SLC8A1

Summary

SLC8A1 (solute carrier family 8 member A1, HGNC:11068) is a protein-coding gene on chromosome 2p22.1, encoding Sodium/calcium exchanger 1 (P32418). Mediates the exchange of one Ca(2+) ion against three to four Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes.

In cardiac myocytes, Ca(2+) concentrations alternate between high levels during contraction and low levels during relaxation. The increase in Ca(2+) concentration during contraction is primarily due to release of Ca(2+) from intracellular stores. However, some Ca(2+) also enters the cell through the sarcolemma (plasma membrane). During relaxation, Ca(2+) is sequestered within the intracellular stores. To prevent overloading of intracellular stores, the Ca(2+) that entered across the sarcolemma must be extruded from the cell. The Na(+)-Ca(2+) exchanger is the primary mechanism by which the Ca(2+) is extruded from the cell during relaxation. In the heart, the exchanger may play a key role in digitalis action. The exchanger is the dominant mechanism in returning the cardiac myocyte to its resting state following excitation.

Source: NCBI Gene 6546 — RefSeq curated summary.

At a glance

• GWAS associations: 52
• Clinical variants (ClinVar): 137 total
• Druggable target: yes
• MANE Select transcript: NM_021097

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11068
Approved symbol	SLC8A1
Name	solute carrier family 8 member A1
Location	2p22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000183023
Ensembl biotype	protein_coding
OMIM	182305
Entrez	6546

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 36 protein_coding, 1 nonsense_mediated_decay

ENST00000332839, ENST00000402441, ENST00000403092, ENST00000405269, ENST00000405901, ENST00000406391, ENST00000406785, ENST00000407929, ENST00000408028, ENST00000417271, ENST00000448531, ENST00000455476, ENST00000705225, ENST00000705281, ENST00000705282, ENST00000705283, ENST00000705603, ENST00000705604, ENST00000705605, ENST00000952074, ENST00000952075, ENST00000952076, ENST00000952077, ENST00000952078, ENST00000952079, ENST00000952080, ENST00000952081, ENST00000952082, ENST00000952083, ENST00000952084, ENST00000952085, ENST00000952086, ENST00000952087, ENST00000952088, ENST00000952089, ENST00000952090, ENST00000952091

RefSeq mRNA: 23 — MANE Select: NM_021097 NM_001112800, NM_001112801, NM_001112802, NM_001252624, NM_001351483, NM_001351484, NM_001351485, NM_001351486, NM_001351487, NM_001351488, NM_001351489, NM_001351490, NM_001351491, NM_001351492, NM_001351493, NM_001351494, NM_001372263, NM_001394103, NM_001394104, NM_001394105, NM_001394106, NM_001394107, NM_021097

CCDS: CCDS1806, CCDS46264, CCDS46265, CCDS59430, CCDS92742, CCDS92743, CCDS92744, CCDS92745, CCDS92746

Canonical transcript exons

ENST00000332839 — 11 exons

Exon	Start	End
ENSE00001294421	40175261	40175281
ENSE00001312640	40170281	40170349
ENSE00001327652	40178387	40178493
ENSE00001384190	40428473	40430304
ENSE00002494453	40174706	40174720
ENSE00003963718	40451904	40452090
ENSE00003993274	40097270	40115629
ENSE00003993276	40174825	40174842
ENSE00003993278	40139401	40139676
ENSE00003993279	40164854	40164984
ENSE00003993280	40160765	40160864

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 97.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.8674 / max 925.4548, expressed in 1075 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27962	6.8571	977
27967	1.8016	119
27959	0.7471	312
27961	0.6557	233
27963	0.5194	315
27964	0.4269	266
27958	0.1994	89
27960	0.1992	89
27938	0.1492	60
27965	0.1265	27

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	97.94	gold quality
adrenal tissue	UBERON:0018303	96.21	gold quality
endothelial cell	CL:0000115	96.06	gold quality
saphenous vein	UBERON:0007318	95.84	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.59	gold quality
colonic epithelium	UBERON:0000397	94.48	gold quality
vena cava	UBERON:0004087	93.77	gold quality
myocardium	UBERON:0002349	93.59	gold quality
postcentral gyrus	UBERON:0002581	93.36	gold quality
parietal lobe	UBERON:0001872	93.09	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.99	gold quality
middle temporal gyrus	UBERON:0002771	92.88	gold quality
urethra	UBERON:0000057	92.42	gold quality
entorhinal cortex	UBERON:0002728	92.34	gold quality
substantia nigra pars compacta	UBERON:0001965	91.99	gold quality
medial globus pallidus	UBERON:0002477	91.75	gold quality
stromal cell of endometrium	CL:0002255	91.74	gold quality
cardiac atrium	UBERON:0002081	91.45	gold quality
cardiac ventricle	UBERON:0002082	91.42	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.30	gold quality
heart left ventricle	UBERON:0002084	91.19	gold quality
right atrium auricular region	UBERON:0006631	90.98	gold quality
heart	UBERON:0000948	90.71	gold quality
superior frontal gyrus	UBERON:0002661	90.38	gold quality
substantia nigra pars reticulata	UBERON:0001966	90.16	gold quality
cauda epididymis	UBERON:0004360	89.91	gold quality
monocyte	CL:0000576	89.25	gold quality
seminal vesicle	UBERON:0000998	89.09	gold quality
buccal mucosa cell	CL:0002336	88.98	gold quality
mononuclear cell	CL:0000842	88.89	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	21858.48
E-GEOD-131882	yes	20294.84
E-CURD-135	yes	965.34
E-HCAD-35	yes	58.15
E-HCAD-10	yes	38.79
E-HCAD-25	yes	14.37
E-MTAB-9067	yes	11.04
E-ANND-3	yes	9.35
E-HCAD-30	no	1905.31
E-MTAB-7381	no	497.59
E-GEOD-98556	no	261.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
ATP2B1	Unknown

