Acid-base transporters, such as the sodium-hydrogen exchangers (NHEs) and bicarbonate-dependent transporters, play an important role in the regulation of intracellular pH (pH i ) in the CNS. Previous studies from our laboratory have shown that the absence of the major NHE isoform 1 (NHE1) reduced the steady-state pH i and recovery rate from an acid load in the hippocampal neurons not only in HEPES but also in HCO 3 - solutions (Yao et al., 1999). The purpose of the current study was to determine whether the NHE1 null mutation affects the expression of pH-regulatory transporters in the mouse CNS. Immunoblotting and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) were performed to examine the protein and mRNA levels of NHE1-4, electrogenic sodium-bicarbonate cotransporter 1 variants (NBCe1), and brain-specific anion exchanger 3 (AE3) in four brain regions (cerebral cortex, hippocampus, cerebellum and brainstem-diencephalon). NHE1 null mutant mice were compared with their wild type controls at the average age of approximately 4 weeks. Our results revealed that the NHE1 null mutation caused a significant increase in NHE3 in the cerebellum (84% for protein, 105% for mRNA), an increase in NBCe1 expression in the brainstem-diencephalon (approximately 40-50% for protein, 9-15% for mRNA), as well as a decrease in AE3 in the hippocampus (approximately 60% for protein, 24% for mRNA).We conclude that the NHE1 null mutation does alter the expression of other membrane transporters at both protein and mRNA levels. The alteration is region-specific. An increase in acid extruders (e.g. NHE3) and a decrease in acid loaders (e.g. AE3) suggest that there are some compensatory mechanisms that occur in NHE1 null mutant mice.