Q7RTT9 · S29A4_HUMAN
- ProteinEquilibrative nucleoside transporter 4
- GeneSLC29A4
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids530 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Utilizes the physiologic inside-negative membrane potential as a driving force to facilitate cellular uptake of organic cations (PubMed:15448143, PubMed:20592246, PubMed:22396231).
Functions as a Na+- and Cl--independent bidirectional transporter (PubMed:15448143, PubMed:16099839, PubMed:22396231, PubMed:31537831).
Substrate transport is pH-dependent and enhanced under acidic condition, which is most likely the result of allosteric changes in the transporter structure (PubMed:16873718, PubMed:17018840, PubMed:20592246, PubMed:22396231, PubMed:31537831).
Implicated in monoamine neurotransmitters uptake such as serotonin, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, histamine and tyramine, thereby supporting a role in homeostatic regulation of aminergic neurotransmission in the central nervous system (PubMed:15448143, PubMed:16099839, PubMed:17018840, PubMed:17121826, PubMed:20858707, PubMed:22396231).
Also responsible for the uptake of bioactive amines and drugs through the blood-cerebrospinal fluid (CSF) barrier, from the CSF into choroid plexus epithelial cells, thereby playing a significant role in the clearance of cationic neurotoxins, xenobiotics and metabolic waste in the brain (By similarity).
Involved in bidirectional transport of the purine nucleoside adenosine and plays a role in the regulation of extracellular adenosine concentrations in cardiac tissues, in particular during ischemia (PubMed:16873718, PubMed:20592246, PubMed:31537831).
May be involved in organic cation uptake from the tubular lumen into renal tubular cells, thereby contributing to organic cation reabsorption in the kidney (PubMed:17018840).
Also transports guanidine (PubMed:16099839).
Miscellaneous
Mediates the uptake of neurotoxin 1-methyl-4-phenylpyridinium (MPP+) (PubMed:15448143, PubMed:16099839, PubMed:17018840, PubMed:17121826, PubMed:20592246, PubMed:20858707, PubMed:23255610).
Catalytic activity
- serotonin(out) = serotonin(in)
- dopamine(out) = dopamine(in)
- (R)-noradrenaline(out) = (R)-noradrenaline(in)
- (R)-adrenaline(out) = (R)-adrenaline(in)
- histamine(out) = histamine(in)
- tyramine(in) = tyramine(out)
- guanidine(out) = guanidine(in)
- adenosine(in) = adenosine(out)This reaction proceeds in the forward and the backward directions.
Activity regulation
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
114 μM | serotonin | 7.4 | ||||
283 μM | serotonin | 7.4 | ||||
1900 μM | serotonin | 5.5 | ||||
283 μM | tyramine | 7.4 | ||||
329 μM | dopamine | 7.4 | ||||
406 μM | dopamine | 7.4 | ||||
15323 μM | adrenaline | 7.4 | ||||
951 μM | adrenaline | 7.4 | ||||
1078 μM | noradrenaline | 7.4 | ||||
2606 μM | noradrenaline | 7.4 | ||||
10471 μM | histamine | 7.4 | ||||
4379 μM | histamine | 7.4 | ||||
15323 μM | histamine | 7.4 | ||||
413 μM | adenosine | 7.4 | ||||
780 μM | adenosine | 5.5 |
Vmax | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|
2.01 nmol/min/mg | 7.4 | for adenosine uptake | |||
14.19 nmol/min/mg | 7.4 | for serotonin uptake | |||
6.5 nmol/min/mg | 7.4 | for serotonin uptake | |||
5.05 nmol/min/mg | 7.4 | for tyramine uptake | |||
22.4 nmol/min/mg | 7.4 | for dopamine uptake | |||
18.2 nmol/min/mg | 7.4 | for dopamine uptake | |||
38.4 nmol/min/mg | 7.4 | for adrenaline uptake | |||
7.25 nmol/min/mg | 7.4 | for adrenaline uptake | |||
20.6 nmol/min/mg | 7.4 | for noradrenaline uptake | |||
8.82 nmol/min/mg | 7.4 | for noradrenaline uptake | |||
99.61 nmol/min/mg | 7.4 | for histamine uptake | |||
42.37 nmol/min/mg | 7.4 | for histamine uptake |
pH Dependence
Optimum pH is 6.6 for adenosine, serotonin and inosine uptake (PubMed:20592246).
