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. © FASEB.