Chloride shift

Mechanism

Carbon dioxide (CO₂) is produced in tissues as a byproduct of normal aerobic metabolism. It dissolves in the solution of blood plasma and into red blood cells (RBC), where carbonic anhydrase catalyzes its hydration to carbonic acid (H₂CO₃). Carbonic acid then spontaneously dissociates to form bicarbonate Ions (HCO₃^–) and a hydrogen ion (H⁺). In response to the decrease in intracellular pCO₂, more CO₂ passively diffuses into the cell.

Cell membranes are generally impermeable to charged ions (i.e. H⁺, HCO₃^–) but RBCs are able to exchange bicarbonate for chloride using the anion exchanger protein Band 3. Thus, the rise in intracellular bicarbonate leads to bicarbonate export and chloride intake. The term "chloride shift" refers to this exchange. Consequently, chloride concentration is lower in systemic venous blood than in systemic arterial blood: high venous pCO₂ leads to bicarbonate production in RBCs, which then leaves the RBC in exchange for chloride coming in.

The opposite process occurs in the pulmonary capillaries of the lungs when the pO₂ rises and pCO₂ falls, and the Haldane effect decreases. This releases hydrogen ions from hemoglobin, increases free H⁺ concentration within RBCs, and shifts the equilibrium towards CO₂ and water formation from bicarbonate. The subsequent decrease in intracellular bicarbonate concentration reverses chloride-bicarbonate exchange: bicarbonate moves into the cell in exchange for chloride moving out. Inward movement of bicarbonate via the Band 3 exchanger allows carbonic anhydrase to convert it to CO₂ for expiration.

The chloride shift may also regulate the affinity of hemoglobin for oxygen through the chloride ion acting as an allosteric effector.