SLC6A4 (Sodium-Dependent Serotonin Transporter SERT Gene)
SLC6A4 (solute carrier family 6 member 4; HGNC:11050, NCBI Gene ID 6532) is a human locus mapped to chromosome band 17q11.2 that encodes 12-transmembrane Na+/Cl--dependent serotonin transporter SERT (630 aa). SLC6A4 acts in presynaptic serotonin (5-HT) reuptake & platelet serotonin storage, together with Serotonin Transporter (SERT) Pharmacology, Serotonin, and Serotonin 5-HT2A Receptor. Encodes the presynaptic serotonin transporter (SERT), the primary molecular target of SSRI antidepressants.
Approved Symbol
SLC6A4
Chromosomal Locus
17q11.2
Encoded Product
12-transmembrane Na+/Cl--dependent serotonin transporter SERT (630 aa)
Genomic Organization & Cytogenetic Locus: 14-exon gene spanning ~37.8 kb on chromosome 17q11.2, containing an upstream polymorphic GC-rich repetitive element (5-HTTLPR, short 14-repeat vs. long 16-repeat alleles, further stratified by rs25531) and an intron 2 variable number tandem repeat (STin2).
Cellular & Tissue Expression Profile: Expressed on presynaptic axon terminals and somatodendritic membranes of dorsal and median raphe serotonergic neurons projecting throughout the brain, enterochromaffin-adjacent enteric neurons, pulmonary vascular endothelium, and circulating blood platelets.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Operates via an alternating-access LeuT-fold symport mechanism that couples the inward electrochemical gradient of one Na+ ion and one Cl- ion (with counter-transport of one K+ ion) to drive high-affinity reuptake of synaptic serotonin (5-hydroxytryptamine) back into the presynaptic terminal, terminating serotonergic signaling.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Coding gain-of-function variants (such as p.Gly56Ala and p.Ile425Val) that alter PKG/p38-MAPK phosphorylation and constitutively elevate SERT surface transport have been identified in families with autism spectrum disorder and obsessive-compulsive disorder.
Therapeutic & Clinical Pharmacology: Direct high-affinity binding site of selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline, escitalopram, paroxetine), serotonin-norepinephrine reuptake inhibitors (SNRIs: venlafaxine, duloxetine), and tricyclic antidepressants, which lock SERT in an outward-open conformation.