Details for: SLC8B1

Gene ID: 80024

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: SLC8B1

Ensembl ID: ENSG00000089060

Description: solute carrier family 8 member B1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • Kupffer cell CL0000091
    CSI 4.97
    rCSI 11.36%
    PRS 85.35
  • double negative thymocyte CL0002489
    CSI 4.37
    rCSI 3.04%
    PRS 93.95
  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI 3.78
    rCSI 2.72%
    PRS 94.63
  • squamous epithelial cell CL0000076
    CSI 3.74
    rCSI 8.87%
    PRS 83.3
  • cerebellar granule cell CL0001031
    CSI 3.61
    rCSI 5.31%
    PRS 77.91
  • central memory CD4-positive, alpha-beta T cell CL0000904
    CSI 3.47
    rCSI 2.05%
    PRS 96.28
  • inflammatory macrophage CL0000863
    CSI 3.46
    rCSI 5.91%
    PRS 95.54
  • alternatively activated macrophage CL0000890
    CSI 3.36
    rCSI 4.22%
    PRS 91.99
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 3.26
    rCSI 3.93%
    PRS 90.93
  • pro-B cell CL0000826
    CSI 3.24
    rCSI 2.68%
    PRS 86.64
  • naive T cell CL0000898
    CSI 3.09
    rCSI 2.15%
    PRS 95.09
  • melanocyte CL0000148
    CSI 3.06
    rCSI 2.26%
    PRS 78.77
  • lung secretory cell CL1000272
    CSI 2.92
    rCSI 7.22%
    PRS 84.64
  • epithelial cell of lower respiratory tract CL0002632
    CSI 2.77
    rCSI 2.14%
    PRS 87.69
  • small pre-B-II cell CL0000954
    CSI 2.55
    rCSI 2.45%
    PRS 94.31
  • glial cell CL0000125
    CSI 2.53
    rCSI 9.63%
    PRS 76.09
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.53
    rCSI 2.19%
    PRS 87.75
  • vascular leptomeningeal cell CL4023051
    CSI 2.51
    rCSI 4.41%
    PRS 79.05
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.48
    rCSI 3.09%
    PRS 65.83
  • hepatic stellate cell CL0000632
    CSI 2.38
    rCSI 8.9%
    PRS 77.71
  • chondrocyte CL0000138
    CSI 2.37
    rCSI 3.76%
    PRS 78.09
  • alveolar type 1 fibroblast cell CL4028004
    CSI 2.32
    rCSI 2.54%
    PRS 86.08
  • alveolar macrophage CL0000583
    CSI 2.19
    rCSI 3.61%
    PRS 87.68
  • double-positive, alpha-beta thymocyte CL0000809
    CSI 2.18
    rCSI 2.22%
    PRS 92.08
  • secretory cell CL0000151
    CSI 2.15
    rCSI 2.25%
    PRS 83.68
  • extravillous trophoblast CL0008036
    CSI 2.15
    rCSI 2.66%
    PRS 82.68
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 1.93
    rCSI 5.03%
    PRS 85.48
  • common myeloid progenitor CL0000049
    CSI 1.9
    rCSI 1.54%
    PRS 86.5
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 1.87
    rCSI 2.45%
    PRS 92.87
  • elicited macrophage CL0000861
    CSI 1.86
    rCSI 1.71%
    PRS 90.9
  • colon epithelial cell CL0011108
    CSI 1.83
    rCSI 1.91%
    PRS 81.82
  • lung macrophage CL1001603
    CSI 1.8
    rCSI 4.03%
    PRS 90.55
  • Langerhans cell CL0000453
    CSI 1.79
    rCSI 2.74%
    PRS 93.09
  • intestine goblet cell CL0019031
    CSI 1.78
    rCSI 1.58%
    PRS 82.06
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 1.72
    rCSI 4.44%
    PRS 80.39
  • kidney connecting tubule epithelial cell CL1000768
    CSI 1.7
    rCSI 4.3%
    PRS 75.94
  • intermediate monocyte CL0002393
    CSI 1.62
    rCSI 2.45%
    PRS 89.32
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 1.6
    rCSI 1.23%
    PRS 87.68
  • ependymal cell CL0000065
    CSI 1.55
    rCSI 3.14%
    PRS 64.31
  • blood vessel smooth muscle cell CL0019018
    CSI 1.47
    rCSI 11.99%
    PRS 79.52
  • dendritic cell, human CL0001056
    CSI 1.31
    rCSI 2.01%
    PRS 91.45
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.27
    rCSI 2.85%
    PRS 68.79
  • lymphoid lineage restricted progenitor cell CL0000838
    CSI 1.24
    rCSI 4.84%
    PRS 95.75
  • large pre-B-II cell CL0000957
    CSI 1.21
    rCSI 3.46%
    PRS 87.91
  • late pro-B cell CL0002048
    CSI 1.14
    rCSI 2.86%
    PRS 94.22
  • myeloid dendritic cell CL0000782
    CSI 1.08
    rCSI 1.57%
    PRS 94.46
  • stromal cell of ovary CL0002132
    CSI 0.92
    rCSI 2.54%
    PRS 89.5
  • colon macrophage CL0009038
    CSI 0.69
    rCSI 3.19%
    PRS 93.88
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.64
    rCSI 3.79%
    PRS 68.33
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.58
    rCSI 2.09%
    PRS 65.83

