In Brief:
Significance StatementSLC4 proteins play numerous important roles in the kidneys and elsewhere because they translocate what appears to be bicarbonate through cell membranes. Although previous studies supported three mechanisms with particular hypothesized substrate(s), HCO3−per se, CO3=, or H+, none could definitively discriminate among them. Now, novel three-dimensional mathematical simulations show that these mechanisms would cause markedly different cell-surface pH changes, normalized to translocated charge. Using electrophysiology to test these predictions for the electrogenic Na/HCO3 cotransporter NBCe1, the authors unambiguously rule out two mechanisms—those involving HCO3− and H+—and conclude that inward flux of CO3= is the only straightforward mechanism tenable. Thus, surface chemistry can differentiate three modes of acid-base transport previously thought to be indistinguishable. This mechanistic insight might have value for applications such as drug design.
