2 are electroneutral Na⁺-HCO₃⁻ transporters. depending on experimental conditions NBCn2 can also mediate Na⁺-dependent Cl⁻-HCO₃⁻.

Figure 2

Topologic structure of NBCe1 (NBCe1-A depicted): NBCe1 transporters have a large N-terminal cytoplasmic region, a transmembrane region, and a C-terminal cytoplasmic tail. The topologic properties of NBCe1-A have been most thoroughly studied and because they share the identical transmembrane region, the structural features depicted also encompass the NBCe1-B/C/D/E variants. The majority of missense mutations (numbering depicted based on NBCe1-A) causing pRTA reside in the transmembrane region. NBCe1-A has an N-terminal cytoplasmic autostimulatory domain (ASD) and putatively interacts with carbonic anhydrase II in its C-terminal cytoplasmic region. NBCe1-A is hypothesized to be stimulated by PIP2 via interaction with positively charged residues in the C-terminus. Mg²⁺ is hypothesized to modulate NBCe1-A function via a Mg²⁺-dependent phosphatase (5′-lipid phosphatase) that dephosphorylates PIP2. The unique N-terminus of NBCe1-B unlike NBCe1-A has an autoinhibitory domain (AID) that is regulates the function of the transporter by interacting with IRBIT and potentially PIP2 and Mg²⁺ (see text for details). Kinase phosphorylation sites are also depicted. STCH interacts with residues that are common to all NBCe1 variants.

Figure 3

Proximal tubule cell models of wt-NBCe1-A and mutant NBCe1-A-T485S transport. wt-NBCe1-A is depicted as either mediating electrogenic Na⁺-CO₃²⁻ transport (1:2 charge transport stoichiometry) or Na⁺-CO₃²⁻-HCO₃⁻ transport (1:3 charge transport stoichiometry). Electroneutral NBCe1-A-T485S is predicted to transport Na⁺-HCO₃⁻ into proximal tubule cells causing pRTA. wt-NBCe1-A mediating Na⁺-CO₃²⁻ cotransport (1:2 charge transport stoichiometry) is modeled to lose its electrogenecity because the T485S mutant preferentially transports Na⁺-HCO₃⁻ rather Na⁺-CO₃²⁻. wt-NBCe1-A mediating 1 Na+ + 1 HCO₃⁻ + 1 CO₃²⁻ cotransport (1:3 charge transport stoichiometry), is converted into an electroneutral Na⁺-HCO₃⁻ transporter as a result of loss of CO₃²⁻ interaction in the T485S mutant.