Evaluating the role of carbonic anhydrases in the transport of HCO3−-related species

The soluble enzyme carbonic anhydrase II (CAII) plays an important role in CO2 influx and efflux by red blood cells (RBCs), a process initiated by changes in the extracellular [CO2] (CO2-initiated CO2 transport). Evidence suggests that CAII may be part of a macromolecular complex at the inner surface of the RBC membrane. Some have suggested CAII specifically binds to a motif on the cytoplasmic C terminus (Ct) of the Cl–HCO3 exchanger AE1 and some other members of the SLC4 family of HCO3− transporters, a transport metabolon. Moreover, others have suggested that this bound CAII enhances the transport of HCO3−-related species—HCO3−, CO3, or CO3 ion pairs—when the process is initiated by altering the activity of the transporter (HCO3−-initiated HCO3− transport). In this review, I assess the theoretical roles of CAs in the transport of CO2 and HCO3−-related species, concluding that although the effect of bound CAII on CO2-initiated CO2 transport is expected to be substantial, the effect of bound CAs on HCO3−-initiated HCO3− transport is expected to be modest at best. I also assess the experimental evidence for CAII binding to AE1 and other transporters, and the effects of this binding on HCO3−-initiated HCO3− transport. The early conclusion that CAII binds to the Ct of AE1 appears to be the result of unpredictable effects of GST in the GST fusion proteins used in the studies. The early conclusion that bound CAII speeds HCO3−-initiated HCO3− transport appears to be the result of CAII accelerating the pH changes used as a read-out of transport. Thus, it appears that CAII does not bind directly to AE1 or other SLC4 proteins, and that bound CAII does not substantially accelerate HCO3−-initiated HCO3− transport.