As a graduate student, I imposed acute intracellular acid loads and found that the sudden pHi decrease is followed by a recovery—the first demonstration of pHi regulation. Later work showed that this recovery is mediated by a Na+-driven Cl-HCO3 exchanger (NDCBE)—the first documented pHi regulator. As a fellow, we identified the electrogenic Na/HCO3 cotransporter (NBCe1), which not only regulates pHi but also mediates HCO3− movement of across many epithelia.
Since cloning the cDNA encoding NBCe1, our group has studied the molecular mechanism of Na+-coupled HCO3− transporters (NCBTs)—members of the SLC4 family of transport proteins. For example, emerging data indicate that NBCe1 and NDCBE—expressed in Xenopus oocytes—transport CO3= rather than HCO3−. Carbonic anhydrases do not change transport rate but stabilize surface pH. Chimera making shows that extracellular loop #4 is critical for determining electroneutrality vs electrogenicity. Certain splice variants have autoinhibitory or autostimulatory domains. The large cytoplasmic N terminus of NBCe1 binds to and thereby activates the transmembrane domain. Finally, we are producing large quantities of NBC-related proteins to study their molecular biophysical properties.
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