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Analyzed for its specificity (CSI Z-Score), the gene [SLC8B1](/details-gene/80024) is revealed to be a broadly expressed gene with very low cell-type specificity. It encodes the protein NCLX, the primary mitochondrial sodium/calcium exchanger responsible for extruding calcium from the mitochondrial matrix. Its widespread expression pattern across diverse cell lineages, including immune, epithelial, and neuronal cells, is consistent with its foundational role in mitochondrial calcium homeostasis, a process fundamental to cellular bioenergetics, signaling, and survival. ## Cellular Roles and Expression Landscape The expression profile of [SLC8B1](/details-gene/80024), when analyzed through the lens of cell-type specificity, underscores its role as a housekeeping or foundational gene rather than a specific cell-type marker. The **Overall** context analysis shows that despite being expressed in a wide variety of cells, its CSI (Z-SCORE) is 0.00 across all top-ranked cell types, and the associated p-values are non-significant (p > 0.6). This indicates that the expression of [SLC8B1](/details-gene/80024) is not a statistically distinguishing feature for any single cell type. The list of cells with detectable expression is notably diverse, including immune cells like [Kupffer cell](/details-cell/CL0000091), [inflammatory macrophage](/details-cell/CL0000863), and various T-cell subsets such as [CD4-positive, alpha-beta memory T cell](/details-cell/CL0000897). It is also found in non-immune cells like [cerebellar granule cell](/details-cell/CL0001031) and [squamous epithelial cell](/details-cell/CL0000076). This broad expression landscape is consistent with the ubiquitous need for mitochondria and the tight regulation of mitochondrial calcium, which is critical for processes ranging from ATP production to the prevention of apoptosis. Therefore, [SLC8B1](/details-gene/80024) does not serve to define a cell's unique identity but rather supports a function common to most metabolically active cells. ## Pathways and Molecular Function The functional annotations for [SLC8B1](/details-gene/80024) strongly align with its observed broad expression and its established role as the mitochondrial Na+/Ca2+ exchanger, NCLX. Its primary function is captured by Gene Ontology terms such as '[Calcium export from the mitochondrion](/details-go/GO:0099093)' and '[Mitochondrial calcium ion homeostasis](/details-go/GO:0051560)', localizing its activity to the '[mitochondrial inner membrane](/details-go/GO:0005743)'. This molecular function has been extensively validated in the literature, establishing NCLX as the essential component for this transport process ([PubMed: 20018762](https://pubmed.ncbi.nlm.nih.gov/20018762/)). Reactome pathway analysis further situates [SLC8B1](/details-gene/80024) within the broader context of ion transport, specifically '[Mitochondrial calcium ion transport](/details-pathway/R-HSA-8949215)' and '[Sodium/calcium exchangers](/details-pathway/R-HSA-425561)'. The biological consequences of this core function are far-reaching, impacting processes such as '[regulation of insulin secretion](/details-go/GO:0050796)' in pancreatic cells ([PubMed: 23056385](https://pubmed.ncbi.nlm.nih.gov/23056385/)), '[regulation of lymphocyte chemotaxis](/details-go/GO:1901623)', and neuronal survival ([PubMed: 26440884](https://pubmed.ncbi.nlm.nih.gov/26440884/)). This explains its necessity in the diverse cell types observed in the expression profile, from immune cells requiring metabolic flexibility for activation and migration to neurons that must avoid calcium-induced excitotoxicity. ## Research Directions