SLC4A3 Membrane Protein Introduction

Introduction of SLC4A3

Solute carrier family 4 member 3 (SLC4A3), also known as AE3, is a member of the SLC4 family of anion transporters which involves the bicarbonate transport across plasma membranes. SLC4A3 protein is encoded by SLC4A3 gene and has two variants, brain or full-length AE3 [AE3(fl)] and cardiac AE3 (cAE3). The topological structure of SLC4A3 reveals that it has two cytoplasmic domains and 10 membrane-spanning helixes.

Basic Information of SLC4A3
Protein Name	Anion exchange protein 3
Gene Name	SLC4A3
Aliases	AE3, SLC2C, CAE3/BAE3
Organism	Homo sapiens (Human)
UniProt ID	P48751
Transmembrane Times	10
Length (aa)	1259
Sequence	MANGVIPPPGGASPLPQVRVPLEEPPLSPDVEEEDDDLGKTLAVSRFGDLISKPPAWDPEKPSRSYSERDFEFHRHTSHHTHHPLSARLPPPHKLRRLPPTSARHTRRKRKKEKTSAPPSEGTPPIQEEGGAGVDEEEEEEEEEEGESEAEPVEPPHSGTPQKAKFSIGSDEDDSPGLPGRAAVTKPLPSVGPHTDKSPQHSSRPCSELRDGDGTTDLALSSPRLLCCLPSSPSPRARASRLAGEKSRPWSPSASYDLRERLCPGSALGNPGGPEQQVPTDEAEAQMLGSADLDDMKSHRLEDNPGVRRHLVKKPSRTQGGRGSPSGLAPILRRKKKKKKLDRRPHEVFVELNELMLDRSQEPHWRETARWIKFEEDVEEETERWGKPHVASLSFRSLLELRRTIAHGAALLDLEQTTLPGIAHLVVETMIVSDQIRPEDRASVLRTLLLKHSHPNDDKDSGFFPRNPSSSSMNSVLGNHHPTPSHGPDGAVPTMADDLGEPAPLWPHDPDAKEKPLHMPGGDGHRGKSLKLLEKIPEDAEATVVLVGCVPFLEQPAAAFVRLNEAVLLESVLEVPVPVRFLFVMLGPSHTSTDYHELGRSIATLMSDKLFHEAAYQADDRQDLLSAISEFLDGSIVIPPSEVEGRDLLRSVAAFQRELLRKRREREQTKVEMTTRGGYTAPGKELSLELGGSEATPEDDPLLRTGSVFGGLVRDVRRRYPHYPSDLRDALHSQCVAAVLFIYFAALSPAITFGGLLGEKTEGLMGVSELIVSTAVLGVLFSLLGAQPLLVVGFSGPLLVFEEAFFKFCRAQDLEYLTGRVWVGLWLVVFVLALVAAEGSFLVRYISPFTQEIFAFLISLIFIYETFYKLYKVFTEHPLLPFYPPEGALEGSLDAGLEPNGSALPPTEGPPSPRNQPNTALLSLILMLGTFFIAFFLRKFRNSRFLGGKARRIIGDFGIPISILVMVLVDYSITDTYTQKLTVPTGLSVTSPDKRSWFIPPLGSARPFPPWMMVAAAVPALLVLILIFMETQITALIVSQKARRLLKGSGFHLDLLLIGSLGGLCGLFGLPWLTAATVRSVTHVNALTVMRTAIAPGDKPQIQEVREQRVTGVLIASLVGLSIVMGAVLRRIPLAVLFGIFLYMGVTSLSGIQLSQRLLLILMPAKHHPEQPYVTKVKTWRMHLFTCIQLGCIALLWVVKSTAASLAFPFLLLLTVPLRHCLLPRLFQDRELQALDSEDAEPNFDEDGQDEYNELHMPV

Function of SLC4A3 Membrane Protein

SLC4A3 (AE3) is a plasma membrane anion exchange protein and mediates Cl^- /HCO3^- exchange across cellular membranes. It is primarily found in neurons and in the heart where it is important for the normal brain and cardiac function. A variant of SLC4A3 p.Ala867Asp can decrease AE3 transport activity and cause abnormal intracellular pH and changes in cell volume, thus may promote neuron hyperexcitability and the generation of seizures. Besides, SLC4A3 is also involved in myocardial intracellular pH recovery from alkaline loads. A missense mutation in SLC4A3 is identified in two unrelated families with short Q-T syndrome (SQTS). And the mutation reduces the expression of AE3 and membrane bicarbonate transport. SLC4A3 knockdown leads to increased cardiac pH, short QTc, and decreased systolic duration. These findings suggest that SLC4A3 plays a role in the development of arrhythmia and can act as a therapeutic target for the disease. In addition, SLC4A3 has been shown to be an excellent candidate gene for human retinal degeneration.

Fig.1 Topology model of SLC4 proteins based on NBC hydropathies and the model of AE1. (Romero, 2013)

Application of SLC4A3 Membrane Protein in Literature

Downs L.M., et al. Investigation of SLA4A3 as a candidate gene for human retinal disease. Journal of Negative Results in Biomedicine. 2016, 15(1):11. PubMed ID: 27211793

In this investigation, authors identify SLC4A3 remains an excellent candidate gene for human retinal degeneration using whole exome and whole genome sequencing of 200 patients with autosomal recessive retinal degeneration.
Vilas G.L., et al. Characterization of an epilepsy-associated variant of the human Cl-/HCO3(-) exchanger AE3. American Journal of Physiology Cell Physiology. 2009, 297(3):526-36. PubMed ID: 19605733

The article reveals that the loss-of-function A867D mutation in AE3 gene may lead to alterations in cell volume and abnormal intracellular pH, thereby promoting neuron hyperexcitability and the generation of seizures.
Thorsen K., et al. Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome. Nature Communications. 2017, 8(1):1696. PubMed ID: 29167417

The experimental results show that SLC4A3 knockdown in zebrafish can increase cardiac pH, short QTc, and decrease systolic duration, which provides a new therapeutic target for arrhythmia.
Salameh A.I., et al. Role of Cl^--HCO3^- exchanger AE3 in intracellular pH homeostasis in cultured murine hippocampal neurons, and in crosstalk to adjacent astrocytes. Journal of Physiology. 2017, 595(1):93-124. PubMed ID: 27353306

These findings suggest that neuronal AE3 expression is involved in neuron-astrocyte communication, which provides a novel explanation that how AE3 reduces seizure susceptibility.
Downs L.M., et al. A frameshift mutation in golden retriever dogs with progressive retinal atrophy endorses slc4a3 as a candidate gene for human retinal degenerations. Plos One. 2011, 6(6):e21452. PubMed ID: 21738669

The study indicates that SLC4A3 plays an important role in the retinal function and act as a candidate for human retinal degenerations.

SLC4A3 Preparation Options

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Reference

Romero M F, et al. (2013). The SLC4 family of bicarbonate (HCO3-) transporters. Mol Aspects Med. 34(2-3): 159-82.

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