2.A.31.2.12
Electrogenic sodium bicarbonate cotransporter 1, NBCe1 (Sodium bicarbonate cotransporter, NBC) (Na⁺/HCO3^- cotransporter) (Solute carrier family 4 member 4) (kNBC1) of 1079 aas (Boron et al. 2009). Mutations cause proximal renal tubular acidosis and ocular pathology (Demirci et al. 2006). NBCe1, together with carbonic anhydrase II, CAII, provides an efficient mechanism of bicarbonate sensing in cortical astrocytes (Theparambil et al. 2017). NBCe1-B is widely expressed in many tissues, including the pancreas, submandibular gland, brain, heart, etc. It has very low activity under basal conditions due to auto-inhibition, but can be fully activated by interaction with IRBIT (TC# 8.A.151.1.1). IRBIT activates NBCe1-B by releasing the auto-inhibition module from the transmembrane domain (Su et al. 2020). NHE-3 (TC# 2.A.53.2.18) was markedly downregulated, while NBCe1 and the Na⁺-glucose transporter type-2 (SGLT2 or SGLT-2; TC#2.A.1.7.26) were upregulated after kidney transplantation (Velic et al. 2004). NBCe1 transports CO₂ (Michenkova et al. 2021). R730 in hAE1 (TC# 2.A.31.1.1) is crucial for anion binding to both the entry and central sites, while in hNBCe1, a Na⁺ acts as an anchor for CO₃^2- binding to the central site. Protonation of central acidic residues (E681 in hAE1 and D754 in hNBCe1) alters the ion dynamics in the permeation cavity and may contribute to the transport mode differences in SLC4 proteins (Zhekova et al. 2021). The phosphorylation status of Ser982 is not a key determinant of NBCe1 stoichiometry but correlates with NBCe1 activity (Alsufayan et al. 2021). NBCe1 in the influx mode may move 1 Na⁺ + 2 HCO₃^- across the plasma membrane, whereas in the efflux mode, it moves 1 Na⁺ +1 HCO₃^- +1 CO₃^2- (Wu et al. 2022). However, Lee et al. 2022 concluded that CO₂^2- is the transported species.  Exocrine pancreatic insufficiency is an unusual extrarenal manifestation of proximal renal tubular acidosis associated with a novel SLC4A4 mutation (Hasturk et al. 2025).  Periplocin has anti-tumor actions in prostate cancer through modulating the miR-3614-5p/SLC4A4 axis (Tian and Zhang 2025).  Na⁺/ ${\mathrm{HCO}}^{-}$  cotransporter NBCe1 (SLC4A4) functions in intracellular pH regulation and transepithelial transport of fluid and electrolytes. Wu et al. 2025 explored the structural mechanisms of NBCe1-A regulation by two phosphorylation modules: P-loop in the amino-terminal domain and H-loop in the transmembrane domain. Mimic-phosphorylation of P-loop or H-loop decreases NBCe1-A activity. Inhibition of NBCe1 by P-loop is abolished by mutations to specific basic residues in the fourth intracellular loop (IL4) in the carrier domain and IL3/IL6 in the scaffold. Inhibition by H-loop is abolished by specific mutations to IL3. Thus, (1) P-loop inactivates NBCe1-A by binding to the carrier and the scaffold; (2) H-loop blocks NBCe1-A by interacting with IL3 in the scaffold (Wu et al. 2025).