Upstream regulators (CollecTRI, top): AP1, AR, ATP1B1, EGR1, ESR1, GATA4, HIF1A, JUN, JUNB, NKX2-5, RCOR2, REST, SRF

miRNA regulators (miRDB)

185 targeting SLC8A1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3692-3P	99.98	70.27	2139

Literature-anchored findings (GeneRIF, showing 40)

• data are consistent with a stoichiometry for the NCX1.1 protein of 4 Na+ to 1 Ca2+ to 2 charges moved per transport cycle (PMID:11916852)
• Na/Ca exchanger overexpression, by depleting ER Ca(2+) stores, triggers the activation of caspase-12 and increases apoptotic cell death (PMID:12031969)
• Characterization and functional activity of a truncated Na/Ca exchange isoform resulting from a new splicing pattern (PMID:12502539)
• functional and physical interaction of nonselective TRPC cation channels with NCX proteins as a novel principle of TRPC-mediated Ca(2+) signaling. (PMID:14736881)
• collagen-induced increase in Ca2+ in platelets is dependent on concentration of Na+ in the extracellular milieu: the collagen-induced increase in Ca2+ causes reversal of the NCX, resulting in an increase in Ca2+ and platelet aggregation (PMID:14981087)
• Overexpression increases apoptosis induced by endoplasmic reticulum ca-atpase inhibitors and activates caspase-12 (PMID:15033764)
• Ca(2+) entry mode operation of the Na(+)/Ca(2+) exchanger is required for des-Arg(10)-kallidin- and TGF-beta1-stimulated fibrogenesis and participates in the maintenance of the myofibroblast phenotype (PMID:15703175)
• NCX1 is one of the genes related to susceptibility to essential hypertension in the Japanese general population. (PMID:15785003)
• an ankyrin-B-based macromolecular complex of Na/K ATPase, Na/Ca exchanger 1, and InsP3 receptor that is localized in cardiomyocyte T-tubules in discrete microdomains distinct from classic dihydropyridine receptor/ryanodine receptor “dyads (PMID:16292983)
• These results highlight the importance of ionic regulation in controlling NCX1 activity under conditions that promote Ca2+ overload. (PMID:16399865)
• plasma membrane Na+/Ca2+ exchangers have inhibitory interactions with the 14-3-3 proteins (PMID:16679322)
• PLM interacts with the intracellular loop of NCX1, most likely at residues 218-358 (PMID:16921169)
• Results describe the involvement of the Na+-Ca2+ exchanger as well as the role of non-selective-cation channels in cardiac myofibroblast cell function in vitro. (PMID:17541957)
• NKCC1 in conjunction with NCX1 plays a role in reperfusion-induced brain injury after ischemia. (PMID:17912271)
• Data show that activity of beta-cell NCX1 splice variants is modulated by acyl-CoAs and is dependent upon the intrinsic properties of the NCX1 splice variant and on the side chain length and degree of saturation of the acyl-CoA moiety. (PMID:18635667)
• Membrane targeting and coupling of NHE1-integrinalphaIIbbeta3-NCX1 by lipid rafts following integrin-ligand interactions trigger Ca2+ oscillations. (PMID:18996841)
• Results indicate the nuclear NCX/GM1 complex acts to gate Ca(2+) transfer from cytosol to ER, an alternate route to the sarcoplasmic/endoplasmic reticulum calcium ATPase pump. (PMID:19541636)
• These results suggest that recovery from intracellular acidosis causes a transient increase in cytosolic Ca(2+) due to reversal of Ca(2+) transport via Na(+)/Ca(2+) exchanger coactivated with Na(+)/H(+) exchanger, which can cause cell death. (PMID:19830548)
• Results show that the Na(+)/Ca(2+) exchanger NCLX is enriched in mitochondria, where it is localized to the cristae. (PMID:20018762)
• characterization of NCX1 intronic hypervariable non-coding region enriched in human-specific indel variants (PMID:20109173)
• NCX1 protein expression in urinary bladder smooth muscle increases approximately 4-fold in NCX1.3 transgenic mice compared to that in wild-type. (PMID:20173311)
• Taken together, these data demonstrate a potentially important role for NCX1 in control of Ca2+ homeostasis and link store depletion via STIM1 directly with NCX activation. (PMID:21126331)
• Immunohistochemical analysis revealed thatNCKX3 and NCX1 were abundantly localized in the cytoplasm of luminal and glandular epithelial uterine cells throughout the menstrual cycle. NCX1 expression was not affected by estradiol and progesterone. (PMID:21321244)
• Results demonstrate a selective regulation of NCX1, NCX2 and NCX3 isoforms in Alzheimer’s disease cortex, specifically in terminals containing amyloid-beta. (PMID:21382638)
• an increase in the NCX1 mRNA due to the apoptosis induction is not regulated by HIF-1alpha (PMID:21613675)
• Human platelets express K(+) -independent Na(+) /Ca(2+) exchangers NCX1.3, NCX3.2 and NCX3.4. (PMID:21790537)
• There were no differences of gene frequency between Alzheimer disease cases and controls for any of three polymorphisms of NCX1 gene. However, among AD patients whose age at onset (AAO) was >65 years, carriers of a 14 bp insertion showed a lower AAO. (PMID:21833492)
• Data suggest that NCX-mediated Ca(2+) fluxes normally exist in human ASM (potentially contributing to rapid Ca(2+) fluxes), and contribute to enhanced Ca(2+) regulation in airway inflammation. (PMID:21858195)
• Ca(2+) influx through reverse mode NCX is required for the activation and the targeting of PKCalpha to the plasma membrane, an essential step for VEGF-induced ERK1/2 phosphorylation and downstream EC functions in angiogenesis (PMID:21873429)
• an essential component in the mechanism governing cardiac steroid-induced slow Ca(2+) oscillations (PMID:21930298)
• a novel function for NHE1 and NCX1 in membrane blebbing and permeability, and establish a link between membrane blebbing and integrin signaling. (PMID:22270364)
• NCX1 is upregulated in chronic atrial fibrillation. A larger I(NCX) for a given SR Ca(2+) release contributes to AF-promoting atrial delayed afterdepolarizations/triggered activity in cAF patients. (PMID:22456474)
• interaction of NCX1 and EAAC1 transporters leads to glutamate-enhanced ATP production in brain mitochondria (PMID:22479505)
• this study validated the association between a SNP, rs13017846, which maps to near SLC8A1 (sodium/calcium exchanger 1 precursor, overall p = 8.0 x 10(-14)), and the QT interval. (PMID:22726844)
• alpha(2)-Na(+) pumps, NCX1, receptor-operated channels, and the sarcoplasmic reticulum regulate Ca(2+) homeostasis and signaling in human arterial smooth muscle cells. (PMID:22842068)
• these results demonstrate that REST, by regulating NCX1 expression, may represent a potential druggable target for the treatment of brain ischemia (PMID:23069678)
• Ncx1 expression is required for increasing sinus rates and in isolated sinoatrial cells. (PMID:23192947)
• NCX1: mechanism of transport. (PMID:23224869)
• Functional and structural properties of the NCKX2 Na(+)-Ca (2+)/K (+) exchanger: a comparison with the NCX1 Na (+)/Ca (2+) exchanger. (PMID:23224872)
• the transcriptional network regulating Ncx1 expression is also mediating many of the other changes in genetic remodeling contributing to the development of cardiac dysfunction (PMID:23224875)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc8a1a	ENSDARG00000013422
danio_rerio	slc8a1b	ENSDARG00000043406
mus_musculus	Slc8a1	ENSMUSG00000054640
rattus_norvegicus	Slc8a1	ENSRNOG00000008479