Optimum pH is 6.0 for adenosine uptake (PubMed:16873718, PubMed:31537831).
Does not transport adenosine at pH 7.4 (PubMed:16873718).
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 206 | Essential for cation selectivity | ||||
Sequence: E |
GO annotations
Keywords
- Biological process
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameEquilibrative nucleoside transporter 4
- Short nameshENT4
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ7RTT9
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Targeted to the apical membranes of differentiated kidney epithelial cells (PubMed:17018840).
Localized to the apical blood-cerebrospinal fluid (CSF)-facing membrane of the choroid plexus epithelium (PubMed:23255610).
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-68 | Extracellular | ||||
Sequence: MGSVGSQRLEEPSVAGTPDPGVVMSFTFDSHQLEEAAEAAQGQGLRARGVPAFTDTTLDEPVPDDRYH | ||||||
Transmembrane | 69-89 | Helical | ||||
Sequence: AIYFAMLLAGVGFLLPYNSFI | ||||||
Topological domain | 90-101 | Cytoplasmic | ||||
Sequence: TDVDYLHHKYPG | ||||||
Transmembrane | 102-122 | Helical | ||||
Sequence: TSIVFDMSLTYILVALAAVLL | ||||||
Topological domain | 123-139 | Extracellular | ||||
Sequence: NNVLVERLTLHTRITAG | ||||||
Transmembrane | 140-160 | Helical | ||||
Sequence: YLLALGPLLFISICDVWLQLF | ||||||
Topological domain | 161-166 | Cytoplasmic | ||||
Sequence: SRDQAY | ||||||
Transmembrane | 167-187 | Helical | ||||
Sequence: AINLAAVGTVAFGCTVQQSSF | ||||||
Topological domain | 188-231 | Extracellular | ||||
Sequence: YGYTGMLPKRYTQGVMTGESTAGVMISLSRILTKLLLPDERAST | ||||||
Transmembrane | 232-252 | Helical | ||||
Sequence: LIFFLVSVALELLCFLLHLLV | ||||||
Topological domain | 253-351 | Cytoplasmic | ||||
Sequence: RRSRFVLFYTTRPRDSHRGRPGLGRGYGYRVHHDVVAGDVHFEHPAPALAPNESPKDSPAHEVTGSGGAYMRFDVPRPRVQRSWPTFRALLLHRYVVAR | ||||||
Transmembrane | 352-372 | Helical | ||||
Sequence: VIWADMLSIAVTYFITLCLFP | ||||||
Topological domain | 373-381 | Extracellular | ||||
Sequence: GLESEIRHC | ||||||
Transmembrane | 382-402 | Helical | ||||
Sequence: ILGEWLPILIMAVFNLSDFVG | ||||||
Topological domain | 403-416 | Cytoplasmic | ||||
Sequence: KILAALPVDWRGTH | ||||||
Transmembrane | 417-437 | Helical | ||||
Sequence: LLACSCLRVVFIPLFILCVYP | ||||||
Topological domain | 438-450 | Extracellular | ||||
Sequence: SGMPALRHPAWPC | ||||||
Transmembrane | 451-471 | Helical | ||||
Sequence: IFSLLMGISNGYFGSVPMILA | ||||||
Topological domain | 472-486 | Cytoplasmic | ||||
Sequence: AGKVSPKQRELAGNT | ||||||
Transmembrane | 487-509 | Helical | ||||
Sequence: MTVSYMSGLTLGSAVAYCTYSLT | ||||||
Topological domain | 510-530 | Extracellular | ||||
Sequence: RDAHGSCLHASTANGSILAGL |
Keywords
- Cellular component
Disease & Variants
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_040044 | 79 | in dbSNP:rs17854505 | |||
Sequence: V → E | ||||||
Mutagenesis | 91 | No significant change in dopamine, serotonin and MPP+ uptake. | ||||
Sequence: D → A | ||||||
Mutagenesis | 107 | Loss of dopamine, serotonin and MPP+ uptake. | ||||
Sequence: D → A | ||||||
Natural variant | VAR_040045 | 124 | in dbSNP:rs17855675 | |||
Sequence: N → K | ||||||
