SLC4A5

Summary

SLC4A5 (solute carrier family 4 member 5, HGNC:18168) is a protein-coding gene on chromosome 2p13.1, encoding Electrogenic sodium bicarbonate cotransporter 4 (Q9BY07). Mediates sodium- and bicarbonate-dependent electrogenic sodium bicarbonate cotransport, with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3.

This gene encodes a member of the sodium bicarbonate cotransporter (NBC) family, part of the bicarbonate transporter superfamily. Sodium bicarbonate cotransporters are involved in intracellular pH regulation and electroneural or electrogenic sodium bicarbonate transport. This protein is thought to be an integral membrane protein. Multiple transcript variants encoding different isoforms have been found for this gene, but the biological validity of some variants has not been determined.

Source: NCBI Gene 57835 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 210 total
• MANE Select transcript: NM_133478

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18168
Approved symbol	SLC4A5
Name	solute carrier family 4 member 5
Location	2p13.1
Locus type	gene with protein product
Status	Approved
Aliases	NBC4
Ensembl gene	ENSG00000188687
Ensembl biotype	protein_coding
OMIM	606757
Entrez	57835

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000346834, ENST00000358683, ENST00000377632, ENST00000377634, ENST00000394019, ENST00000423644, ENST00000425249, ENST00000432728, ENST00000436454, ENST00000444570, ENST00000479776, ENST00000480696, ENST00000483195, ENST00000637036, ENST00000964339

RefSeq mRNA: 3 — MANE Select: NM_133478 NM_001386136, NM_021196, NM_133478

CCDS: CCDS1936, CCDS1937

Canonical transcript exons

ENST00000394019 — 31 exons

Exon	Start	End
ENSE00001517249	74342458	74342534
ENSE00001517250	74343356	74343416
ENSE00001876001	74216242	74218792
ENSE00003463331	74252974	74253128
ENSE00003471789	74285773	74285902
ENSE00003473323	74338855	74338903
ENSE00003473558	74262137	74262232
ENSE00003484679	74259588	74259643
ENSE00003485393	74222868	74222952
ENSE00003495498	74232469	74232647
ENSE00003497877	74304489	74304680
ENSE00003516310	74227810	74227878
ENSE00003518432	74255775	74255932
ENSE00003551001	74247036	74247307
ENSE00003554765	74254619	74254706
ENSE00003563593	74252179	74252388
ENSE00003565270	74265104	74265264
ENSE00003566073	74226957	74227130
ENSE00003593017	74264147	74264299
ENSE00003609066	74241994	74242052
ENSE00003619592	74328120	74328186
ENSE00003620082	74250343	74250517
ENSE00003621581	74314945	74315025
ENSE00003623409	74248353	74248486
ENSE00003629814	74334027	74334177
ENSE00003637831	74221434	74221501
ENSE00003639252	74239335	74239535
ENSE00003641525	74231236	74231308
ENSE00003671177	74233402	74233563
ENSE00003685941	74235101	74235214
ENSE00003745640	74224840	74224995

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 91.77.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3901 / max 221.5614, expressed in 97 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29169	0.1309	16
29177	0.0610	20
29176	0.0482	15
29178	0.0390	4
29174	0.0331	17
29173	0.0217	8
29172	0.0146	9
29170	0.0138	5
29168	0.0110	5
29175	0.0101	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	91.77	gold quality
thyroid gland	UBERON:0002046	87.92	gold quality
right lobe of thyroid gland	UBERON:0001119	87.84	gold quality
left lobe of thyroid gland	UBERON:0001120	87.64	gold quality
right testis	UBERON:0004534	83.83	gold quality
left testis	UBERON:0004533	83.66	gold quality
testis	UBERON:0000473	83.42	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.68	gold quality
corpus callosum	UBERON:0002336	78.12	gold quality
tibial nerve	UBERON:0001323	77.44	gold quality
cerebellar hemisphere	UBERON:0002245	77.30	gold quality
cerebellar cortex	UBERON:0002129	77.23	gold quality
right hemisphere of cerebellum	UBERON:0014890	77.14	gold quality
cerebellum	UBERON:0002037	77.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.66	gold quality
calcaneal tendon	UBERON:0003701	75.15	gold quality
pituitary gland	UBERON:0000007	74.14	gold quality
right uterine tube	UBERON:0001302	74.10	gold quality
mucosa of stomach	UBERON:0001199	73.19	gold quality
skin of leg	UBERON:0001511	73.15	gold quality
adenohypophysis	UBERON:0002196	72.92	gold quality
ventricular zone	UBERON:0003053	72.77	gold quality
subcutaneous adipose tissue	UBERON:0002190	72.38	gold quality
zone of skin	UBERON:0000014	72.35	gold quality
blood	UBERON:0000178	72.35	gold quality
popliteal artery	UBERON:0002250	72.32	gold quality
tibial artery	UBERON:0007610	72.32	gold quality
bone marrow cell	CL:0002092	72.22	gold quality
cortical plate	UBERON:0005343	72.11	gold quality
skeletal muscle tissue	UBERON:0001134	71.45	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.48

