ϩ -HCO 3 Ϫ cotransporter (NBC-1) cause proximal renal tubular acidosis (pRTA) associated with ocular abnormalities. One pRTA patient had increased serum amylase, suggesting possible evidence of pancreatitis. To further delineate a link between NBC-1 inactivation and pancreatic dysfunction, immunohistochemical analysis was performed on rat and human pancreas using antibodies against kidney-type (kNBC-1) and pancreatic-type (pNBC-1) transporters. In rat pancreas, the anti-pNBC-1 antibody labeled acinar cells and both apical and basolateral membranes of medium and large duct cells. In human pancreas, on the other hand, the anti-pNBC-1 antibody did not label acinar cells, although it did label the basolateral membranes of the entire duct system. The labeling by anti-kNBC-1 antibody was detected in only a limited number of rat pancreatic duct cells. To examine the effects of pRTA-related mutations, R342S and R554H, on pNBC-1 function, we performed functional analysis and found that both mutants had reduced transport activities compared with the wild-type pNBC-1. These results indicate that pNBC-1 is the predominant variant that mediates basolateral HCO 3 Ϫ uptake into duct cells in both rat and human pancreas. The loss of pNBC-1 function is predicted to have significant impact on overall ductal HCO 3 Ϫ secretion, which could potentially lead to pancreatic dysfunction. Na ϩ -HCO 3 Ϫ cotransporter; pRTA; pancreatic duct cells; pancreatitis THE NA ϩ -HCO 3 Ϫ COTRANSPORTER (NBC-1), originally cloned from amphibian kidney (32), has multiple functions. In the renal proximal tubules, it mediates HCO 3 Ϫ efflux from cells (7, 36, 42), whereas in other epithelial cells, such as the pancreatic duct cells and the corneal endothelium, it mediates HCO 3 Ϫ influx into cells (22,23, 41). The expression of NBC-1 in nonepithelial cells such as trabecular meshwork cells or neurons has been also demonstrated (35, 40). Up to now, three NBC-1 variants have been identified: kNBC-1 from kidney, pNBC-1 from pancreas, and hNBC-1 from heart. Although kNBC-1 differs from pNBC-1 only at the NH 2 terminus, pNBC-1 is identical to hNBC-1 at the amino acid level and differs only in its 5Ј-untranslated region (1,8,10). These NBC-1 variants originate from the same SLC4A4 gene by alternative splicing (2). It is therefore predictable that mutational inactivation of NBC-1 variants may induce a variety of clinical manifestations, including renal and extrarenal phenotypes. Indeed, we have recently shown that mutations in the common coding region of NBC-1, corresponding to R298S and R510H in kNBC-1 or R342S and R554H in pNBC-1, cause renal proximal tubular acidosis (pRTA) associated with ocular abnormalities such as band keratopathy, glaucoma, and cataracts (19). The expression study in ECV304 cells showed that the kidneytype mutants, R298S and R510H, have reduced transport activities compared with the wild-type kNBC-1 (19). The expression of both kNBC-1 and pNBC-1 in several ocular tissues has been confirmed (6, 40). It remains to be clarified, however, w...