Abstract
The electrogenic Na+-HCO3– cotransporter NBCe1 encoded by SLC4A4 gene plays essential roles in the regulation of intracellular/extracellular pH. Three NBCe1 variants are thought to mediate distinct physiological roles with different modes of transport stoichiometry. Homozygous inactivating mutations in NBCe1 cause the isolated proximal renal tubular acidosis (pRTA) invariably associated with ocular abnormalities. Functional analyses indicate that more than 50% reduction in NBCe1 activity may be required to induce severe acidemia. Some of the pRTA- related NBCe1 mutations, which show defective me-mbrane expression in mammalian cells, are also associated with migraine. Dysregulation of local pH in brain due to the loss of NBCe1 activity in astrocytes may underlie this association. Two types of NBCe1 deficient animals, NBCe1 knockout and W516X knockin mice, have been reported. Both of them show severe acidemia and early lethality unless they are treated with alkali. In isolated renal proximal tubules from W516X knockin mice, both NBCe1 activity and the rate of bicarbonate absorption are severely reduced, confirming the essential role of NBCe1 in bicarbonate absorption from this nephron segment. In this review, we summarize the recent data about physiological and pathophysiological roles of NBCe1 in health and diseases.
Highlights
The electrogenic Na+- HCO3 cotransporter NBCe1 is thought to mediate a majority of sodium-coupled bicarbonate absorption from the basolateral membrane of renal proximal tubules [1]
The electrogenic Na+- HCO3 cotransporter NBCe1 encoded by SLC4A4 gene plays essential roles in the regulation of intracellular/extracellular pH
The proximal renal tubular acidosis (pRTA) patients carrying homozygous NBCe1 mutations usually presented with the severe acidemia, as defined as the reduction of blood HCO3 concentration to less than 13 mM, short stature and the ocular abnormalities
Summary
The electrogenic Na+- HCO3 cotransporter NBCe1 is thought to mediate a majority of sodium-coupled bicarbonate absorption from the basolateral membrane of renal proximal tubules [1]. NBCe1 plays important roles in other biological processes such as the maintenance of homeostasis in several ocular tissues, the bicarbonate secretory process in pancreatic ducts and intestinal tracts, and the regulation of synaptic pH in brain [1,4,5,6]. Consistent with this view, the pRTArelated NBCe1 mutations invariably cause the ocular abnormalities [2,7,8,9,10,11,12], and some of these NBCe1 mutations are associated with migraine [13]. We summarize the recent data about physiological and pathophysiological roles of NBCe1
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