Understanding of the Serotonin Transporter Mechanism‐Targeting Drug Therapy

Depression and anxiety are ranked in the top five of causes of disabilities worldwide and are the most prevalent psychiatric disorders. Serotonin is a vital hormone that commonly acts as a neurotransmitter to modulate brain activity and enable communication between nervous system cells. The serotonin transporter (SERT) is a protein located within the presynaptic membrane and is activated by 5‐hydroxytryptamine (5‐HT), a chemical messenger that releases serotonin. The SERT protein re‐uptakes 5‐HT during its release, leading to the regulation of the neurotransmitter’s concentration in the synaptic cleft. Over‐activation of SERT leads to less 5‐HT, in turn lowering serotonin concentration, resulting in a higher chance of developing depression. Common drug treatments such as citalopram and paroxetine then bind at the central site, creating an outward‐open conformation. The central site of this protein is located halfway across the membrane, wedged into a cavity made up of residues from transmembrane helices. This new structure exposes a cone‐shaped extracellular vestibular that provides an open pathway to the central site. This process does not directly inhibit the serotonin transporter, but instead allosterically opens the Thr497‐Phe335 motif and creates a new binding pathway called S2. The opened S2 allows for new chemical binding that will inhibit SERT and prevent re‐uptake. Our research attempts to explore how various antidepressants prevent the re‐uptake of 5‐HT by inhibiting this serotonin transporter.