Physiological roles of NBCe1 in kidney and pancreas

There are at least five mammalian NBCe1 variants, NBCe1A through NBCe1E as shown in Figure 1 [15,16]. NBCe1B differs from NBCe1A at the N-terminus, where the first 85 amino acids of NBCe1B replace the first 41 amino acids of NBCe1A [17]. NBCe1C differs from NBCe1B at the C-terminus, where the last 61 amino acids of NBCe1C replace the last 46 amino acids of NBCe1B [18]. NBCe1D and NBCe1E, identified from mouse reproductive tract tissues, contain a deletion of 9 amino acids in exon 6 of NBCe1A and NBCe1B, respectively [16].

Among these variants, NBCe1C is predominantly expressed in brain, but its physiological roles remain speculative [18]. NBCe1B is widely expressed in several tissues including pancreatic ducts, intestinal tracts, ocular tissues, and brain [2,12,13,19-22]. In the basolateral membranes of pancreatic ducts NBCelB is thought to mediate bicarbonate uptake into cells, which may be essential for the bicarbonate secretion from pancreas [23-25]. Consistent with this view, some pRTA patients with NBCel mutations presented with an elevated serum amylase level [3,7]. However, none of these patients presented with a distinct form of pancreatitis. Probably, other acid/base transporters such as Na+/H+ exchanger 1 (NHE1) or H+-ATPase in the basolateral membranes of pancreatic duct cells could at least partially compensate for the NBCe1 inactivation [26].

Figure 1. Structures of NBCel variants. Numbers of boxes indicate numbers of amino acids in N- or C-terminus. Note that NBCelD and NBCelE lack 9 amino acids (9-aa) in exon 6 of NBCelA and NBCelB, respectively. TMD: transmembrane domain.

NBCelA is predominantly expressed in the basolateral membranes of renal proximal tubules, where it mediates bicarbonate exit from cells [2,27]. The opposite transport directions between NBCelA in kidney and NBCelB in pancreas may be related to the different stoichiometric ratios. Thus, NBCelA in in vivo renal proximal tubules functions with lNa+ to 3HCO3- stoichiometry, whereas NBCelB in pancreatic ducts may function with lNa+ to 2HCO3- stoichiometry [23,28]. However, these differences in transport stoichiometry may not be due to the intrinsic properties of NBCel variants, but rather reflect the environmental factors such as incubation conditions or cell types. Indeed, NBCelA in isolated renal proximal tubules can function with either lNa+ to 2HCO3- or lNa+ to 3HCO3-stoichiometry depending on the incubation conditions [29-3l]. Such changes in transport stoichiometry of NBCelA can be also induced in Xenopus oocytes [32]. Moreover, NBCelB may function with lNa+ to 2HCO3- stoichiometry in cultured pancreatic duct cells, but may function with lNa+ to 3HCO3- stoichiometry when expressed in cultured renal proximal tubular cells [33]. Regarding the electrogenicity of NBCelA, recent work by Chen and Boron suggests that the predicted fourth extracellular loop corresponding to amino acids 704 to 735 may have an important role [34]. They found that replacing these residues with the corresponding residues of electroneutral Na+-HCO3- cotransporter NBCn1-A creates an electroneutral NBC.

Although the basolateral membranes of renal proximal tubules are known to contain several bicarbonate transporters such as Na+-dependent and Na+-independent Cl-/HCO3- exchangers [35,36], NBCe1A seems to play an essential role in bicarbonate absorption in this nephron segment. Consistent with this view, the homozygous inactivating mutations in NBCe1A cause severe pRTA with the blood bicarbonate concentration often less than 10 mM [3-11]. Functional deletion of NBCe1 in mice produces even more severe acidemia with the blood bicarbonate concentration around 5 mM [11,14]. By contrast, functional deletion of Cl-/HCO3- exchanger AE1, which is responsible for a majority of basolateral bicarbonate exit from a-intercalated duct cells, produces only moderate acidemia in mice with the blood bicarbonate concentration around 17 mM [37]. This may probably reflect much higher bicarbonate absorbing capacity of renal proximal tubules than that of renal distal tubules.

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