SLC8A1 Membrane Protein Introduction

Introduction of SLC8A1

SLC8A1 (Solute carrier family 8 member 1), also known as sodium/calcium (often denoted Na⁺/Ca²⁺) exchanger 1 (NCX1), is encoded by SLC8A1 gene in human. SLC8A1 belongs to the Na⁺/Ca²⁺ exchanger family, CaCA (Ca²⁺/cation antiporter) superfamily, which is predicted to have 10 transmembrane helices (10TM) with a diamond-shaped site for substrate binding, an N-terminal domain with the first 5TMs (residues 1-217), a C-terminal domain comprising the last 4TMs (residues 765-973). Notably, a large cytoplasmic loop containing two structurally homologous Ca²⁺ binding domains CBD1 and CBD2 is located in residues 218-764 region, forming the calcium regulatory exchanger loop of SLC8A1. SLC8A1 gene is mapped to the chromosome 2p22.1. SLC8A1 is expressed abundantly in the heart and brain, while in the retina and skeletal and smooth muscles, SLC8A1 expression maintains at very low levels.

Function of SLC8A1 Membrane Protein

The contribution to the electrical activity of the heart is due to the regulation of SLC8A1 in calcium transport in cardiac myocytes, where SLC8A1 can mediate the extrusion of Ca(2+) that enters the cell across the sarcolemma during relaxation, preventing overloading of intracellular stores. So SLC8A1 may play a key role in digitalis action in heart, returning the cardiac myocyte to its resting state following excitation. Moreover, SLC8A1 is an effective regulator in calcium (Ca(2+)) homeostasis in many tissues including excitation-secretion coupling in pancreatic beta-cells. In addition, SLC8A1 has the ability to regulate osteoclasts cytosolic calcium and bone resorption, and adjust constriction of small arteries, contributing to the development of salt-dependent hypertension, through calcium entry. As Na⁺/Ca²⁺ exchanger, SLC8A1 plays a crucial role in ionic regulation, promoting the efflux and influx of Na(+) and Ca(2+) ions. Combined with SLC8A3, SLC8A1 represents a novel additional molecular target for the prosurvival action of the PI3-K/Akt pathway. In summary, it has been documented that SLC8A1 is responsible for the excitation-contraction coupling, long-term potentiation of the brain and learning, blood pressure regulation, immune response, neurotransmitter, and insulin secretion.

Fig.1 The associated calcium handling genes in postnatal skeletal muscle development. (Brinegar, 2017)

Application of SLC8A1 Membrane Protein in Literature

1. Liu K., et al. Genetic variation in SLC8A1 gene involved in blood pressure responses to acute salt loading. American journal of hypertension. 2017, 31(4): 415-421. PubMed ID: 29182730
   
   

   The authors used a modified Sullivan's acute oral saline load and diuresis shrinkage test to demonstrate that CYP11B2, PRKG1, and SLC8A1 genes single-nucleotide polymorphisms (SNPs) were significantly associated with systolic blood pressure (SBP) rising in the additive and recessive model; while SNPs in CYP4A11, PRKG1, SLC8A1, and ADRB2 genes were closely associated with diastolic blood pressure (DBP) rising.

2. Lubelwana Hafver T., et al. Mapping the in vitro interactome of cardiac sodium (Na⁺)-calcium (Ca²⁺) exchanger 1 (NCX1). Proteomics. 2017, 17(17-18). PubMed ID: 28755400
   
   

   This article used affinity purification coupled with MS to identify a series of protein partners for NCX1. They verified 10 novel protein partners (DYRK1A, PPP2R2A, SNTB1, DMD, RABGGTA, DNAJB4, BAG3, PDE3A, POPDC2, STK39) that can bind to NCX1, and two partners (DYRK1A, SNTB1) can increase NCX1 activity when expressed in HEK293 cells.

3. Shimizu C., et al. Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities. Circulation: Genomic and Precision Medicine. 2016, 9(6): 559-568. PubMed ID: 29988369
   
   

   The authors identified 100 significant pathways and 116 single nucleotide polymorphisms in 26 genes associated with Kawasaki disease (KD), among which three SNPs in SLC8A1 can alter calcium flux in cells, mediating coronary artery damage in KD. So it was suggested that SLC8A1 might be a therapeutic target in acute KD.

4. Muñoz J.J., et al. Down-regulation of SLC8A1 as a putative apoptosis evasion mechanism by modulation of calcium levels in penile carcinoma. The Journal of urology. 2015, 194(1): 245-251. PubMed ID: 25481039
   
   

   The authors revealed that miR-223 was overexpressed in penile carcinoma, which downregulated SLC8A1 expression, associated with decreased calcium distribution, high Ki-67, and low caspase-3 immunoexpression, indicating suppressed apoptosis and increased tumor cell proliferation.

5. Brinegar A.E., et al. Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions. elife. 2017, 6: e27192. PubMed ID: 28826478
   
   

   The authors used RNA-Seq to identify transcriptome changes from late embryonic to adult mouse muscle and demonstrated calcineurin isoforms and their broader impact of alternative splicing during muscle postnatal development.

SLC8A1 Preparation Options

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Reference

1. Brinegar A E, et al. (2017). Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions. elife. 6, e27192.

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