ABSTRACT
The electrogenic Na(+)-HCO(3)(-) cotransporters play an essential role in regulating intracellular pH and extracellular acid-base homeostasis. Of the known members of the bicarbonate transporter superfamily (BTS), NBC1 and NBC4 proteins have been shown to be electrogenic. The electrogenic nature of these transporters results from the unequal coupling of anionic and cationic fluxes during each transport cycle. This unique property distinguishes NBC1 and NBC4 proteins from other sodium bicarbonate cotransporters and members of the bicarbonate transporter superfamily that are known to be electroneutral. Structure-function studies have played an essential role in revealing the basis for the modulation of the coupling ratio of NBC1 proteins. In addition, the recent transmembrane topographic analysis of pNBC1 has shed light on the potential structural determinants that are responsible for ion permeation through the cotransporter. The experimentally difficult problem of determining the nature of anionic species being transported by these proteins (HCO(3)(-) versus CO(3)(2-)) is analyzed using a theoretical equilibrium thermodynamics approach. Finally, our current understanding of the molecular mechanisms responsible for the regulation of ion coupling and flux through electrogenic sodium bicarbonate cotransporters is reviewed in detail.
Subject(s)
Sodium Bicarbonate/metabolism , Sodium-Bicarbonate Symporters/metabolism , Acid-Base Equilibrium , Amino Acid Sequence , Animals , Biological Transport , Gene Expression , Humans , Molecular Sequence Data , Protein Binding , Protein Isoforms/genetics , Protein Isoforms/metabolism , Rats , Sequence Alignment , Sequence Homology, Amino Acid , Sodium-Bicarbonate Symporters/genetics , Structure-Activity Relationship , Thermodynamics , XenopusABSTRACT
In eukaryotes, it is rare for a single gene to encode two functionally unrelated proteins. p150(Glued) is a component of the dynactin heteromultimeric complex of proteins which is required for dynein-mediated vesicle and organelle transport by microtubules. NBC4 is an electrogenic sodium bicarbonate cotransporter, which regulates intracellular pH. Here we report that NBC4 and p150(Glued) are encoded by the same locus, DCTN1-SLC4A5. We have characterized the genomic organization of the human DCTN1-SLC4A5 locus which spans approximately 230 kilobases on chromosome 2p13 and contains 66 exons. This information should allow the study of potential genomic alterations of DCTN1-SLC4A5 in patients with diseases mapping to this genomic region.
