Anion exchange protein 3

SLC4A3
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
Gene location (Human)
Chr.	Chromosome 2 (human)
End	219,641,980 bp
Gene location (Mouse)
Chr.	Chromosome 1 (mouse)
End	75,538,816 bp
RNA expression pattern
	Top expressed in
	apex of heart; ; right auricle; ; left ventricle; ; left ovary; ; right ovary; ; myocardium of left ventricle; ; right ventricle; ; nucleus accumbens; ; cardiac muscle tissue of right atrium; ; lateral nuclear group of thalamus;
	Top expressed in
	perirhinal cortex; ; entorhinal cortex; ; interventricular septum; ; right ventricle; ; myocardium of ventricle; ; cardiac muscles; ; central gray substance of midbrain; ; CA3 field; ; pontine nuclei; ; cingulate gyrus;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	antiporter activity; inorganic anion exchanger activity; anion transmembrane transporter activity; sodium:bicarbonate symporter activity;
Cellular component	integral component of membrane; integral component of plasma membrane; plasma membrane; membrane;
Biological process	anion transport; regulation of intracellular pH; ion transport; inorganic anion transport; bicarbonate transport; transmembrane transport; anion transmembrane transport;
	Sources:Amigo / QuickGO
Orthologs
	6508
	20536
	ENSG00000114923
	ENSMUSG00000006576
	P48751
	P16283
	NM_005070; NM_201574; NM_001326559
	NM_009208; NM_001357149; NM_001357150
	NP_001313488; NP_005061; NP_963868
	NP_033234; NP_001344078; NP_001344079
	Wikidata
View/Edit Human	View/Edit Mouse

Biological Functions

Anion exchange protein 3 (AE3) is a membrane transport protein that in humans is encoded by the SLC4A3 gene.^[5]^[6] AE3 is functionally similar to the Band 3 Cl⁻/HCO3⁻ exchange protein but it is expressed primarily in brain neurons and in the heart. Like AE2 its activity is sensitive to pH.^[7]^[8] AE3 mutations have been linked to seizures.^[9]^[10]

Structural features

The cryo-EM studies on the structures of human AE3 revealed that it forms a homodimer, similar to AE1 and AE2. ^[11]. AE3 is stabilized in an outward-facing conformation as its resting state, in contrast to AE2, which rests in an inward-facing conformation ^[12]. This outward-facing conformation makes AE3 more vulnerable to the pan-inhibitor of anion transporters, DIDS (4,4-diisothiocyanatostilbene-2,2'-disulfonic acid). In addition to the transmembrane domain (TMD) resolved by cryo-EM, the soluble N-terminal domain (NTD) of AE3 has also been solved in a chimera consisting of the AE3 NTD and AE2 TMD.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000114923 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000006576 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Su YR, Klanke CA, Houseal TW, Linn SC, Burk SE, Varvil TS, Otterud BE, Shull GE, Leppert MF, Menon AG (Jan 1995). "Molecular cloning and physical and genetic mapping of the human anion exchanger isoform 3 (SLC2C) gene to chromosome 2q36". Genomics. 22 (3): 605–9. doi:10.1006/geno.1994.1433. PMID 8001971.
^ "Entrez Gene: SLC4A3 solute carrier family 4, anion exchanger, member 3".
^ 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". Am. J. Physiol., Cell Physiol. 297 (5): C1091–102. doi:10.1152/ajpcell.00177.2009. PMC 2777400. PMID 19692653.
^ Hayashi H, Suruga K, Yamashita Y (June 2009). "Regulation of intestinal Cl-/HCO3- exchanger SLC26A3 by intracellular pH". Am. J. Physiol., Cell Physiol. 296 (6): C1279–90. doi:10.1152/ajpcell.00638.2008. PMID 19321737.
^ Hentschke M, Wiemann M, Hentschke S, Kurth I, Hermans-Borgmeyer I, Seidenbecher T, Jentsch TJ, Gal A, Hübner CA (January 2006). "Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold". Mol. Cell. Biol. 26 (1): 182–91. doi:10.1128/MCB.26.1.182-191.2006. PMC 1317631. PMID 16354689.
^ Vilas GL, Johnson DE, Freund P, Casey JR (September 2009). "Characterization of an epilepsy-associated variant of the human Cl-/HCO3(-) exchanger AE3". Am. J. Physiol., Cell Physiol. 297 (3): C526–36. doi:10.1152/ajpcell.00572.2008. PMID 19605733. S2CID 29802528.
^ Jian, Liyan; Zhang, Qing; Yao, Deqiang; Wang, Qian; Chen, Moxin; Xia, Ying; Li, Shaobai; Shen, Yafeng; Cao, Mi; Qin, An; Li, Lin; Cao, Yu (2024-07-20). "The structural insight into the functional modulation of human anion exchanger 3". Nature Communications. 15 (1): 6134. doi:10.1038/s41467-024-50572-x. ISSN 2041-1723.
^ Zhang, Qing; Jian, Liyan; Yao, Deqiang; Rao, Bing; Xia, Ying; Hu, Kexin; Li, Shaobai; Shen, Yafeng; Cao, Mi; Qin, An; Zhao, Jie; Cao, Yu (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.