Paralogs (7): SLC8A3 (ENSG00000100678), SLC8A2 (ENSG00000118160), FRAS1 (ENSG00000138759), FREM2 (ENSG00000150893), ADGRV1 (ENSG00000164199), FREM1 (ENSG00000164946), FREM3 (ENSG00000183090)

Protein

Protein identifiers

Sodium/calcium exchanger 1 — P32418 (reviewed: P32418)

Alternative names: Na(+)/Ca(2+)-exchange protein 1, Solute carrier family 8 member 1

All UniProt accessions (8): P32418, A0A994J4U7, A0A994J5G5, A0A994J7E1, A0A994J7G2, E7EV41, E9PB98, E9PCL8

UniProt curated annotations — full annotation on UniProt →

Function. Mediates the exchange of one Ca(2+) ion against three to four Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes. Contributes to Ca(2+) transport during excitation-contraction coupling in muscle. In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca(2+) levels due to release of Ca(2+) stores from the endoplasmic reticulum. SLC8A1 mediates the export of Ca(2+) from the cell during the next phase, so that cytoplasmic Ca(2+) levels rapidly return to baseline. Required for normal embryonic heart development and the onset of heart contractions.

Subcellular location. Cell membrane.

Tissue specificity. Detected primarily in heart and at lower levels in brain. Expressed in cardiac sarcolemma, brain, kidney, liver, pancreas, skeletal muscle, placenta and lung.

Activity regulation. Activated by micromolar levels of Ca(2+).

Domain organisation. The cytoplasmic Calx-beta domains bind the regulatory Ca(2+). The first Calx-beta domain can bind up to four Ca(2+) ions. The second domain can bind another two Ca(2+) ions that are essential for calcium-regulated ion exchange.