Mutagenesis | 128 | No significant change in dopamine, serotonin and MPP+ uptake. | ||||
Sequence: E → A | ||||||
Mutagenesis | 154 | Loss of dopamine, serotonin and MPP+ uptake; increased uridine uptake. | ||||
Sequence: D → A | ||||||
Mutagenesis | 163 | Loss of dopamine, serotonin and MPP+ uptake. | ||||
Sequence: D → A | ||||||
Mutagenesis | 206 | Loss of dopamine, serotonin and MPP+ uptake; gain of uridine transport activity. | ||||
Sequence: E → A | ||||||
Mutagenesis | 206 | No change in dopamine, serotonin and MPP+ uptake; no uridine uptake activity. | ||||
Sequence: E → D | ||||||
Mutagenesis | 206 | Loss of dopamine, serotonin, adenosine and MPP+ uptake; gain of uridine transport activity. | ||||
Sequence: E → Q | ||||||
Mutagenesis | 206 | Loss of dopamine, serotonin and MPP+ uptake; no uridine uptake activity. | ||||
Sequence: E → R | ||||||
Mutagenesis | 220 | Reduced dopamine, serotonin and MPP+ uptake. | ||||
Sequence: T → A | ||||||
Mutagenesis | 220 | Loss of dopamine, serotonin and MPP+ uptake. | ||||
Sequence: T → I | ||||||
Mutagenesis | 220 | Reduced dopamine, serotonin and MPP+ uptake. | ||||
Sequence: T → S | ||||||
Mutagenesis | 227 | Functional with slight increased dopamine, serotonin and MPP+ uptake. | ||||
Sequence: E → A | ||||||
Mutagenesis | 242 | Reduced dopamine, serotonin and MPP+ uptake. | ||||
Sequence: E → A | ||||||
Mutagenesis | 336 | Loss of dopamine, serotonin and MPP+ uptake. | ||||
Sequence: W → A | ||||||
Mutagenesis | 375 | Functional with increased dopamine, serotonin and MPP+ uptake. | ||||
Sequence: E → A | ||||||
Mutagenesis | 375 | No change in adenosine uptake. | ||||
Sequence: E → Q | ||||||
Natural variant | VAR_040046 | 429 | in dbSNP:rs17857336 | |||
Sequence: P → T |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 868 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue (large scale data), glycosylation.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000326251 | 1-530 | UniProt | Equilibrative nucleoside transporter 4 | |||
Sequence: MGSVGSQRLEEPSVAGTPDPGVVMSFTFDSHQLEEAAEAAQGQGLRARGVPAFTDTTLDEPVPDDRYHAIYFAMLLAGVGFLLPYNSFITDVDYLHHKYPGTSIVFDMSLTYILVALAAVLLNNVLVERLTLHTRITAGYLLALGPLLFISICDVWLQLFSRDQAYAINLAAVGTVAFGCTVQQSSFYGYTGMLPKRYTQGVMTGESTAGVMISLSRILTKLLLPDERASTLIFFLVSVALELLCFLLHLLVRRSRFVLFYTTRPRDSHRGRPGLGRGYGYRVHHDVVAGDVHFEHPAPALAPNESPKDSPAHEVTGSGGAYMRFDVPRPRVQRSWPTFRALLLHRYVVARVIWADMLSIAVTYFITLCLFPGLESEIRHCILGEWLPILIMAVFNLSDFVGKILAALPVDWRGTHLLACSCLRVVFIPLFILCVYPSGMPALRHPAWPCIFSLLMGISNGYFGSVPMILAAGKVSPKQRELAGNTMTVSYMSGLTLGSAVAYCTYSLTRDAHGSCLHASTANGSILAGL | |||||||
Modified residue (large scale data) | 306 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 310 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Glycosylation | 523 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N |
Post-translational modification
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
In brain, expressed in cerebellum, cerebral cortex, medulla oblongata, occipital pole, frontal and temporal lobes putamen, spinal cord, substancia nigra, hippocampus, caudate nucleus, nucleus accumbens, pons and choroid plexus (PubMed:15448143, PubMed:16873718, PubMed:20858707, PubMed:23255610).