Alper SL, Darman RB, Chernova MN, Dahl NK (2002). "The AE gene family of Cl/HCO3- exchangers". J. Nephrol. 15. Suppl 5: S41–53. PMID 12027221.
Kopito RR, Lee BS, Simmons DM, et al. (1990). "Regulation of intracellular pH by a neuronal homolog of the erythrocyte anion exchanger". Cell. 59 (5): 927–37. doi:10.1016/0092-8674(89)90615-6. PMID 2686841. S2CID 32780443.
Yannoukakos D, Stuart-Tilley A, Fernandez HA, et al. (1994). "Molecular cloning, expression, and chromosomal localization of two isoforms of the AE3 anion exchanger from human heart". Circ. Res. 75 (4): 603–14. doi:10.1161/01.res.75.4.603. PMID 7923606.
Morgans CW, Kopito RR (1993). "Association of the brain anion exchanger, AE3, with the repeat domain of ankyrin". J. Cell Sci. 105. ( Pt 4) (4): 1137–42. doi:10.1242/jcs.105.4.1137. PMID 8227202.
Dudeja PK, Hafez N, Tyagi S, et al. (1999). "Expression of the Na+/H+ and Cl-/HCO-3 exchanger isoforms in proximal and distal human airways". Am. J. Physiol. 276 (6 Pt 1): L971–8. doi:10.1152/ajplung.1999.276.6.L971. PMID 10362722.
Einum DD, Zhang J, Arneson PJ, et al. (2000). "Genomic structure of human anion exchanger 3 and its potential role in hereditary neurological disease". Neurogenetics. 1 (4): 289–92. doi:10.1007/s100480050043. PMID 10732805. S2CID 22195848.
Soleimani M, Greeley T, Petrovic S, et al. (2001). "Pendrin: an apical Cl-/OH-/HCO3- exchanger in the kidney cortex". Am. J. Physiol. Renal Physiol. 280 (2): F356–64. doi:10.1152/ajprenal.2001.280.2.f356. PMID 11208611.
Alrefai WA, Tyagi S, Nazir TM, et al. (2001). "Human intestinal anion exchanger isoforms: expression, distribution, and membrane localization". Biochim. Biophys. Acta. 1511 (1): 17–27. doi:10.1016/S0005-2736(00)00366-7. PMID 11248201.
Sterling D, Reithmeier RA, Casey JR (2002). "A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers". J. Biol. Chem. 276 (51): 47886–94. doi:10.1074/jbc.M105959200. PMID 11606574.
Alvarez BV, Fujinaga J, Casey JR (2002). "Molecular basis for angiotensin II-induced increase of chloride/bicarbonate exchange in the myocardium". Circ. Res. 89 (12): 1246–53. doi:10.1161/hh2401.101907. PMID 11739292.
Wang Z, Petrovic S, Mann E, Soleimani M (2002). "Identification of an apical Cl(-)/HCO3(-) exchanger in the small intestine". Am. J. Physiol. Gastrointest. Liver Physiol. 282 (3): G573–9. doi:10.1152/ajpgi.00338.2001. PMID 11842009.
Sterling D, Alvarez BV, Casey JR (2002). "The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger binds carbonic anhydrase IV". J. Biol. Chem. 277 (28): 25239–46. doi:10.1074/jbc.M202562200. PMID 11994299.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000114923 – Ensembl, May 2017

[refGRCm38Ensembl-2] 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.

[pmid8001971-5] Su YR, Klanke CA, Houseal TW, Linn SC, Burk SE, Varvil TS, Otterud BE, Shull GE, Leppert MF, Menon AG (Jan 1995). "Molecular cloning and physical and genetic mapping of the human anion exchanger isoform 3 (SLC2C) gene to chromosome 2q36". Genomics. 22 (3): 605–9. doi:10.1006/geno.1994.1433. PMID 8001971.

[entrez-6] "Entrez Gene: SLC4A3 solute carrier family 4, anion exchanger, member 3".

[pmid19692653-7] 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". Am. J. Physiol., Cell Physiol. 297 (5): C1091–102. doi:10.1152/ajpcell.00177.2009. PMC 2777400. PMID 19692653.

[pmid19321737-8] Hayashi H, Suruga K, Yamashita Y (June 2009). "Regulation of intestinal Cl-/HCO3- exchanger SLC26A3 by intracellular pH". Am. J. Physiol., Cell Physiol. 296 (6): C1279–90. doi:10.1152/ajpcell.00638.2008. PMID 19321737.

[pmid16354689-9] Hentschke M, Wiemann M, Hentschke S, Kurth I, Hermans-Borgmeyer I, Seidenbecher T, Jentsch TJ, Gal A, Hübner CA (January 2006). "Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold". Mol. Cell. Biol. 26 (1): 182–91. doi:10.1128/MCB.26.1.182-191.2006. PMC 1317631. PMID 16354689.

[pmid19605733-10] Vilas GL, Johnson DE, Freund P, Casey JR (September 2009). "Characterization of an epilepsy-associated variant of the human Cl-/HCO3(-) exchanger AE3". Am. J. Physiol., Cell Physiol. 297 (3): C526–36. doi:10.1152/ajpcell.00572.2008. PMID 19605733. S2CID 29802528.

[11] Jian, Liyan; Zhang, Qing; Yao, Deqiang; Wang, Qian; Chen, Moxin; Xia, Ying; Li, Shaobai; Shen, Yafeng; Cao, Mi; Qin, An; Li, Lin; Cao, Yu (2024-07-20). "The structural insight into the functional modulation of human anion exchanger 3". Nature Communications. 15 (1): 6134. doi:10.1038/s41467-024-50572-x. ISSN 2041-1723.

[12] Zhang, Qing; Jian, Liyan; Yao, Deqiang; Rao, Bing; Xia, Ying; Hu, Kexin; Li, Shaobai; Shen, Yafeng; Cao, Mi; Qin, An; Zhao, Jie; Cao, Yu (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.

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Anion exchange protein 3

Biological Functions

Structural features

See also

References

Further reading