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 8)

• Genomic organization of the DCTN1-SLC4A5 locus encoding both NBC4 and p150(Glued). (PMID:12063394)
• These results additionally confirm the involvement of SLC4A5 with blood pressure control, although the mechanism is still unclear. (PMID:16365189)
• Summarizing, the observed associations with resting and submaximal-exercise cardiovascular and metabolic traits in the HERITAGE Family Study are likely due to neither variation in the promoter nor known coding SNPs of SLC4A5 (PMID:19384345)
• The additive effect of rs10177833 of SLC4A5 on systolic blood pressure is statistically different between women with dark skin color and women with medium skin color (P = .0153). (PMID:22764636)
• Data indicate that 2 SNPs in SLC4A5 (rs7571842 and rs10177833) showed highly significant results and large effects sizes. (PMID:22987918)
• we summarize the potential function of NBCe2 in the regulation of blood pressure, acid-base, and K(+) and Ca(2+) transport in the distal nephron–{REVIEW} (PMID:26136555)
• NBCe2 could be important in proximal kidney tubule apical sodium and bicarbonate cotransport under high-salt conditions. (PMID:26447209)
• NBCe2 activity is stimulated by an increase in intracellular sodium and is hyper-responsive in hRPTCs carrying HV SLC4A5 rs7571842 through an aberrant HNF4A-mediated mechanism (PMID:29642240)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc4a5a	ENSDARG00000002771
danio_rerio	slc4a5b	ENSDARG00000104387
mus_musculus	Slc4a5	ENSMUSG00000068323
rattus_norvegicus	Slc4a5	ENSRNOG00000010378
drosophila_melanogaster	Ae2	FBGN0036043
drosophila_melanogaster	Ndae1	FBGN0259111
caenorhabditis_elegans	abts-1	WBGENE00009920
caenorhabditis_elegans		WBGENE00019844

Paralogs (9): SLC4A1 (ENSG00000004939), SLC4A7 (ENSG00000033867), SLC4A8 (ENSG00000050438), SLC4A4 (ENSG00000080493), SLC4A11 (ENSG00000088836), SLC4A9 (ENSG00000113073), SLC4A3 (ENSG00000114923), SLC4A10 (ENSG00000144290), SLC4A2 (ENSG00000164889)

Protein

Protein identifiers

Electrogenic sodium bicarbonate cotransporter 4 — Q9BY07 (reviewed: Q9BY07)

Alternative names: NBCe2, Solute carrier family 4 member 5

All UniProt accessions (7): A0A1B0GUV9, A0A1B0GVY3, C9JNL6, C9JU12, C9JW32, E7EQT3, Q9BY07

UniProt curated annotations — full annotation on UniProt →

Function. Mediates sodium- and bicarbonate-dependent electrogenic sodium bicarbonate cotransport, with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3.

Subcellular location. Apical cell membrane. Basolateral cell membrane.

Tissue specificity. Highest expression observed in liver, spleen and testis; moderate expression in the choroid plexus, hippocampus, cerebrum and cerebellum of brain, and in kidney cortex and kidney medulla. Also observed in heart, pancreas, muscle, lung, placenta, stomach and small intestine. Weakest expression seen in peripheral blood lymphocytes, colon, duodenum, jejunum, ileum and skeletal muscle. Expressed in the brain, heart, kidney, testis, pancreas, muscle and peripheral blood leukocytes.

Activity regulation. Activity is inhibited by 4,4’-di-isothiocyanatostilbene-2,2’-disulfonic acid (DIDS - an inhibitor of several anion channels and transporters). Activity is inhibited by 4,4’-di-isothiocyanatostilbene-2,2’-disulfonic acid (DIDS - an inhibitor of several anion channels and transporters). Activity is inhibited by 4,4’-di-isothiocyanatostilbene-2,2’-disulfonic acid (DIDS - an inhibitor of several anion channels and transporters).

