SLC8A3 (solute carrier family 8 member 3), also called Na+/Ca2+ exchanger 3 (NCX3), is encoded by SLC8A3 gene, which is located on chromosome 14q24.2. SLC8A3 gene contains 8 exons, and there are multiple variants have been observed due to alternative splicing in this gene. Belonging to the Na+/Ca2+ exchanger family, SLC8A3 is constituted of 10 transmembrane (TM) domains with a diamond-shaped site for substrate binding, a cytoplasmic N and C termini. The 10 TMs are arranged in two clusters separated by a large cytoplasmic loop of 500 residues, which contains two structurally homologous Ca2+ binding domains CBD1 and CBD2. The conserved TM 2 and TM 7 domains are engaged in the transition between inward and outward conformation. SLC8A3 is abundant in both the plasma membrane and intracellular organellar membranes in the brain and skeletal muscle, involved in Na+/Ca2+ exchange and Ca2+ homeostasis maintenance.
|Basic Information of SLC8A3|
|Protein Name||Sodium/calcium exchanger 3|
|Organism||Homo sapiens (Human)|
Contributing to intracellular Ca2+ homeostasis in excitable cells, SLC8A3 is critical for a lot of physiological processes throughout the body. SLC8A3 has been reported to participate in diverse processes such as bone formation, TNF-α production, slow-twitch muscle contraction, and long-term potentiation in the hippocampus and so on. In osseous tissues, SLC8A3 regulates the Ca2+ delivery to the osteoid to control osteoblast differentiation and contributes to Ca2+ efflux from the osteoblasts in order to produce calcifying bone matrix. In the immune system, SLC8A3 is associated with the Ca2+ uptake and production of tumor necrosis factor-alpha (TNF-α) in macrophages and monocytes. Moreover, SLC8A3 absence is responsible for dysfunctional stimulation of the muscle and in particular a delayed neurotransmitter release during repetitive nerve stimulation. In the brain, SLC8A3 is involved in numerous cellular processes, such as glial cell differentiation, driving the maturation of oligodendrocytes and myelin formation, modulation of the long-term potentiation (LTP) in the hippocampus, etc. Furthermore, SLC8A3 induced aberrant Ca2+ influx during neuronal excitotoxicity is very common in Alzheimer’s disease, brain stroke, and neuronal injuries.
Fig.1 Ion transport cycle and NCX backbone dynamics. (Giladi, 2016)
The authors demonstrated echinacoside protected against A/R-induced apoptosis in a dosed manner, accompanied with a remarkable reduction of Ca2+ uptake and up-regulation of p-AKT and SLC8A3. Coincidently SLC8A3 silencing increased apoptosis, Ca2+ uptake and protein levels of caspase 3 in H9c2 cells under normoxic conditions.
This article used a genome-wide association approach to identify new susceptibility genes for ACPA-positive rheumatoid arthritis and they evaluated an intronic SNP in the SLC8A3 was found to be associated with ACPA-positive RA at a genome-wide level.
The authors used whole-cell patch-clamp, western blotting and immunofluorescence techniques to record the currents and expression of NCX3 in the hippocampus and cerebrocortex of rats with hyperthermia-induced convulsion, and they found that NCX currents and NCX3 expression were decreased in rats after febrile convulsion, indicating a potential link between NCX3 expression, febrile convulsion in early childhood, and adult onset of epilepsy.
The authors firstly demonstrated that calpain-3 (CAPN3) increased NCX3 activity and only NCX3-AC was sensitive to calpain. When removing the six residues coded in exon C of NCX3-AC, the sensitivity to CAPN1 and CAPN3 could be abrogated.
This review summarized various data from the X-ray crystallography, molecular dynamics simulations, hydrogen-deuterium exchange mass-spectrometry (HDX-MS), and ion-flux analyses of mutants and demonstrated that the conserved α₁ and α₂ repeats at ion-coordinating residues of NCX were involved in transport activities. The review significantly provided the structure-functional basis of NCX and improved our understanding of ion transport mechanisms in NCX and similar proteins.
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