Anion exchange protein 3 (AE3) is a
membrane transport protein
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral membrane proteins, integral transmembr ...
encoded by the human ''SLC4A3''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
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
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s 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
Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
, supporting its involvement in human seizure disorders.
More recently, loss-of-function mutations in ''SLC4A3'' have been linked to
Short QT syndrome
Short QT syndrome (SQT) is a very rare genetics, genetic disease of the electrical system of the heart, and is associated with an increased risk of Heart arrhythmia, abnormal heart rhythms and sudden cardiac death. The syndrome gets its name from ...
(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.
See also
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Solute carrier family
The solute carrier (SLC) group of membrane transport proteins include over 400 members organized into 66 families. Most members of the SLC group are located in the cell membrane. The SLC gene nomenclature system was originally proposed by the HUGO ...
References
Further reading
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Solute carrier family
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