Expressed in heart, in both cardiomyocytes and vascular endothelial cells (PubMed:15448143, PubMed:16873718, PubMed:20858707).
Also expressed in adrenal gland, small intestine, pancreas, kidney, liver, bone marrow, lymph node (PubMed:15448143, PubMed:16873718, PubMed:17018840, PubMed:20858707).
Located in endometrial stroma, where the expression is high in the proliferative phase, decreases during the secretory phase, and is no longer detectable in the menstrual phase (PubMed:17393420).
Gene expression databases
Organism-specific databases
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-21 | Disordered | ||||
Sequence: MGSVGSQRLEEPSVAGTPDPG |
Domain
Sequence similarities
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q7RTT9-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length530
- Mass (Da)58,059
- Last updated2003-12-15 v1
- Checksum3FE5D5ED1D248A13
Q7RTT9-2
- Name2
- Differences from canonical
- 139-182: GYLLALGPLLFISICDVWLQLFSRDQAYAINLAAVGTVAFGCTV → ASATCGCSSSLGTRPTPSTWPLWAPWPSAA
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Sequence caution
Features
Showing features for sequence conflict, alternative sequence.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 25 | in Ref. 2; BAC03836 | ||||
Sequence: S → C | ||||||
Sequence conflict | 41 | in Ref. 2; BAC03836 | ||||
Sequence: Q → R | ||||||
Alternative sequence | VSP_032647 | 139-182 | in isoform 2 | |||
Sequence: GYLLALGPLLFISICDVWLQLFSRDQAYAINLAAVGTVAFGCTV → ASATCGCSSSLGTRPTPSTWPLWAPWPSAA | ||||||
Sequence conflict | 196 | in Ref. 2; BAC03836 | ||||
Sequence: K → R | ||||||
Sequence conflict | 261 | in Ref. 2; BAC11612 | ||||
Sequence: Y → H | ||||||
Sequence conflict | 301 | in Ref. 2; BAC03836 | ||||
Sequence: L → P |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AY485959 EMBL· GenBank· DDBJ | AAS65965.1 EMBL· GenBank· DDBJ | mRNA | ||
AK075422 EMBL· GenBank· DDBJ | BAC11612.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AK092242 EMBL· GenBank· DDBJ | BAC03836.1 EMBL· GenBank· DDBJ | mRNA | ||
CH471144 EMBL· GenBank· DDBJ | EAW87329.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471144 EMBL· GenBank· DDBJ | EAW87330.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC025325 EMBL· GenBank· DDBJ | AAH25325.1 EMBL· GenBank· DDBJ | mRNA | ||
BC047592 EMBL· GenBank· DDBJ | AAH47592.1 EMBL· GenBank· DDBJ | mRNA | ||
BK000627 EMBL· GenBank· DDBJ | DAA00308.1 EMBL· GenBank· DDBJ | Genomic DNA |