Abstract
NBCe1 belongs to the SLC4 family of base transporting membrane proteins that plays a significant role in renal, extrarenal, and systemic acid-base homeostasis. Recent progress has been made in characterizing the structure-function properties of NBCe1 (encoded by the SLC4A4 gene), and those factors that regulate its function. In the kidney, the NBCe1-A variant that is expressed on the basolateral membrane of proximal tubule is the key transporter responsible for overall transepithelial bicarbonate absorption in this nephron segment. NBCe1 mutations impair transepithelial bicarbonate absorption causing the syndrome of proximal renal tubular acidosis (pRTA). Studies of naturally occurring NBCe1 mutant proteins in heterologous expression systems have been very helpful in elucidation the structure-functional properties of the transporter. NBCe1 mutations are now known to cause pRTA by various mechanisms including the alteration of the transporter function (substrate ion interaction, electrogenicity), abnormal processing to the plasma membrane, and a perturbation in its structural properties. The elucidation of how NBCe1 mutations cause pRTA in addition to the recent studies which have provided further insight into the topology of the transporter have played an important role in uncovering its critically important structural-function properties.
Highlights
Renal tubular acidosis (RTA) can be divided clinically into proximal RTA caused by defective proximal tubule bicarbonate absorption (Haque et al, 2012), and distal RTA resulting from impaired collecting duct net acid excretion (Battle and Haque, 2012)
This review highlights the structure-function abnormalities in NBCe1-A caused by mutations in the transporter that result in autosomal recessive proximal RTA (pRTA)
Transepithelial bicarbonate absorption in the proximal tubule is an indirect two-step process driven by the coupled transport of the apical Na+/H+ exchanger NHE3, in parallel with basolateral electrogenic Na+-base transport mediated by NBCe1-A (Figure 1; Boron, 2006; Hamm et al, 2013)
Summary
Renal tubular acidosis (RTA) can be divided clinically into proximal RTA (pRTA) caused by defective proximal tubule bicarbonate absorption (Haque et al, 2012), and distal RTA (dRTA) resulting from impaired collecting duct net acid excretion (Battle and Haque, 2012). Based on the most recent topology of NBCe1 (Zhu et al, 2010b) other than the cytosolic Q29X, R298S, and Cterminal 65 base-pair deletion mutations, and the 2311 delA frameshift stop codon mutation in intracellular loop 4 (IL4), the remaining pRTA mutations reside in the transmembrane region. This finding is clinically relevant since the human SLC4A4 gene (Abuladze et al, 2000) encodes 3 variants (-A, -B, and -C) with additional variants (-D and -E) having been reported in mouse (Liu et al, 2011). Studies of the cytoplasmic N-terminally localized R298S pRTA mutation indicate that it resides in an aqueous inaccessible tightly folded region that forms a “HCO−3 tunnel” whose structure is disrupted in the mutant transporter
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