Miscellaneous. Incomplete sequence.

Similarity. Belongs to the anion exchanger (TC 2.A.31) family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q9BY07-1	1, NBC4a	yes
Q9BY07-2	2, NBC4b
Q9BY07-3	3, NBC4c
Q9BY07-4	4, NBC4d
Q9BY07-5	5, isoform d variant
Q9BY07-6	6, NBC4f
Q9BY07-7	7
Q9BY07-8	8, NBC4e

RefSeq proteins (3): NP_001373065, NP_067019, NP_597812* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003020	HCO3_transpt_euk	Family
IPR003024	Na/HCO3_transpt	Family
IPR011531	HCO3_transpt-like_TM_dom	Domain
IPR013769	Band3_cytoplasmic_dom	Domain
IPR016152	PTrfase/Anion_transptr	Homologous_superfamily

Pfam: PF00955, PF07565

Catalyzed reactions (Rhea), 2 shown:

• 2 hydrogencarbonate(out) + Na(+)(out) = 2 hydrogencarbonate(in) + Na(+)(in) (RHEA:72215)
• 3 hydrogencarbonate(out) + Na(+)(out) = 3 hydrogencarbonate(in) + Na(+)(in) (RHEA:72219)

UniProt features (54 total): topological domain 13, transmembrane region 12, splice variant 12, sequence conflict 6, region of interest 5, compositionally biased region 3, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BY07-F1	69.27	0.18

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-425381	Bicarbonate transporters
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 148 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_MONOATOMIC_CATION_TRANSPORT, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, WTGAAAT_UNKNOWN, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_BICARBONATE_TRANSPORT, GOBP_SECRETION, APPIERTO_RESPONSE_TO_FENRETINIDE_DN, SANSOM_APC_TARGETS_DN, GOBP_REGULATION_OF_PH

GO Biological Process (16): epithelial cell development (GO:0002064), renal system process (GO:0003014), regulation of systemic arterial blood pressure (GO:0003073), regulation of gene expression (GO:0010468), bicarbonate transport (GO:0015701), cerebrospinal fluid secretion (GO:0033326), mitochondrion distribution (GO:0048311), regulation of intracellular pH (GO:0051453), transmembrane transport (GO:0055085), retina development in camera-type eye (GO:0060041), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), monoatomic anion transport (GO:0006820), inorganic anion transport (GO:0015698), sodium ion transmembrane transport (GO:0035725), monoatomic anion transmembrane transport (GO:0098656)

GO Molecular Function (6): solute:inorganic anion antiporter activity (GO:0005452), monoatomic anion transmembrane transporter activity (GO:0008509), sodium:bicarbonate symporter activity (GO:0008510), bicarbonate transmembrane transporter activity (GO:0015106), antiporter activity (GO:0015297), solute:sodium symporter activity (GO:0015370)

GO Cellular Component (4): plasma membrane (GO:0005886), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
SLC-mediated transport of inorganic anions	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	4
plasma membrane region	2
epithelial cell differentiation	1
cell development	1
system process	1
regulation of blood pressure	1
gene expression	1
regulation of macromolecule biosynthetic process	1
body fluid secretion	1
secretion by tissue	1
mitochondrion localization	1
regulation of pH	1
intracellular monoatomic cation homeostasis	1
regulation of biological quality	1
cellular process	1
camera-type eye development	1
anatomical structure development	1
metal ion transport	1
monoatomic ion transport	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic anion transport	1
monoatomic ion transmembrane transport	1
antiporter activity	1
monoatomic ion transmembrane transporter activity	1
monoatomic anion transmembrane transport	1
solute:sodium symporter activity	1
monoatomic cation:bicarbonate symporter activity	1
bicarbonate transport	1
transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
solute:monoatomic cation symporter activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1
basal plasma membrane	1
apical part of cell	1

