Serotonin transporter protein (SERT)

The serotonin transporter protein, abbreviated as **SERT** and classified as a sodium-dependent serotonin transporter or solute carrier family 6 member 4 (**SLC6A4**), is an integral membrane protein responsible for the reuptake of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) from the synaptic cleft back into presynaptic neurons[1][3][4][5]. This process is crucial for terminating serotonergic signaling and recycling serotonin for reuse. SERT is a member of the SLC6 family of neurotransmitter transporters, characterized by 12 transmembrane domains and a transport mechanism dependent on sodium and chloride gradients[2][3][4]. SERT is the primary target for many antidepressant agents, especially SSRIs and tricyclic antidepressants, which inhibit the transporter and thereby increase serotonin availability in the synaptic cleft to enhance neurotransmission. It is also targeted by psychostimulants such as cocaine and methamphetamine, which block or reverse serotonin uptake[1][5][7]. Alterations in SERT function, including those due to genetic polymorphisms, are associated with susceptibility to a variety of neuropsychiatric conditions, such as depression, anxiety, PTSD, and others[1][4]. In addition to its role in neurons, SERT functions in platelets to mediate serotonin uptake and storage, contributing to vascular tone and platelet aggregation. Structural studies have elucidated the binding sites for drugs and highlighted its mechanism of action through alternating-access transport powered by ion gradients[3][6][8].

Other names

sodium-dependent serotonin transportersolute carrier family 6 member 4SLC6A45-HT transporter5-HTT

Inhibition of serotonin reuptake to increase synaptic serotonin levels (primary mechanism for SSRIs, SNRIs, tricyclics) Competitive inhibition at the central binding site Allosteric inhibition at extracellular allosteric site (secondary binding site for some inhibitors) Competitive substrate binding (for drugs like amphetamines and cocaine)