Disease relevance of SLC4A4

• Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities [1].
• A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects [2].
• Localization of NBC-1 variants in human kidney and renal cell carcinoma [3].
• Proximal renal tubular acidosis associated with ocular abnormalities such as band keratopathy, glaucoma, and cataracts is caused by mutations in the Na(+)-HCO(3)(-) cotransporter (NBC-1) [4].
• NBC1(-/-) mice exhibited severe metabolic acidosis, growth retardation, reduced plasma Na(+), hyperal-dosteronism, splenomegaly, abnormal dentition, intestinal obstructions, and death before weaning [5].

Psychiatry related information on SLC4A4

• These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation [6].
• This study investigated the effects of pyridostigmine pretreatment, NBC protective gear, and heat-exercise exposure on psychomotor performance and subjective sensations in eight healthy male volunteers [7].

High impact information on SLC4A4

• By immunological analysis of human and rat eyes, we demonstrate that both kidney type (kNBC-1) and pancreatic type (pNBC-1) transporters are present in the corneal endothelium, trabecular meshwork, ciliary epithelium, and lens epithelium [4].
• In addition, up to 80% of amiloride-insensitive pH(i) recovery from acid load in the presence of HCO(3)(-)/CO(2) was inhibited by adenovirus-mediated transfer of a specific hammerhead ribozyme against NBC-1, consistent with a major role of NBC-1 in overall HCO(3)-transport by the lens epithelium [4].
• These results indicate that the normal transport activity of NBC-1 is indispensable not only for the maintenance of corneal and lenticular transparency but also for the regulation of aqueous humor outflow [4].
• Cloning and comparison of full-length rabbit with human gastrointestinal and kidney NBC1 subtype revealed a conserved protein kinase A consensus sequence in the cytoplasmic N-terminus of the gastrointestinal NBC1 [8].
• Pancreatic bicarbonate secretion: role of CFTR and the sodium-bicarbonate cotransporter [9].

Chemical compound and disease context of SLC4A4

• Mutations in the SLC4A4 gene cause an autosomal recessive proximal renal tubular acidosis (pRTA), a disease characterized by impaired ability of the proximal tubule to reabsorb HCO(3)(-) from the glomerular filtrate [10].
• The Na(+)-HCO(3)(-) cotransporter (NBC) is also stimulated by intracellular acidification, and part of the benefit of angiotensin-converting enzyme inhibitors after myocardial infarction may be due to inhibition of the NBC [11].
• In addition, we describe both the organ and nephron segment distributions and the regulation of NBC-1 mRNA under three models of pH stress: chloride-depletion alkalosis (CDA), metabolic acidosis, and bicarbonate loading [12].

Biological context of SLC4A4

• Cloning, tissue distribution, genomic organization, and functional characterization of NBC3, a new member of the sodium bicarbonate cotransporter family [13].
• Mutation screening was performed by using direct PCR sequencing of SLC4A4 exons and flanking intronic regions [14].
• With the NBC amino acid sequence 30-35% identical to the anion exchangers (AE1-3), a superfamily of HCO3- transporters is emerging [15].
• We have measured the voltage-dependent transport activity of an NBC from human kidney, type hkNBCe1, expressed in oocytes of the frog Xenopus laevis, by recording membrane current and the changes in intracellular pH and sodium at different membrane potentials between -20 and -100 mV [16].
• Ser(982) in the C-terminus of kNBC1 is a target for PKA phosphorylation [17].