Given its fundamental role in mitochondrial physiology, research on [SLC8B1](/details-gene/80024) can illuminate how diverse cell types manage bioenergetic and signaling demands. The broad but vital nature of this gene suggests that its dysregulation could contribute to a wide range of pathologies. ### Testable Hypotheses: 1. **Hypothesis:** The activity of [SLC8B1](/details-gene/80024) is a critical bottleneck in T-cell exhaustion. Chronic antigen stimulation leads to sustained high cytosolic Ca2+, causing mitochondrial Ca2+ overload that [SLC8B1](/details-gene/80024) activity cannot fully compensate for, resulting in mitochondrial dysfunction, reduced ATP production, and an exhausted phenotype. * **Experimental Approach:** Utilize a model of T-cell exhaustion (e.g., chronic LCMV infection in mice or in-vitro chronic stimulation of human T cells). Overexpress [SLC8B1](/details-gene/80024) using a lentiviral vector in T cells and assess markers of exhaustion (PD-1, TIM-3), cytokine production (IFN-gamma), and metabolic fitness (e.g., Seahorse metabolic flux analysis) compared to control cells. 2. **Hypothesis:** In macrophages, the direction of [SLC8B1](/details-gene/80024)-mediated ion exchange is context-dependent and helps dictate polarization. In pro-inflammatory (M1) macrophages, relative Na+ accumulation in the matrix may promote Ca2+ efflux via [SLC8B1](/details-gene/80024) to sustain metabolic activity, while in anti-inflammatory (M2) macrophages, altered ion gradients may limit its activity to support oxidative phosphorylation. * **Experimental Approach:** Isolate human monocytes and differentiate them into M1 (LPS/IFN-gamma) and M2 (IL-4/IL-13) macrophages. Use pharmacological inhibitors of [SLC8B1](/details-gene/80024) (e.g., CGP-37157) or siRNA-mediated knockdown and measure the impact on the expression of M1/M2 markers, cytokine secretion, and key metabolic pathways like glycolysis and oxidative phosphorylation. 3. **Hypothesis:** The expression of [SLC8B1](/details-gene/80024) in [cerebellar granule cell](/details-cell/CL0001031) is neuroprotective against age-related decline. A gradual decrease in [SLC8B1](/details-gene/80024) expression or function during aging lowers the threshold for mitochondrial calcium overload, making these neurons more vulnerable to excitotoxic stress and contributing to cerebellar ataxia. * **Experimental Approach:** Quantify [SLC8B1](/details-gene/80024) transcript and protein levels in cerebellar tissue from young versus aged mice. Create a conditional knockout of [SLC8B1](/details-gene/80024) specifically in cerebellar granule cells and assess motor coordination (e.g., rotarod test) and neuronal viability over the lifespan of the animals, with and without a mild excitotoxic challenge. ### Therapeutic Potential: The central role of [SLC8B1](/details-gene/80024) in preventing mitochondrial calcium overload makes it a compelling therapeutic target. Small molecule activators could be beneficial in conditions characterized by mitochondrial dysfunction, such as Parkinson's disease, where they might protect dopaminergic neurons from cell death ([PubMed: 26440884](https://pubmed.ncbi.nlm.nih.gov/26440884/)). Conversely, inhibitors could be explored in cancers that rely on mitochondrial calcium signaling for proliferation and survival. However, the gene's ubiquitous and critical function presents a major challenge for systemic therapies, as off-target effects could be significant. Developing cell-type-specific delivery systems or identifying modulators that act only under specific pathological conditions will be crucial for translating [SLC8B1](/details-gene/80024)-targeted therapies into clinical practice.