Similarity. Belongs to the Ca(2+):cation antiporter (CaCA) (TC 2.A.19) family. SLC8 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
P32418-1	1, NaCa1, NCX1.1	yes
P32418-2	3, NaCa3, NCX1.3
P32418-3	7, NaCa7, NCX1.7
P32418-4	10, NaCa10, NCX1.10
P32418-5	5

RefSeq proteins (23): NP_001106271, NP_001106272, NP_001106273, NP_001239553, NP_001338412, NP_001338413, NP_001338414, NP_001338415, NP_001338416, NP_001338417, NP_001338418, NP_001338419, NP_001338420, NP_001338421, NP_001338422, NP_001338423, NP_001359192, NP_001381032, NP_001381033, NP_001381034, NP_001381035, NP_001381036, NP_066920* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001623	DnaJ_domain	Domain
IPR002987	NaCa_exhngr1	Family
IPR003644	Calx_beta	Domain
IPR004836	Na_Ca_Ex	Family
IPR004837	NaCa_Exmemb	Domain
IPR032452	Na_Ca_Ex_C-exten	Domain
IPR038081	CalX-like_sf	Homologous_superfamily
IPR044880	NCX_ion-bd_dom_sf	Homologous_superfamily
IPR051171	CaCA	Family

Pfam: PF01699, PF03160, PF16494

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) + 3 Na(+)(out) = Ca(2+)(out) + 3 Na(+)(in) (RHEA:69955)

UniProt features (126 total): strand 34, binding site 27, helix 25, topological domain 11, transmembrane region 10, splice variant 4, turn 3, repeat 2, domain 2, modified residue 2, glycosylation site 2, signal peptide 1, chain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8SGI	ELECTRON MICROSCOPY	2.9
8SGJ	ELECTRON MICROSCOPY	3.1
8JP0	ELECTRON MICROSCOPY	3.5
9IV8	ELECTRON MICROSCOPY	3.5
8SGT	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P32418-F1	74.64	0.35

Antibody-complex structures (SAbDab): 3 — 8SGI, 8SGJ, 8SGT

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (27): 420; 420; 420; 456; 456; 481; 482; 482; 482; 482; 484; 486 …

Post-translational modifications (2): 285, 392

Glycosylation sites (2): 44, 160

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-418359	Reduction of cytosolic Ca++ levels
R-HSA-425561	Sodium/Calcium exchangers
R-HSA-5578775	Ion homeostasis
R-HSA-109582	Hemostasis
R-HSA-382551	Transport of small molecules
R-HSA-397014	Muscle contraction
R-HSA-418346	Platelet homeostasis
R-HSA-418360	Platelet calcium homeostasis
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 362 (showing top): GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_RESPONSE_TO_MUSCLE_STRETCH, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_RELAXATION_OF_CARDIAC_MUSCLE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION_BY_REGULATION_OF_THE_RELEASE_OF_SEQUESTERED_CALCIUM_ION, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_STRIATED_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE

GO Biological Process (39): regulation of the force of heart contraction (GO:0002026), regulation of heart rate (GO:0002027), monoatomic ion transport (GO:0006811), intracellular calcium ion homeostasis (GO:0006874), intracellular sodium ion homeostasis (GO:0006883), muscle contraction (GO:0006936), regulation of gene expression (GO:0010468), regulation of cell communication by electrical coupling (GO:0010649), regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion (GO:0010881), regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882), vascular associated smooth muscle contraction (GO:0014829), positive regulation of bone mineralization (GO:0030501), cellular response to reactive oxygen species (GO:0034614), sodium ion transmembrane transport (GO:0035725), response to muscle stretch (GO:0035994), sodium ion export across plasma membrane (GO:0036376), relaxation of smooth muscle (GO:0044557), negative regulation of cytosolic calcium ion concentration (GO:0051481), cardiac muscle cell development (GO:0055013), calcium ion homeostasis (GO:0055074), relaxation of cardiac muscle (GO:0055119), cardiac muscle contraction (GO:0060048), calcium ion transport into cytosol (GO:0060402), calcium ion import (GO:0070509), calcium ion transmembrane transport (GO:0070588), cellular response to caffeine (GO:0071313), membrane depolarization during cardiac muscle cell action potential (GO:0086012), cell communication by electrical coupling involved in cardiac conduction (GO:0086064), calcium ion transmembrane import into cytosol (GO:0097553), calcium ion import across plasma membrane (GO:0098703), sodium ion import across plasma membrane (GO:0098719), positive regulation of the force of heart contraction (GO:0098735), calcium ion export (GO:1901660), negative regulation of intracellular signal transduction (GO:1902532), regulation of cardiac conduction (GO:1903779), sodium ion transport (GO:0006814), calcium ion transport (GO:0006816), cell communication (GO:0007154), transmembrane transport (GO:0055085)

GO Molecular Function (9): calcium:sodium antiporter activity (GO:0005432), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), cytoskeletal protein binding (GO:0008092), ankyrin binding (GO:0030506), transmembrane transporter binding (GO:0044325), protein binding (GO:0005515), antiporter activity (GO:0015297), metal ion binding (GO:0046872)

