Na⁺-HCO₃ cotransporters mediate the transport of HCO₃ into or out of the cell. Two Na⁺-HCO₃ cotransporters (NBC) have been identified previously, which are referred to as NBC-1 and NBC-2. A cDNA library from uninduced human NT-2 cells was screened with an NBC-2 cDNA probe. Several clones were identified and isolated. Sequence analysis of these clones identified a partial coding region (2 kb) of a novel NBC (called here NBC-3), which showed 53% and 72% identity with NBC-1 and NBC-2, respectively. 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. NBC-3 is highly expressed in brain and spinal column, with moderate levels in trachea, thyroid, and kidney. In contrast with NBC-1, NBC-3 shows low levels of expression in pancreas and kidney cortex. In the kidney, NBC-3 expression is predominantly limited to the medulla. Cultured mouse inner medullary collecting duct (mIMCD-3) cells showed high levels of NBC-1 and low levels of NBC-3 mRNA expression. Subjecting the mutagenized mIMCD-3 cells to sublethal acid stress decreased the mRNA expression of NBC-1 by ~90% but increased the Na⁺-dependent HCO₃ cotransport activity by ~7-fold (as assayed by DIDS-sensitive, Na⁺-dependent, HCO₃-mediated intracellular pH recovery). This increase was associated with ~5.5-fold enhancement of NBC-3 mRNA levels. NBC showed significant affinity for Li⁺ in the mutant but not the parent mIMCD-3 cells. On the basis of the widespread distribution of NBC-3, we propose that this isoform is likely involved in cell pH regulation by transporting HCO₃ from blood to the cell. We further propose that enhanced expression of NBC-3 in severe acid stress could play an important role in cell survival by mediating the influx of HCO₃ into the cells.

kidney; acid-base; sodium-bicarbonate cotransporter; NBC-1; inner medullary collecting duct cells

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