Dopamine Reuptake Inhibition as the Means of Antidepressant Mechanism of Function (LB92)

Abstract

Maintaining the equilibrium of neurotransmitters (NT) at neural synapses is essential for normal brain functioning. Lack of regulation of NT levels is associated with disorders including depression, Parkinson’s disease, ADHD, and epilepsy. The dopamine transporter (DAT) is the primary removal mechanism of the NT, dopamine, from the synaptic cleft. The regulation of NT reuptake is critical for preventing chemical imbalance and the inhibition of reuptake has become the primary target for antidepressants. The Drosophila melanogaster DAT was crystallized in complex with a tricyclic antidepressant (TCA) and found induced in an outward‐open conformation towards the synaptic cleft. Three factors contribute to inhibiting the inward‐facing conformation required for DAT activity: the antidepressant nortriptyline bound at the substrate‐binding site blocks important helix movement, a cholesterol molecule stabilizes the outward conformation, and lastly the C‐terminus caps the cytoplasmic gate. The Madison West SMART (Students Modeling a Research Topic) modeled the DAT structure using 3D printing technology. The structure of TCA‐bound DAT provides new knowledge of eukaryotic transporters and enables a better understanding of the critical factors and conformational changes associated with NT transport inhibition to allow for targeted drug research.Grant Funding Source: Supported by grants from the NIH‐SEPA and NIH‐CTSA.