Band 3: The Anion Exchanger

The band 3 protein is a 95 kDa multipass membrane protein that exchanges bicarbonate ion for chloride ion. It is the predominant membrane transporter in red blood cells and plays a central role in structure and function of those cells and in acid-secreting cells in the kidney. The name derived from its position on electrophorsis gels of red cell membrane proteins. This protein is also known as AE1.

The plasma membrane of most cells is relatively impermiable to chloride and bicarbonate ions. In contrast, a high concentration of band 3 allows the red cell membrane to very efficiently transport these anions, a process integral to their function in transporting CO₂ in blood. This process occurs in a series of steps:

• CO₂ in peripheral cells diffuses into blood, then into red cells.
  
  
• Within red cells, carbonic anhydrase catalyses the combination of CO₂ with water to form carbonic acid, which rapidly dissociates into a proton and bicarbonate ion. The proton binds to hemoglobin, which serves as a buffer.
  
  
• Bicarbonate is transported by band 3 out of the red cell in exchange for chloride, thus allowing CO₂ to be transported to the lungs predominantly as bicarbonate. Each red cell contains roughly one million molecules of band 3, which are arranged as dimers or tetramers, allowing approximately 5 billion bicarbonate ions are transported out of the cell in a span of about 50 ms!
  
  
• In the pulmonary capillaries, bicarbonate is again transported by band 3 across the red cell membrane into the cell and chloride is expelled.
  
  
• As hemoglobin binds oxygen and releases protons, carbonic anhydrase goes to work again, catalyzing the conversion of bicarbonate and a proton to CO₂ and water. The CO₂ diffuses out of the red cell and is expired.
  
  

Band 3 thus performs bidirectional, one-for-one exchange of bicarbonate and chloride, greatly increasing the capacity of blood to carry CO₂. In the kidney, band 3 performs a similar function, and in so doing serves a significant role in maintaining blood pH.

Band 3 also appears to contribute significantly to maintaining cell shape, in particular, the biconcave shape of erythrocytes. In the red cell, the cytoplasmic domain of the protein interacts spectin through an ankyrin bridge, and this tie to the cytoskeleton seems to define cell shape and stability.

Null mutations in the band 3 gene are not uncommon in human populations. Heterozygotes manifest a condition known as hereditary spherocytosis. Erythrocytes in such patients are small, round instead of biconcave, and fragile, which leads to accelerated destruction and anemia. This of course is consistent with the cytoskeletal influence of of band 3. Humans homozygous for band 3 mutations have not been recognized and complete absense of this protein has been thought to be lethal. Interestingly, Japanese black cattle have been found which apparently have a total lack of band 3 protein (Inaba et al, 1996) and mice with targeted deletion of the band 3 gene have been produced (Peters et al, 1996). The cattle are moderately acidotic with mild anemia and spherocytosis. Some of the homozygous knockout mice survive to adulthood, but they have severe hemolytic anemia associated with alterations in erythrocyte shape. The fact that these animals survive at all points to the existance and potential importance of redundant anion exchange proteins.

References and Reviews

• Inaba M, Yawata A, Koshino I, etc: J Clin Invest 97:1804, 1996. [homozygous null mice]
• Jay DG: Role of band 3 in homeostasis and cell shape. Cell 86:853, 1996.
• Jennings ML: Oligomeric structure and the anion transport function of human erythrocyte band 3 protein. J Membrane Biol 80:105, 1984.
• Peters LL, Shivdasani RA, Liu S-C, etc: Anion exchanger 1 (Band 3) is required to prevent erythrocyte membrane surface loss, but not to form the membrane skeleton. Cell 86:917, 1996. [band 3 knockout mice]