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Abstract
Backround and Aims: Duodenal bicarbonate secretion in the resting state is in part mediated by an apical anion exchanger whose molecular nature is unknown. Recent data suggest that the dra gene, which is defective in congenital chlorid diarrhea, encodes an anion exchanger which, in oocytes, mediates sulfate as well as Cl uptake. We now investigated if the DRA gene product may be the apical anion exchanger in the duodenum. Methods: To test this hypothesis, we cloned rat and rabbit DRA cDNA fragments and studied the relative expression levels of DRA and NHE3 (Na+/H+ exchanger isoform 3) in the different segments of the rat and rabbit intestine by Northern analysis and semiquantitative PCR. We then isolated rat and rabbit duodenal and jejunal brush border membrane vesicles and studied 36Clund 35S0~uptake into Cl, HCOj, SO~and gluconate-loaded vesicles in the absence and presence of a pH-gradient (to distinguish SO~from HS04 transport) and the absence and presence of DIDS. We also examined HC03secretion in stripped rat and rabbit intestinal mucosa in the Ussing-chamber. Results: DRA was highly expressed in rat and rabbit intestinal tract, with the expression pattern colon>duodenum>ileum>jejunum in the rat and ileumc-colon> duodenum in the rabbit, and clearly differed from the expression pattern for NHE3 which was colon>ileum> jejunum>duodenum in both species. This excess DRA over NHE3 expression in the small intestine but not the proximal colon may explain why the resting state (absorbing) small intestine in the Ussing-chamber displays electroneutral HC03secretion whereas the proximal colon acidifies the luminal perfusate under resting conditions. Both rat and rabbit BBMvs displayed DIDS-sensitive CIICI-, HC03-/Ct, SO~-/Cl, and CIISO~exchange, findings compatible with DRA characteristics. Anion affinity for the internal and external anion binding sites differed somewhat between rat and rabbit but were Cl >HCOj in both species. Summary and Conclusions: The high duodenal DRA expression levels and the fact that the transport characteristics of rat and rabbit BBM anion exchange corresponds with those found in oocytes and Hek293 cells suggests that DRA is the likely transport protein which mediates electroneutral HCOj secretion in the duodenum.
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