Anatomical context of SLC4A4

• SLC4A4 codes for an electrogenic Na(+), HCO(3) (-)-cotransporter (NBCe1), which is present in the basolateral membranes of proximal tubules and is responsible for the bicarbonate efflux here, and thus about 80% of the renal bicarbonate reabsorption [18].
• Expression of mNBC3 cRNA in Xenopus laevis oocytes demonstrated that the protein encodes a novel stilbene-insensitive 5-(N-ethyl-N-isopropyl)-amiloride-inhibitable sodium bicarbonate cotransporter [13].
• We report the cloning, sequence analysis, tissue distribution, genomic organization, and functional analysis of a new member of the sodium bicarbonate cotransporter (NBC) family, NBC3, from human skeletal muscle. mNBC3 encodes a 1214-residue polypeptide with 12 putative membrane-spanning domains [13].
• Electrogenic NBC1 catalyzes HCO(3)(-) fluxes in mammalian kidney, pancreas, and heart cells [19].
• In secretory epithelia (such as pancreatic duct cells) NBC is responsible for the transport of bicarbonate from blood to the cell for eventual secretion at the apical membrane [20].

Associations of SLC4A4 with chemical compounds

• GFP was linked to the NH2 terminus of NBC1, and labeling was examined by confocal microscopy [21].
• To address this question, cDNAs for wild-type kidney NBC1 and its mutants R510H and S427L were generated, fused in frame with NH(2) terminally tagged GFP, and transiently expressed in Madin-Darby canine kidney cells [22].
• Critical glutamate, aspartate, lysine, arginine and histidine residues in ILs/ELs and TMs were detected that were essential for kNBC1-mediated Na(+)-dependent base transport [23].
• In addition to shifting the stoichiometry, 8-Br-cAMP caused a significant increase in the 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS)-sensitive basolateral membrane conductance (GDS) of cells expressing pNBC1, but not kNBC1 [24].
• NBC1 activity is stimulated by 10% CO2, however, the mechanism is poorly understood [25].

Physical interactions of SLC4A4

• A significant correlation between the magnitude of CAII binding and kNBC1-mediated flux was shown [26].
• We have identified extracellular regions of AE1 and NBC1 that directly interact with CAIV, to form a physical complex between the proteins [27].

Regulatory relationships of SLC4A4

• NBC1-mediated pH(i) recovery rate after acid load was inhibited by 40 +/- 7% when coexpressed with the inactive human CAII mutant, V143Y [19].
• NBC is activated by cystic fibrosis transmembrane conductance regulator (CFTR) and plays an important role in HCO3- secretion in the agonist-stimulated state in pancreatic duct cells [28].

Other interactions of SLC4A4

• RESULTS: The coding region of the mouse kNBC-3 has 1089 amino acids and shows 73 and 56% identity to human NBC-2 and NBC-1, respectively [29].
• In addition to the kidney, NBC1 is expressed in pancreatic duct cells, is activated by cystic fibrosis transmembrane conductance regulator (CFTR) and plays an important role in HCO3- secretion [20].
• Molecular mechanism of kNBC1-carbonic anhydrase II interaction in proximal tubule cells [26].
• Assignment of the human solute carrier family 4, sodium bicarbonate cotransporter-like, member 10 gene (SLC4A10) to 2q23-->q24 by in situ hybridization and radiation hybrid mapping [30].
• Functional characterization of NBC4: a new electrogenic sodium-bicarbonate cotransporter [31].

Analytical, diagnostic and therapeutic context of SLC4A4

• Molecular cloning of a new sodium bicarbonate cotransporter cDNA from human retina [32].
• SLCA5 codes for an electrogenic NBC (called NBC4 and NBCe2), which based on RT-PCR is located to the kidney but the exact localization awaits a good antibody [18].
• Northern blot analysis revealed that NBC-3 encodes a 4.4-kb mRNA with a tissue distribution pattern distinct from NBC-1 and NBC-2 [33].
• In oocytes injected with the wild-type or mutant GFP-NBC1 cRNAs, Western blot analysis showed that wild-type NBC1 is predominantly localized in the membrane fraction, whereas NBC1-R510H mutant was predominantly expressed in the cytoplasm [22].
• Indirect immunofluorescence indicated that NBC-1 is expressed on the basolateral, but not apical side of human corneal endothelium [34].

References