Distinguishing HCO3‐ from CO3= transport by the electrogenic Na/HCO3 cotransporter NBCe1 (SLC4A4) (1098.7)

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Theoretically, the electrogenic NBCe1 (SLC4A4), could operate by five thermodynamically equivalent mechanisms: (1) 1 Na+ + 2 HCO3‐, (2) 1 Na+ + 1 CO3=, (3) NaCO3‐ ion pair uptake, (4) 1 Na+ + 1 HCO3‐ uptake with 1 H+ extruded, and (5) CO2/HCO3‐‐stimulated extrusion of 2 H+. We obtained current‐voltage (I‐V) relationships from NBCe1 expressing oocytes superfused with out‐of‐equilibrium (OOE) solutions that vary extracellular pH (pHo) from 9.0 to 6.0 at a constant [CO2]o and [HCO3‐]o. Ignoring direct pHo effects on NBCe1, #1 predicts under constant [CO2]o & [HCO3‐]o, Erev will not change. #4 & #5 predict graded decreases in pHo produce steep graded decreases in H+ efflux that manifest as steep graded decreases in slope conductance (GNBC) and inward rectification. #2 & #3 predict pHo decreases will act by lowering [CO3=]o and [NaCO3‐]o, thereby reducing GNBC as predicted by the Michaelis‐Menten equation; the I‐V relationship will remain linear. We find that Erev shifts appropriately for pHo 9.0‐6.0, excluding #1. Importantly, the I‐Vs are linear and exhibit only small GNBC decreases at low pHo, eliminating #4 & #5. In fact ‐‐ based on the experimentally determined Km(CO3=) = 4 μM (constant pHo 7.5 and 5% CO2)‐‐ these GNBC decreases at low pHo, and the increases at high pHo are smaller than expected. In conclusion, the major carbon substrate for NBCe1 must be either CO3= or NaCO3‐ and, extreme pHo paradoxically modulates NBCe1 to minimize changes in transport rate.Grant Funding Source: Supported by NIH DK30344 and NS18400