Protein interactions and networks

STRING

1134 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC4A5	ALMS1	Q8TCU4	824
SLC4A5	DCTN1	Q14203	776
SLC4A5	SLC9A1	P19634	566
SLC4A5	SLC12A2	P55011	552
SLC4A5	SLC26A9	Q7LBE3	544
SLC4A5	SLC35A5	Q9BS91	508
SLC4A5	SLC9A3	P48764	500
SLC4A5	SLC12A4	Q9UP95	493
SLC4A5	SLC9A2	Q9UBY0	492
SLC4A5	SLC12A7	Q9Y666	479
SLC4A5	SLC26A4	O43511	476
SLC4A5	SLC26A6	Q9BXS9	475
SLC4A5	ACTR1A	P42024	469
SLC4A5	SLC26A7	Q8TE54	463
SLC4A5	SLC33A1	O00400	456
SLC4A5	SLC67A1	Q96BI1	456

IntAct

25 interactions, top by confidence:

A	B	Type	Score
SLC4A5	RBP1	psi-mi:“MI:0915”(physical association)	0.400
SLC4A5	E6	psi-mi:“MI:0915”(physical association)	0.370
SLC4A5	ESYT2	psi-mi:“MI:0914”(association)	0.350
AGO2	DDX39A	psi-mi:“MI:0914”(association)	0.350
FBXW7	SLC4A5	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	SLC4A5	psi-mi:“MI:2364”(proximity)	0.270
SLC4A5	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	SLC4A5	psi-mi:“MI:2364”(proximity)	0.270
SPOP	SLC4A5	psi-mi:“MI:2364”(proximity)	0.270
SLC4A5	SPOP	psi-mi:“MI:2364”(proximity)	0.270
EGFR	SLC4A5	psi-mi:“MI:2364”(proximity)	0.270
SLC4A5	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
SLC4A5	TP53	psi-mi:“MI:2364”(proximity)	0.270
SLC4A5	PTEN	psi-mi:“MI:2364”(proximity)	0.270
SLC4A5	AKT1	psi-mi:“MI:2364”(proximity)	0.270
BRAF	SLC4A5	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (123): SLC4A5 (Affinity Capture-RNA), RBP1 (Affinity Capture-MS), SLC4A5 (Affinity Capture-MS), SLC4A5 (Reconstituted Complex), SLC4A5 (Affinity Capture-RNA), SLC4A5 (Affinity Capture-MS), SLC4A5 (Two-hybrid), ABCE1 (Affinity Capture-MS), AGTPBP1 (Affinity Capture-MS), ALDH2 (Affinity Capture-MS), APOBEC3C (Affinity Capture-MS), ASNS (Affinity Capture-MS), C1GALT1C1 (Affinity Capture-MS), CADM1 (Affinity Capture-MS), CAMLG (Affinity Capture-MS)

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: A0A096X8J7, A0A494BA31, B1MTL0, E9Q3M5, O13134, O18917, O88343, P02730, P04919, P04920, P13808, P15575, P16283, P23347, P23348, P23562, P32847, P48746, P48751, Q2Y0W8, Q32LP4, Q4U116, Q5DTL9, Q5RB85, Q5RD44, Q6RI88, Q6RVG2, Q6SJP2, Q6U841, Q80ZA5, Q8BTY2, Q8JZR6, Q8K4V2, Q96Q91, Q9BY07, Q9GKY1, Q9GL77, Q9JI66, Q9R1N3, Q9XSZ4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	158
Likely benign	25
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001825 (2:74241422 C>T), RS1000047194 (2:74330154 C>G), RS1000110285 (2:74284730 T>A,C), RS1000165986 (2:74291716 C>T), RS1000228520 (2:74265786 A>C), RS1000251787 (2:74260575 C>T), RS1000276708 (2:74242430 C>A,T), RS1000277372 (2:74217499 T>G), RS1000309562 (2:74272034 G>A,C), RS1000340475 (2:74278196 T>C), RS1000352661 (2:74228812 A>G), RS1000385278 (2:74318420 C>G,T), RS1000429302 (2:74325855 G>A), RS1000482992 (2:74325567 C>G), RS1000483992 (2:74330435 G>T)

Disease associations

OMIM: gene MIM:606757 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Sodium-dependent HCO₃^- transporters

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases methylation	2
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
sodium arsenite	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects methylation	1
Arsenicals	increases expression	1
Clorgyline	increases expression	1
Gasoline	decreases expression, increases abundance, affects cotreatment	1
Malathion	decreases expression	1
Phthalic Acids	decreases methylation	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Smoke	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
1-Butanol	decreases expression, increases abundance, affects cotreatment	1
Acrylamide	decreases expression	1
S-Nitrosoglutathione	increases expression	1
Particulate Matter	affects cotreatment, decreases expression, increases abundance	1

Clinical trials (associated diseases)

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