Serotonin and Norepinephrine Reuptake Transporters (SERT and NET)

The serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane transport proteins belonging to the neurotransmitter sodium symporter (NSS) family. They are responsible for the sodium- and chloride-dependent reuptake of serotonin and norepinephrine, respectively, from the synaptic cleft into presynaptic neurons. Both transporters share structural similarities, including 12 transmembrane spanning helices, and cycle through outward-open, occluded, and inward-open conformational states during the transport cycle. Substrate binding occurs at a central site (S1). SERT also possesses an allosteric binding site in the extracellular vestibule. These transporters are significant pharmacological targets for drugs used to treat depression, fibromyalgia, and other conditions, including SSRIs (selective SERT inhibitors), SNRIs (inhibiting both SERT and NET), and Tricyclic Antidepressants (blocking both). Psychostimulants like cocaine and methamphetamine also interact with these transporters.

Inhibition of serotonin (by SERT inhibitors) and/or norepinephrine (by NET inhibitors) reuptake from the synaptic cleft into presynaptic neurons, leading to increased extracellular neurotransmitter concentrations. Psychostimulants like cocaine and methamphetamine bind to the central site, stabilizing the outward-open conformation.