SLC6A2 (NET1): Norepinephrine Transporter Gene - Structure, Function, and Clinical Significance
Comprehensive biomedical reference for SLC6A2, encoding the norepinephrine transporter (NET), with curated data from NCBI, Ensembl, UniProt, OMIM, HGNC, COSMIC, and ClinVar.
Gene Information Card
| Symbol | SLC6A2 |
|---|---|
| Full Name | solute carrier family 6 member 2 |
| Gene Type | protein coding |
| Chromosomal Location | 16q12.2 (GRCh38) |
| NCBI Gene ID | 6530 ncbi.nlm.nih.gov/gene/6530 |
| Ensembl ID | ENSG00000103546 |
| UniProt ID | P23975 |
| OMIM ID | 163970 |
| HGNC ID | 11048 |
| Aliases | NET1, NET, SLC6A5, hNET |
Description
The SLC6A2 gene encodes the norepinephrine transporter (NET), a member of the sodium:neurotransmitter symporter family. NET is a presynaptic plasma membrane protein that terminates noradrenergic signaling by high-affinity reuptake of norepinephrine (and to a lesser extent dopamine) into presynaptic terminals. It is a key regulator of synaptic norepinephrine levels and a major target for antidepressants (e.g., tricyclics, SNRIs) and psychostimulants (e.g., cocaine, amphetamines). Mutations in SLC6A2 are associated with orthostatic intolerance and have been implicated in neuropsychiatric disorders such as ADHD and depression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Orthostatic intolerance | Loss-of-function mutations reduce norepinephrine reuptake, leading to elevated synaptic norepinephrine and sympathetic overactivity. | ClinVar; OMIM (163970); Shannon et al. (2000) Nat Genet; multiple case reports. |
| Attention deficit hyperactivity disorder (ADHD) | Genetic variants (e.g., rs5569, rs2242446) may alter transporter expression/function, affecting norepinephrine signaling in prefrontal cortex. | Association studies; meta-analyses (e.g., Gizer et al. 2009); ClinVar. |
| Major depressive disorder | Altered NET function influences noradrenergic transmission; SLC6A2 variants may modulate antidepressant response. | Pharmacogenetic studies; ClinVar. |
| Postural tachycardia syndrome (POTS) | Hypofunctional NET variants lead to impaired norepinephrine clearance, contributing to tachycardia and orthostatic symptoms. | Case studies; ClinVar. |
| Epilepsy | Rare variants may affect neurotransmitter homeostasis, but evidence is limited. | ClinVar (some variants reported). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Adrenal gland | 12.4 | Medium |
| Brain (cerebral cortex) | 8.9 | Low |
| Heart | 5.2 | Low |
| Kidney | 3.1 | Low |
| Liver | 1.2 | Not detected |
| Lung | 0.8 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.3 | High expression; used as neuronal model |
| SK-N-SH (neuroblastoma) | 12.1 | High expression |
| HUVEC (endothelial) | 0.5 | Very low |
| HeLa (cervical carcinoma) | 0.2 | Not expressed |
| A549 (lung carcinoma) | 0.1 | Not expressed |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.147C>A (p.Asn49Lys) | Missense | Rare (MAF <0.01%) | Loss of function; reduced cell surface expression and transport activity; associated with orthostatic intolerance. |
| c.602G>A (p.Arg201His) | Missense | Rare | Loss of function; impaired norepinephrine uptake. |
| c.1165G>A (p.Val389Ile) | Missense | Common (MAF ~5%) | Reduced transport activity; associated with ADHD and altered antidepressant response. |
| c.1287G>A (p.Pro429Pro) | Synonymous | Common (MAF ~30%) | No functional effect; used as a genetic marker (rs5569). |
| c.1804C>T (p.Arg602*) | Nonsense | Very rare | Loss of function; truncated protein; severe orthostatic intolerance. |
Mutation functional classification
Loss of Function (LOF)
Most reported pathogenic mutations (e.g., p.Asn49Lys, p.Arg201His, p.Arg602*) result in loss of norepinephrine transport function, leading to elevated synaptic norepinephrine and sympathetic hyperreactivity.
Gain of Function (GOF)
No clear gain-of-function mutations have been documented; some variants may increase expression but are not clinically characterized.
Dominant Negative (DN)
No evidence for dominant-negative effects; SLC6A2 is not known to form oligomers that would cause dominant-negative interference.
View complete mutation data：
Gene Ontology (GO)
| • norepinephrine:sodium symporter activity | • dopamine:sodium symporter activity |
| • neurotransmitter transporter activity | • plasma membrane |
| • integral component of plasma membrane | • response to cocaine |
| • norepinephrine transport | • dopamine transport |
| • synaptic transmission | • noradrenergic |
| • monoamine transport |
Pathways
• Norepinephrine neurotransmitter release cycle
• Dopamine neurotransmitter release cycle
• Synaptic vesicle cycle
• Monoamine transport
• Cocaine addiction
• Antidepressant action (SNRIs)
Protein Summary
The norepinephrine transporter (NET) is a 617-amino acid integral membrane protein with 12 transmembrane domains. It belongs to the SLC6 family and couples the transport of norepinephrine to the inward sodium and chloride gradients. NET is expressed primarily in noradrenergic neurons of the brain and sympathetic nerves, as well as in adrenal medulla and placenta. It plays a critical role in maintaining neurotransmitter homeostasis and is a target for various therapeutic and abused drugs. Post-translational modifications include glycosylation and phosphorylation, which regulate its trafficking and activity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SLC6A2 Knockout HEK293 Cell Line | EDJ-KQ3598 | Human | 6530 | Details Get a Quote |
| SLC6A20 Knockout HEK293 Cell Line | EDJ-KQ15286 | Human | 54716 | Details Get a Quote |
| SLC6A20 Knockout HCT 116 Cell Line | EDJ-KQ45984 | Human | 54716 | Details Get a Quote |
| SLC6A2 Knockout HeLa Cell Line | EDJ-KQ54491 | Human | 6530 | Details Get a Quote |
| SLC6A20 Knockout HeLa Cell Line | EDJ-KQ56460 | Human | 54716 | Details Get a Quote |
| SLC6A2 Knockout A-549 Cell Line | EDJ-KQ62977 | Human | 6530 | Details Get a Quote |
| SLC6A20 Knockout A-549 Cell Line | EDJ-KQ64953 | Human | 54716 | Details Get a Quote |
| SLC6A2 Knockout HCT 116 Cell Line | EDJ-KQ71448 | Human | 6530 | Details Get a Quote |
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