Unusual transport modes of the Na + ‐coupled HCO 3 − transporters NDCBE (SLC4A8) and NBCn2 (SLC4A10) in the absence of extracellular Cl −

When expressed in Xenopus oocytes, human NDCBE and NBCn2 both mediate the influx of Na and HCO 3 and the HCO 3 ‐dependent efflux of Cl, but with distinct molecular mechanisms. Net HCO 3 influx requires extracellular Na (Na o ) in the case of both NDCBE and NBCn2. However, 36 Cl efflux require Na o in the case of NDCBE, but not in the case of NBCn2 (i.e., Cl efflux continues even though Na/HCO 3 influx halts). We previously showed that, in the absence of extracellular Cl (Cl o ), NBCn2 undergoes a mode switch: NBCn2‐mediated Cl efflux becomes tightly‐coupled to Na/HCO 3 influx (i.e., NBCn2 behaves as a Na‐driven Cl‐HCO 3 exchanger). Here we show that NDCBE appears to undergo the opposite mode switch. In the absence of Cl o , NDCBE‐mediated Cl efflux is undetectable while net HCO 3 influx is unperturbed (i.e., Na/HCO 3 influx becomes uncoupled from Cl efflux and thus NDCBE behaves as a Na/HCO 3 cotransporter). In order to probe the molecular determinants responsible for the functional differences between NDCBE and NBCn2, we created a series of chimeras in which we replaced pieces of NBCn2 with corresponding pieces of NDCBE and asked whether the HCO 3 ‐stimulated 36 Cl efflux (which is normally Na o independent for NBCn2) now becomes Na o dependent (a property of NDCBE). Based on a topology model with 14 transmembrane segments (TMs), the determinants appear to reside partly in a region that includes TMs 6+7 and partly in a region that includes TMs 11–13.