Anion exchange protein 3

Last updated

SLC4A3
HAE3 TMD structure.png
Identifiers
Aliases SLC4A3 , AE3, SLC2C, CAE3/BAE3, solute carrier family 4 member 3
External IDs OMIM: 106195; MGI: 109350; HomoloGene: 129474; GeneCards: SLC4A3; OMA:SLC4A3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6508

20536

Ensembl

ENSG00000114923

ENSMUSG00000006576

UniProt

P48751

P16283

RefSeq (mRNA)

NM_005070
NM_201574
NM_001326559

NM_009208
NM_001357149
NM_001357150

RefSeq (protein)

NP_001313488
NP_005061
NP_963868

NP_033234
NP_001344078
NP_001344079

Location (UCSC) Chr 2: 219.63 – 219.64 Mb Chr 1: 75.52 – 75.54 Mb
PubMed search [3] [4]
Wikidata
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Anion exchange protein 3 (AE3) is a membrane transport protein encoded by the human SLC4A3 gene. [5] [6]

Contents

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. [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.

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. [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]

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. [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]

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000114923 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000006576 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Su YR, Klanke CA, Houseal TW, Linn SC, Burk SE, Varvil TS, et al. (Jan 1995). "Molecular cloning and physical and genetic mapping of the human anion exchanger isoform 3 (SLC2C) gene to chromosome 2q36". Genomics. 22 (3): 605–609. doi:10.1006/geno.1994.1433. PMID   8001971.
  6. ↑ "Entrez Gene: SLC4A3 solute carrier family 4, anion exchanger, member 3".
  7. ↑ Jian L, Zhang Q, Yao D, Wang Q, Chen M, Xia Y, et al. (2024-07-20). "The structural insight into the functional modulation of human anion exchanger 3". Nature Communications. 15 (1): 6134. Bibcode:2024NatCo..15.6134J. doi: 10.1038/s41467-024-50572-x . ISSN   2041-1723. PMC   11271275 . PMID   39033175.
  8. ↑ Zhang Q, Jian L, Yao D, Rao B, Xia Y, Hu K, et al. (2023-03-31). "The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2". Nature Communications. 14 (1): 1812. doi:10.1038/s41467-023-37557-y. ISSN   2041-1723. PMC   10066210 . PMID   37002221.
  9. ↑ Casey JR, Sly WS, Shah GN, Alvarez BV (November 2009). "Bicarbonate homeostasis in excitable tissues: role of AE3 Cl-/HCO3- exchanger and carbonic anhydrase XIV interaction". American Journal of Physiology. Cell Physiology. 297 (5): C1091 –C1102. doi:10.1152/ajpcell.00177.2009. PMC   2777400 . PMID   19692653.
  10. ↑ Hayashi H, Suruga K, Yamashita Y (June 2009). "Regulation of intestinal Cl-/HCO3- exchanger SLC26A3 by intracellular pH". American Journal of Physiology. Cell Physiology. 296 (6): C1279 –C1290. doi:10.1152/ajpcell.00638.2008. PMID   19321737.
  11. ↑ Hentschke M, Wiemann M, Hentschke S, Kurth I, Hermans-Borgmeyer I, Seidenbecher T, et al. (January 2006). "Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold". Molecular and Cellular Biology. 26 (1): 182–191. doi:10.1128/MCB.26.1.182-191.2006. PMC   1317631 . PMID   16354689.
  12. ↑ Vilas GL, Johnson DE, Freund P, Casey JR (September 2009). "Characterization of an epilepsy-associated variant of the human Cl-/HCO3(-) exchanger AE3". American Journal of Physiology. Cell Physiology. 297 (3): C526 –C536. doi:10.1152/ajpcell.00572.2008. PMID   19605733. S2CID   29802528.
  13. ↑ Thorsen K, Dam VS, Kjaer-Sorensen K, Pedersen LN, Skeberdis VA, Jurevičius J, et al. (2017-11-22). "Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome". Nature Communications. 8 (1): 1696. Bibcode:2017NatCo...8.1696T. doi:10.1038/s41467-017-01630-0. ISSN   2041-1723. PMC   5700076 . PMID   29167417.
  14. ↑ Christiansen MK, Kjær-Sørensen K, Clavsen NC, Dittmann S, Jensen MF, Guldbrandsen HØ, et al. (August 2023). "Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome". Heart Rhythm. 20 (8): 1136–1143. doi: 10.1016/j.hrthm.2023.02.010 . ISSN   1556-3871. PMID   36806574.

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