Genular Protein ID: 1739315139

Symbol: NCLX_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q6J4K2 A6NP50 Q4KMS9 Q6J4K1 Q9H6I8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CTD 1 ChEBI 8 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 4 ExpressionAtlas 1 GO 21 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 2 RefSeq 5 Rhea 4 SIGNOR 1 STRING 1 SignaLink 1 SwissPalm 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 15060069

Title: Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger.

PubMed ID: 15060069

DOI: 10.1074/jbc.m401229200

PubMed ID: 16541075

Title: The finished DNA sequence of human chromosome 12.

PubMed ID: 16541075

DOI: 10.1038/nature04569

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 20018762

Title: NCLX is an essential component of mitochondrial Na+/Ca2+ exchange.

PubMed ID: 20018762

DOI: 10.1073/pnas.0908099107

PubMed ID: 22829870

Title: The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic beta-cells.

PubMed ID: 22829870

DOI: 10.1371/journal.pone.0039722

PubMed ID: 23056385

Title: The mitochondrial na(+)/ca(2+) exchanger upregulates glucose dependent ca(2+) signalling linked to insulin secretion.

PubMed ID: 23056385

DOI: 10.1371/journal.pone.0046649

PubMed ID: 24898248

Title: NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state.

PubMed ID: 24898248

DOI: 10.1074/jbc.m113.540898

PubMed ID: 26440884

Title: PKA phosphorylation of NCLX reverses mitochondrial calcium overload and depolarization, promoting survival of PINK1-deficient dopaminergic neurons.

PubMed ID: 26440884

DOI: 10.1016/j.celrep.2015.08.079

PubMed ID: 28130126

Title: Identification of residues that control Li+ versus Na+ dependent Ca2+ exchange at the transport site of the mitochondrial NCLX.

PubMed ID: 28130126

DOI: 10.1016/j.bbamcr.2017.01.011

PubMed ID: 28219928

Title: Mitochondria control store-operated Ca(2+) entry through Na(+) and redox signals.

PubMed ID: 28219928

DOI: 10.15252/embj.201592481

Sequence Information:

  • Length: 584
  • Mass: 64231
  • Checksum: 6B7008661CC12872
  • Sequence:
    • MAGRRLNLRW ALSVLCVLLM AETVSGTRGS STGAHISPQF PASGVNQTPV VDCRKVCGLN 
VSDRCDFIRT NPDCHSDGGY LDYLEGIFCH FPPSLLPLAV TLYVSWLLYL FLILGVTAAK 
FFCPNLSAIS TTLKLSHNVA GVTFLAFGNG APDIFSALVA FSDPHTAGLA LGALFGAGVL 
VTTVVAGGIT ILHPFMAASR PFFRDIVFYM VAVFLTFLML FRGRVTLAWA LGYLGLYVFY 
VVTVILCTWI YQRQRRGSLF CPMPVTPEIL SDSEEDRVSS NTNSYDYGDE YRPLFFYQET 
TAQILVRALN PLDYMKWRRK SAYWKALKVF KLPVEFLLLL TVPVVDPDKD DQNWKRPLNC 
LHLVISPLVV VLTLQSGTYG VYEIGGLVPV WVVVVIAGTA LASVTFFATS DSQPPRLHWL 
FAFLGFLTSA LWINAAATEV VNILRSLGVV FRLSNTVLGL TLLAWGNSIG DAFSDFTLAR 
QGYPRMAFSA CFGGIIFNIL VGVGLGCLLQ ISRSHTEVKL EPDGLLVWVL AGALGLSLVF 
SLVSVPLQCF QLSRVYGFCL LLFYLNFLVV ALLTEFGVIH LKSM