Mechanisms of hydrogen ion or bicarbonate secretion by intercalated cells

3 different types of intercalated cells have been identified: type A, type B, and nontype A/nontype B. Each of these cells is rich in carbonic anhydrase II and is capable of generating abundant intracellular HCO₃^–and H⁺ from the dehydration of H₂CO₃.
Type A intercalated cells: The H⁺ that is generated from the "splitting" of H₂CO₃ is secreted into the lumen mainly via V-type H⁺ ATPase and to a smaller extent via H⁺ K⁺ ATPase. The cytoplasmic HCO₃^– is secreted into the interstitial space/peritubular capillary via AE1 (a product of the solute carrier family 4 member 1 [SLC4A1] gene).
Type B intercalated cells: The H⁺ that is generated from the "splitting" of H₂CO₃ is secreted into the interstitial space/peritubular capillary by V-type H⁺ ATPase in the basolateral membrane (this H⁺ transporter is identical to the transporter in the type A intercalated cells, but in the type A cells it is located on the luminal membrane). The cytoplasmic HCO₃^– generated in this cell is secreted into the lumen via the anion exchanger pendrin (a product of the solute carrier family 26 member 4 [SLC26A4] gene) that exchanges 1 HCO₃^– for 1 Cl^–. Pendrin is distinctly different from AE1 in the type A cells that are present in the basolateral membrane. AE4 (a product of the SLC4A4 gene) is present in the basolateral membrane. Type B intercalated cells also have an NDBCE (a product of the solute carrier family 4 member 8 [SLC4A8] gene) in the luminal membrane. This transporter plays an important role in NaCl reabsorption. (Refer to discussion below.)
Nontype A/nontype B intercalated cells: This is the third type of intercalated cell. Both a V-type H⁺ ATPase, which pumps H⁺, and pendrin, which exchanges HCO₃^– for Cl^–, coexist in the lumen membrane. In the basolateral membrane, AE4 (a product of the SLC4A4 gene) is present. This is a major Na⁺/3HCO₃^– cotransporter, which moves these ions into the interstitial space/peritubular capillary.
Role in salt balance: In addition to their major role in renal acid-base regulation in the distal nephron, intercalated cells have an important role in salt and volume regulation. NDBCE (a product of the SLC4A8 gene), which is present in the luminal membrane of the type B intercalated cells, moves 1 Na⁺ and 2 HCO₃^– ions into the cell while secreting 1 Cl^– into the lumen. Consequently it is an electrically neutral ion exchanger. These 2 HCO₃^– ions then reenter the lumen in exchange for 2 Cl^– ions via pendrin. The net result of these coupled exchanges will be the absorption of 1 molecule of NaCl. The NDBCE exchanger is inhibited by thiazide diuretics.