An Anion Antiporter Is Essential for Transport of CO2 by Erythrocytes

Transmembrane anion exchange is essential for an important function of erythrocytes: the transport of waste CO2 from peripheral tissues to the lungs for exhalation. Waste CO2 released from cells into the capillary blood freely diffuses across the erythrocyte membrane (Figure 11-28a). In its gaseous form, CO2 dissolves poorly in aqueous solutions such as the cytosol or blood plasma, as is apparent to anyone who has opened a bottle of a carbonated beverage. However, the large amount of the potent enzyme carbonic anhydrase in the erythrocyte combines CO2 with hydroxyl ions (OH) to form water-soluble bicarbonate (HCO3) anions. This process occurs while erythrocytes are in systemic (tissue) capillaries and releasing oxygen into the blood plasma. The release of oxygen from hemoglobin induces a change in its conformation that enables a histidine side chain of a globin polypeptide to bind a proton. Thus when erythrocytes are in systemic capillaries, water is split into a proton that binds hemoglobin and an OH that reacts with CO2 to form an HCO3 anion.

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FIGURE 11-28 Carbon dioxide transport in blood requires a Cl/HCO3 antiporter. (a) In systemic capillaries, carbon dioxide gas diffuses across the erythrocyte plasma membrane and is converted into soluble HCO3 by the enzyme carbonic anhydrase; at the same time, oxygen leaves the cell and hemoglobin binds a proton. The anion antiporter AE1 (purple) catalyzes the reversible exchange of Cl and HCO3 ions across the membrane. The overall reaction causes HCO3 to be released from the cell, which is essential for maximal CO2 transport from the tissues to the lungs and for maintaining pH neutrality in the erythrocyte. (b) In the lungs, where carbon dioxide is excreted, the overall reaction is reversed. See text for additional discussion.

In a reaction catalyzed by the antiporter AE1, cytosolic HCO3 is transported out of the erythrocyte in exchange for an entering Cl anion:

HCO3 in + Clout ⇌ HCO3 out + Clin

(see Figure 11-28a). The entire anion-exchange process is completed within 50 milliseconds (ms), during which time 5 × 109 HCO3 ions are exported from each cell down their concentration gradient. If anion exchange did not occur, then during periods such as exercise, when much CO2 is generated, HCO3 would accumulate inside the erythrocyte to toxic levels, as the cytosol would become alkaline. The exchange of HCO3 (equal to OH + CO2) for Cl causes the cytosolic pH to remain nearly neutral. Normally, about 80 percent of the CO2 in blood is transported as HCO3 generated inside erythrocytes; anion exchange allows about two-thirds of this HCO3 to be transported by blood plasma external to the cells, increasing the amount of CO2 that can be transported from tissues to the lungs. In the lungs, where CO2 leaves the body, the overall direction of this anion-exchange process is reversed (Figure 11-28b).

AE1 catalyzes the precise one-for-one sequential exchange of anions on opposite sides of the plasma membrane required to preserve electroneutrality in the cell; only once every 10,000 or so transport cycles does an anion move unidirectionally from one side of the membrane to the other. AE1 is composed of a membrane-embedded domain, folded into at least 12 transmembrane α helices, that catalyzes anion transport, and a cytosolic-facing domain that anchors certain cytoskeletal proteins to the membrane (see Figure 17-21).

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