Anion exchange protein 3

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.^[7] AE3 is stabilized in an outward-facing conformation under resting conditions, contrasting with AE2, which predominantly adopts an inward-facing conformation.^[8] 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.

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.^[9] Like other members of the SLC4 family, including AE2, AE3 activity is sensitive to changes in intracellular pH, which modulates its transport kinetics.^[10]

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.^[11] A variant of AE3 has also been identified in patients with epilepsy, supporting its involvement in human seizure disorders.^[12] 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.^[13] 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.^[14]

• Solute carrier family