GO Cellular Component (15): nucleoplasm (GO:0005654), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), intercalated disc (GO:0014704), Z disc (GO:0030018), T-tubule (GO:0030315), axon (GO:0030424), dendrite (GO:0030425), sarcolemma (GO:0042383), neuronal cell body (GO:0043025), axon terminus (GO:0043679), synapse (GO:0045202), cell periphery (GO:0071944), postsynapse (GO:0098794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Platelet calcium homeostasis	1
Metal ion SLC transporters	1
Cardiac conduction	1
Hemostasis	1
Platelet homeostasis	1
Transport of small molecules	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
regulation of biological quality	3
protein binding	3
regulation of heart contraction	2
intracellular monoatomic cation homeostasis	2
neuron projection	2
transport	1
calcium ion homeostasis	1
sodium ion homeostasis	1
muscle system process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cell communication by electrical coupling	1
regulation of cell communication	1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of cardiac muscle contraction by calcium ion signaling	1
calcium-mediated signaling	1
regulation of cardiac muscle contraction	1
cardiac muscle contraction	1
smooth muscle contraction	1
vasoconstriction	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1
response to reactive oxygen species	1
cellular response to oxidative stress	1
cellular response to oxygen-containing compound	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
response to mechanical stimulus	1
sodium ion transmembrane transport	1
export across plasma membrane	1
relaxation of muscle	1
striated muscle cell development	1
cardiac cell development	1
cardiac muscle cell differentiation	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
sodium ion transmembrane transporter activity	1

Protein interactions and networks

STRING

1616 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC8A1	RYR2	Q92736	826
SLC8A1	PLN	P26678	815
SLC8A1	ATP2A2	P16614	807
SLC8A1	CACNA1C	Q13936	757
SLC8A1	ATP2B1	P20020	752
SLC8A1	TLX2	O43763	708
SLC8A1	ATP2B2	Q01814	671
SLC8A1	TRPC3	Q13507	664
SLC8A1	TRPC6	Q9Y210	633
SLC8A1	SLC24A1	O60721	615
SLC8A1	TRPV5	Q9NQA5	611
SLC8A1	ATP2A3	Q93084	601
SLC8A1	SLC8B1	Q6J4K2	568
SLC8A1	SCN5A	Q14524	565
SLC8A1	CASQ2	O14958	555
SLC8A1	SLN	O00631	555

IntAct

27 interactions, top by confidence:

A	B	Type	Score
S100A1	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.610
SLC8A1	S100A1	psi-mi:“MI:0915”(physical association)	0.610
S100A5	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.540
ANK2	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A2	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A3	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A4	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A6	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A7	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A8	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A9	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A10	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A11	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A12	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A13	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A14	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100A7A	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100B	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100G	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100P	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
S100Z	SLC8A1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC8A1	SLC8A1	psi-mi:“MI:0915”(physical association)	0.400
SLC8A1	ELP6	psi-mi:“MI:0915”(physical association)	0.400
SLC8A1	SCHIP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): SLC8A1 (Synthetic Lethality), FXYD1 (Affinity Capture-Western), FXYD1 (Reconstituted Complex), CAV3 (Affinity Capture-Western), SLC8A1 (Affinity Capture-MS), SLC8A1 (Positive Genetic), EIF5A (Cross-Linking-MS (XL-MS)), SLC8A1 (Affinity Capture-MS), SLC8A1 (Co-fractionation), SLC8A1 (Co-fractionation), SLC8A1 (Co-fractionation), ST13 (Co-fractionation), TMEM37 (Co-fractionation), ELP6 (Affinity Capture-MS), SLC8A1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A096X8J7, B1MTL0, E9Q3M5, G3X939, M5A7P9, O13134, O18917, O88343, P04919, P13808, P16283, P19334, P23347, P23348, P23562, P23685, P26433, P32418, P32847, P34586, P48746, P48751, P48765, P48766, P48767, P48994, P70414, P90895, Q01728, Q28362, Q2Y0W8, Q32LP4, Q4U116, Q5DTL9, Q5RB85, Q5RD44, Q6RI88, Q6RVG2, Q6SJP2, Q6U841

Diamond homologs: B8K1V7, O22252, O54701, P23685, P32418, P48765, P48766, P48767, P48768, P57103, P70414, P70549, Q01728, Q2R041, Q6H641, Q8BUN9, Q8CGQ8, Q8K596, Q8NFF2, Q99PD7, Q9EPQ0, Q9HC58, Q9UI40, Q9UPR5, Q9VDG5, Q9VN12, S4R2P9, O60721, O46383, P45394, P87122, Q0ZAI3, Q28139, Q49SH1, Q57556, Q71RS6, Q8C261, Q8TPA6, Q91WD8, Q9IAL7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Toll Like Receptor TLR6:TLR2 Cascade	5	73.2×	6e-08
Toll Like Receptor 2 (TLR2) Cascade	5	72.1×	6e-08
Toll Like Receptor TLR1:TLR2 Cascade	5	70.0×	6e-08
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	5	63.4×	9e-08
Toll Like Receptor 4 (TLR4) Cascade	5	54.7×	1e-07
Toll-like Receptor Cascades	5	51.7×	2e-07
Innate Immune System	9	19.1×	1e-09
Neutrophil degranulation	6	11.5×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
endothelial cell migration	7	159.8×	1e-12

