Anion exchange protein 3

Structure

Cryo-electron microscopy studies have revealed that AE3 forms a homodimeric complex, structurally similar to other members of the SLC4 family, such as AE1 and AE2. AE3 is stabilized in an outward-facing conformation under resting conditions, contrasting with AE2, which predominantly adopts an inward-facing conformation. This conformational preference renders AE3 more susceptible to inhibition by DIDS (4,4′-Diisothiocyanatostilbene-2,2′-disulfonic acid), a pan-inhibitor of anion transporters. In addition to its transmembrane domain (TMD), which mediates ion exchange, the soluble N-terminal domain (NTD) of AE3 has also been structurally characterized. A chimeric construct combining the AE3 NTD with the AE2 TMD has provided further insights into domain organization and functional modulation.

Function

AE3 mediates the electroneutral exchange of Cl− and HCO3−, contributing to intracellular pH regulation and bicarbonate homeostasis. It is functionally similar to Band 3 (AE1), but exhibits distinct tissue specificity. AE3 is expressed primarily in brain neurons and cardiac tissue. Like other members of the SLC4 family, including AE2, AE3 activity is sensitive to changes in intracellular pH, which modulates its transport kinetics.

Clinical significance

Mutations in the SLC4A3 gene have been associated with neurological and cardiac disorders. Animal models with targeted disruption of AE3 exhibit reduced seizure thresholds, indicating a role for AE3 in neuronal excitability and seizure susceptibility. A variant of AE3 has also been identified in patients with epilepsy, supporting its involvement in human seizure disorders. More recently, loss-of-function mutations in SLC4A3 have been linked to Short QT syndrome (SQTS), a rare cardiac channelopathy associated with a high risk of sudden cardiac death. Subsequent genetic analyses have suggested that SLC4A3 mutations may be one of the most frequent causes of SQTS, underscoring AE3’s importance in cardiac electrophysiology.

References

References

1. (Jan 1995). "Molecular cloning and physical and genetic mapping of the human anion exchanger isoform 3 (SLC2C) gene to chromosome 2q36". Genomics.
2. "Entrez Gene: SLC4A3 solute carrier family 4, anion exchanger, member 3".
3. (2024-07-20). "The structural insight into the functional modulation of human anion exchanger 3". Nature Communications.
4. (2023-03-31). "The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2". Nature Communications.
5. (November 2009). "Bicarbonate homeostasis in excitable tissues: role of AE3 Cl-/HCO3- exchanger and carbonic anhydrase XIV interaction". American Journal of Physiology. Cell Physiology.
6. (June 2009). "Regulation of intestinal Cl-/HCO3- exchanger SLC26A3 by intracellular pH". American Journal of Physiology. Cell Physiology.
7. (January 2006). "Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold". Molecular and Cellular Biology.
8. (September 2009). "Characterization of an epilepsy-associated variant of the human Cl-/HCO3(-) exchanger AE3". American Journal of Physiology. Cell Physiology.
9. (2017-11-22). "Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome". Nature Communications.
10. (August 2023). "Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome". Heart Rhythm.