NBCe1: An Electrogenic Na+ Bicarbonate Cotransporter, in Epithelia

NBCe1-B/C-knockout mice exhibit an impaired respiratory response and an enhanced renal response to metabolic acidosis

“…Mutations in SLC4A4 cause proximal renal tubular acidosis: HCO 3 − wasting acidemia with a variety of extra-renal sequelae such as loss of vision, growth abnormalities, and intellectual disability ( Igarashi et al, 1999 ; Salerno et al, 2019 ). NBCe1 has three primary protein variants (NBCe1-A, -B, and -C), each with a different expression pattern through the body ( Brady et al, 2020 ). In the kidneys, NBCe1-A is exclusively expressed in PTs of the cortical labyrinth where it plays an essential role in both the reabsorption of filtered HCO 3 − ( Burnham et al, 1997 ; Romero et al, 1997 ; 1998 ) and the ammoniagenic response ( Lee et al, 2018 ).…”

Who's on first … Na+, HCO3− or CO32−?

“…The authors postulated that if this was a single protein's activity, then a stoichiometry of at least 1Na + :2HCO 3 − ions was required, but that 1:3 was more energetically favourable for the voltage and ion gradient conditions of the kidney proximal tubule. Soon thereafter, several investigators identified similar activities in mammalian proximal tubules, corneal endothelium, liver, intestine and retinal Müller cells (Brady et al, 2021). These studies initiated a stoichiometry debate that ultimately argued that Na + and HCO 3 − efflux at the basolateral membrane of the kidney proximal tubule should be 1:3.…”

“…NBCe1, as the protein was named, turned out to be a new and fourth member of the SLC4 gene family (SLC4A4) accompanying the three cloned anion exchangers. The mammalian kidney sequences soon followed (NBCe1‐A), but an N‐terminal variant from the mammalian pancreas and heart (NBCe1‐B) was soon identified (reviewed in Brady et al., 2021). This ‘molecular sequence switch’ seemed to conveniently segregate with transport direction and apparent ion coupling; that is Na + / n HCO 3 − efflux by the kidney as the role of NBCe1‐A and the Na + / n HCO 3 − influx by other tissues as the role of NBCe1‐B.…”

“…13 from Wu et al. (2022), while providing a mechanistic, conceptual framework for ordered binding and unbinding of ions, does not incorporate the known dimer structure of NBCe1 (Brady et al., 2021; Huynh et al., 2018). That is, the current work does not address whether monomer‐binding sites in the known dimer structure might be cooperative or interfering or irrelevant.…”