Disease & clinical

Clinical variants and AI predictions

ClinVar

137 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	101
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3902 predictions. Top by Δscore:

Variant	Effect	Δscore
2:40115625:TGTGT:T	acceptor_gain	1.0000
2:40115626:GTGT:G	acceptor_gain	1.0000
2:40115627:TGT:T	acceptor_gain	1.0000
2:40115630:C:CC	acceptor_gain	1.0000
2:40139674:CCC:C	acceptor_gain	1.0000
2:40139675:CCC:C	acceptor_gain	1.0000
2:40139675:CCCT:C	acceptor_loss	1.0000
2:40139677:C:CA	acceptor_loss	1.0000
2:40139677:C:CC	acceptor_gain	1.0000
2:40139678:T:A	acceptor_loss	1.0000
2:40160863:CT:C	acceptor_gain	1.0000
2:40164848:GCATA:G	donor_loss	1.0000
2:40164849:CATA:C	donor_loss	1.0000
2:40164850:ATAC:A	donor_loss	1.0000
2:40164851:TA:T	donor_loss	1.0000
2:40164852:A:AG	donor_loss	1.0000
2:40164885:T:TA	donor_gain	1.0000
2:40164980:TTCGT:T	acceptor_gain	1.0000
2:40164981:TCGT:T	acceptor_gain	1.0000
2:40164982:CGT:C	acceptor_gain	1.0000
2:40164982:CGTC:C	acceptor_gain	1.0000
2:40164983:GTC:G	acceptor_loss	1.0000
2:40164984:TC:T	acceptor_loss	1.0000
2:40164985:C:CC	acceptor_gain	1.0000
2:40164987:G:C	acceptor_gain	1.0000
2:40115627:TGTC:T	acceptor_loss	0.9900
2:40115628:GT:G	acceptor_gain	0.9900
2:40115628:GTC:G	acceptor_loss	0.9900
2:40115630:C:CG	acceptor_loss	0.9900
2:40115633:C:CT	acceptor_gain	0.9900

AlphaMissense

6433 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:40115312:A:G	W955R	1.000
2:40115312:A:T	W955R	1.000
2:40115365:A:G	L937P	1.000
2:40115476:A:C	F900C	1.000
2:40115476:A:G	F900S	1.000
2:40115507:C:G	A890P	1.000
2:40115509:G:T	A889D	1.000
2:40115516:A:G	S887P	1.000
2:40115517:C:A	W886C	1.000
2:40115517:C:G	W886C	1.000
2:40115519:A:G	W886R	1.000
2:40115519:A:T	W886R	1.000
2:40115521:G:T	A885D	1.000
2:40115527:C:A	G883V	1.000
2:40115527:C:T	G883D	1.000
2:40115528:C:G	G883R	1.000
2:40115533:C:A	G881V	1.000
2:40115533:C:T	G881E	1.000
2:40115534:C:G	G881R	1.000
2:40115534:C:T	G881R	1.000
2:40115536:A:G	L880P	1.000
2:40115536:A:T	L880Q	1.000
2:40115538:G:C	F879L	1.000
2:40115538:G:T	F879L	1.000
2:40115540:A:G	F879L	1.000
2:40115542:A:T	V878D	1.000
2:40115544:A:C	N877K	1.000
2:40115544:A:T	N877K	1.000
2:40115553:G:C	N874K	1.000
2:40115553:G:T	N874K	1.000

dbSNP variants (sampled 300 via entrez): RS1000002747 (2:40246013 G>A), RS1000003101 (2:40161829 A>G), RS1000029052 (2:40107287 A>G), RS1000029411 (2:40277099 G>A), RS1000038691 (2:40365893 G>C), RS1000039932 (2:40499797 C>A,T), RS1000052226 (2:40303502 A>G), RS1000054549 (2:40177383 G>T), RS1000065280 (2:40495348 A>G), RS1000068180 (2:40366439 A>G), RS1000069159 (2:40278626 T>C), RS1000070368 (2:40336413 C>T), RS1000071337 (2:40467770 T>C), RS1000072568 (2:40112909 T>G), RS1000079250 (2:40282187 G>A)

Disease associations

OMIM: gene MIM:182305 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

52 associations (top):

