Serotonin transporter and Norepinephrine transporter (SERT and NET)

Serotonin transporter (SERT) and Norepinephrine transporter (NET) are integral membrane proteins that facilitate the sodium- and chloride-dependent transport of released serotonin and norepinephrine, respectively, from the synaptic cleft back into presynaptic nerve terminals. These transporters play key roles in regulating neurotransmitter levels in the brain, which affects mood, sleep, pain perception, and various other physiological functions. The NET is encoded by the SLC6A2 gene located on human chromosome 16 and consists of 617 amino acids with 12 membrane-spanning domains. Both transporters show some promiscuity in their function, with NET capable of reuptaking dopamine in addition to norepinephrine, and SERT showing evidence of dopamine uptake under certain conditions. These transporters are important therapeutic targets for treating depression, anxiety disorders, ADHD, and chronic pain conditions. Drugs targeting these transporters work by blocking the reuptake process, thereby increasing neurotransmitter availability in the synaptic cleft. The selectivity of inhibitors for SERT versus NET is determined by specific residues within the S1 binding pocket of these transporters. Interestingly, drugs that target both transporters (SNRIs) or multiple monoamine transporters often show improved clinical efficacy compared to highly selective agents, suggesting that the natural promiscuity of these transporters may have therapeutic relevance.

Other names

Serotonin transporter (SERT)Norepinephrine transporter (NET)Noradrenaline transporter (NAT)Solute carrier family 6 member 2 (SLC6A2) for NET

Drugs targeting these transporters block the reabsorption (reuptake) of serotonin and/or norepinephrine from the synaptic cleft back into presynaptic neurons. This increases the concentration and availability of these neurotransmitters in the synaptic cleft, which helps ease symptoms associated with their deficiency. Selectivity varies among different drug classes (SSRIs, NRIs, SNRIs). Binding occurs within the central S1 pocket of the transporters.