Study	Trait	p-value
GCST001542_1	HIV-associated dementia	3.000000e-07
GCST001580_1	QT interval	8.000000e-14
GCST001762_799	Obesity-related traits	3.000000e-06
GCST001957_9	Obesity (early onset extreme)	2.000000e-07
GCST002441_11	Immune response to measles-mumps-rubella vaccine	8.000000e-07
GCST002500_15	QT interval	5.000000e-14
GCST002500_28	QT interval	2.000000e-10
GCST002535_1	PR interval	3.000000e-14
GCST002542_4	Electrocardiographic traits	6.000000e-13
GCST002616_14	Mitochondrial DNA levels	8.000000e-06
GCST002704_1	Fractional exhaled nitric oxide levels	9.000000e-07
GCST003831_18	Asthma	5.000000e-06
GCST004280_45	Diastolic blood pressure	4.000000e-08
GCST005080_4	PR interval	2.000000e-09
GCST005171_21	QT interval	8.000000e-11
GCST005235_7	Hand grip strength	8.000000e-09
GCST005348_131	Total body bone mineral density	1.000000e-10
GCST005348_69	Total body bone mineral density	1.000000e-08
GCST005830_41	Hand grip strength	3.000000e-08
GCST006288_227	Heel bone mineral density	3.000000e-10
GCST006288_264	Heel bone mineral density	9.000000e-08
GCST006288_570	Heel bone mineral density	3.000000e-17
GCST006423_16	Fracture	4.000000e-07
GCST006979_918	Heel bone mineral density	1.000000e-20
GCST006979_919	Heel bone mineral density	9.000000e-11
GCST006979_920	Heel bone mineral density	3.000000e-14
GCST006980_1	Fracture	2.000000e-14
GCST007267_284	Systolic blood pressure	3.000000e-11
GCST007576_204	Chronotype	4.000000e-08
GCST007576_364	Chronotype	4.000000e-08

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0004730	hormone measurement
EFO:0004645	response to vaccine
EFO:0004462	PR interval
EFO:0006312	mitochondrial DNA measurement
EFO:0005536	nitric oxide exhalation measurement
EFO:0006336	diastolic blood pressure
EFO:0006941	grip strength measurement
EFO:0009270	heel bone mineral density
EFO:0006335	systolic blood pressure
EFO:0008328	chronotype measurement
EFO:0006917	spontaneous preterm birth
EFO:0010091	tea consumption measurement
EFO:0004872	inflammatory biomarker measurement
EFO:0004644	TPE interval measurement
EFO:0004327	electrocardiography
EFO:0007789	BMI-adjusted waist circumference
EFO:0004980	appendicular lean mass
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4076 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC8 family of sodium/calcium exchangers

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
neurounina-1	Activation	8.85	pEC50
SAR296968	Inhibition	7.13	pIC50

Binding affinities (BindingDB)

360 measured of 360 human assays (360 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-(1,2-oxazol-5-ylmethyl)-2-[[(2S)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazole-4-carboxamide	IC50	92 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]pyridine-3-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]-2-pyridin-3-ylacetamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]-2-pyridin-2-ylacetamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[(2-methylpyrimidin-4-yl)methyl]-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-(1,2-oxazol-5-ylmethyl)-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-(dimethylamino)-4-pyridinyl]methyl]-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[(2S)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-N-(pyridin-4-ylmethyl)-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazol-5-yl]methyl]-2-pyridin-3-ylacetamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]pyridine-3-sulfonamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]-1,2-oxazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-N-(1,2-oxazol-5-ylmethyl)-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
4-methyl-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-N-(pyridin-4-ylmethyl)-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-(pyridin-4-ylmethyl)-2-[(2-thiophen-3-yl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
1-(1,2-oxazol-5-yl)-N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]methanamine	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-(1,2-oxazol-5-ylmethyl)-2-[[(2S)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-(2-hydroxyethyl)-2-[[(2S)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
1-(1,2-oxazol-5-yl)-N-[[2-[[(2S)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazol-5-yl]methyl]methanamine	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
methyl 2-[[2-[[(2S)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazol-5-yl]methylamino]acetate	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[2-[[(2S)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazol-5-yl]methylamino]ethanol	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methylamino]ethanol	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N,N-bis(2-hydroxyethyl)-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
morpholin-4-yl-[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methanone	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-butyl-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-(2-methylpropyl)-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-(2-hydroxyethyl)-2-[[(2S)-2-(2-methylphenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazole-5-carboxamide	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methanamine	IC50	100 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[(2S)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-N-propyl-1,3-thiazole-4-carboxamide	IC50	110 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-(2-hydroxyethyl)-2-[[(2S)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazole-4-carboxamide	IC50	120 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-(2-hydroxypropyl)-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	160 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]-2-pyrrolidin-1-ylacetamide	IC50	170 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[2-(3-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-N-(1,2-oxazol-5-ylmethyl)-1,3-thiazole-5-carboxamide	IC50	180 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[(2-amino-4-pyridinyl)methyl]-2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-N-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-N-(pyridin-4-ylmethyl)-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[(2-morpholin-4-yl-4-pyridinyl)methyl]-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[(4,6-dimethylpyrimidin-2-yl)methyl]-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[(2R)-2-phenyl-3,4-dihydro-2H-chromen-6-yl]oxy]-N-(pyridin-4-ylmethyl)-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[(2-oxo-1H-pyridin-4-yl)methyl]-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazol-5-yl]methyl]pyridine-3-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazol-5-yl]methyl]-2-pyridin-4-ylacetamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
1-methyl-N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]imidazole-4-sulfonamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[(1,5-dimethylpyrazol-4-yl)methyl]-2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-N-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-chromen-6-yl]oxy]-N-[(2-methylpyrimidin-4-yl)methyl]-1,3-thiazole-5-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
3,5-dimethyl-N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]-1,2-oxazole-4-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]pyridine-4-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
3-chloro-N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]pyridine-4-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
N-[[2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]pyrimidine-4-carboxamide	IC50	200 nM	US-8912224: Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals

ChEMBL bioactivities

384 potent at pChembl≥5 of 390 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.16	IC50	70	nM	CHEMBL3662020
7.04	IC50	92	nM	CHEMBL3662028
7.00	IC50	100	nM	CHEMBL3662043
7.00	IC50	100	nM	CHEMBL3657666
7.00	IC50	100	nM	CHEMBL3657667
7.00	IC50	100	nM	CHEMBL3657670
7.00	IC50	100	nM	CHEMBL3657672
7.00	IC50	100	nM	CHEMBL3657675
7.00	IC50	100	nM	CHEMBL3657680
7.00	IC50	100	nM	CHEMBL3657687
7.00	IC50	100	nM	CHEMBL3657696
7.00	IC50	100	nM	CHEMBL3657698
7.00	IC50	100	nM	CHEMBL3657699
7.00	IC50	100	nM	CHEMBL3657700
7.00	IC50	100	nM	CHEMBL3657709
7.00	IC50	100	nM	CHEMBL3657710
7.00	IC50	100	nM	CHEMBL3657801
7.00	IC50	100	nM	CHEMBL3661858
7.00	IC50	100	nM	CHEMBL3661888
7.00	IC50	100	nM	CHEMBL3661894
7.00	IC50	100	nM	CHEMBL3661925
7.00	IC50	100	nM	CHEMBL3661945
7.00	IC50	100	nM	CHEMBL3661987
7.00	IC50	100	nM	CHEMBL3661988
7.00	IC50	100	nM	CHEMBL3661990
7.00	IC50	100	nM	CHEMBL3661992
7.00	IC50	100	nM	CHEMBL3661993
7.00	IC50	100	nM	CHEMBL3662001
6.96	IC50	110	nM	CHEMBL3662026
6.92	IC50	120	nM	CHEMBL3662025
6.80	IC50	160	nM	CHEMBL3662029
6.77	IC50	170	nM	CHEMBL3662021
6.75	IC50	180	nM	CHEMBL3662041
6.70	IC50	200	nM	CHEMBL3657663
6.70	IC50	200	nM	CHEMBL3657668
6.70	IC50	200	nM	CHEMBL3657669
6.70	IC50	200	nM	CHEMBL3657671
6.70	IC50	200	nM	CHEMBL3657679
6.70	IC50	200	nM	CHEMBL3657684
6.70	IC50	200	nM	CHEMBL3657685
6.70	IC50	200	nM	CHEMBL3657688
6.70	IC50	200	nM	CHEMBL3657693
6.70	IC50	200	nM	CHEMBL3657695
6.70	IC50	200	nM	CHEMBL3657697
6.70	IC50	200	nM	CHEMBL3657701
6.70	IC50	200	nM	CHEMBL3657702
6.70	IC50	200	nM	CHEMBL3657705
6.70	IC50	200	nM	CHEMBL3657707
6.70	IC50	200	nM	CHEMBL3657710
6.70	IC50	200	nM	CHEMBL3657714

CTD chemical–gene interactions

60 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, decreases expression, affects cotreatment	7
bisphenol A	decreases expression, increases expression, affects expression, affects cotreatment, affects methylation	4
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
Estradiol	affects cotreatment, increases expression, decreases expression, decreases reaction	3
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Doxorubicin	decreases expression	2
Nickel	increases uptake, decreases expression, increases reaction, decreases reaction	2
Ozone	affects expression, increases abundance, increases expression	2
Silicon Dioxide	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
geldanamycin	increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
cinnamaldehyde	increases expression	1
sodium arsenite	increases abundance, affects cotreatment, decreases expression	1
butyraldehyde	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate	decreases reaction, increases response to substance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
NSC 689534	affects binding, decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 8 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3705519	Binding	Reverse Mode Assay: The assay is based on the monitoring of intracellular Ca2+concentrations using the calcium-sensitive dye Fluo-4. CHO cells expressing NCX1 were loaded with the dye by means of the acetoxymethyl ester Fluo-4 AM (Invitroge	Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals
CHEMBL684973	Functional	Inhibitory activity against Na+/[Ca2+] exchanger after 30 min of K+ free incubation in isolated left atria from guinea pig	Discovery of a novel potent Na+/Ca2+ exchanger inhibitor: design, synthesis and structure-activity relationships of 3,4-dihydro-2(1H)-quinazolinone derivatives. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 1 spontaneously immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1F91	CHO-hNCX1	Spontaneously immortalized cell line	Female
CVCL_D1Z2	Abcam A-549 SLC8A1 KO	Cancer cell line	Male
CVCL_D2D4	Abcam HCT 116 SLC8A1 KO	Cancer cell line	Male
CVCL_D4FG	1321N1-SLC8A1-KO-c4	Cancer cell line	Male
CVCL_D4FH	1321N1-SLC8A1-KO-c7	Cancer cell line	Male
CVCL_D9S5	Ubigene HEK293 SLC8A1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.