Investigating the Mechanism of Sodium Binding to SERT Using Direct Simulations

Abstract

The serotonin transporter (SERT) terminates neurotransmission by transporting serotonin from the synapse into the pre-synaptic nerve terminal. Altered SERT function leads to several neurological diseases including depression, anxiety, mood disorders, and attention deficit hyperactivity disorders (ADHD). Accordingly SERT is the target for their pharmacological treatments, but also targeted by multiple drugs of abuse. Transport of serotonin by SERT is energized by the transmembrane electrochemical gradient of sodium. We used extensive molecular dynamics simulations to investigate the process of sodium binding to SERT, which is the first step in the transport cycle that leads to serotonin uptake. Comparing data from 51 independent simulations, we find a remarkably well-defined path for sodium entry and could identify two transient binding sites, while observing binding kinetics that are comparable to experimental data. Importantly, the structure and dynamics of the sodium binding sites indicate that sodium binding is accompanied by an induced-fit mechanism that leads to new conformations and reduces local dynamics.

Occlusion of the human serotonin transporter is mediated by serotonin-induced conformational changes in the bundle domain

“…In this study, we capture the motions leading to the sequestering of substrate 5HT through occlusion of hSERT in a cholesterol-containing phospholipid bilayer that mimics the physiological cell membrane. The unbiased all atom MD simulations confirmed that the outward-open state of ion-bound hSERT is stable in the absence of 5HT, which is consistent with experimental data showing that the outward-facing conformation of SLC6 transporters is stable in the presence of the co-transported ions ( 26 , 28 , 30 ).…”

“…We used extensive bias-free equilibrium all atom molecular dynamic simulations (40 μs total simulation time) to investigate the substrate-induced occlusion of hSERT, thereby avoiding the danger of inducing structural changes which could deviate from the lowest energy path. Simulations of sodium- and chloride-bound hSERT show that ion binding stabilizes the outward-open state ( 26 , 27 , 28 ), while binding of 5HT to the S1 changes the conformational equilibrium leading to hSERT occlusion. We could identify the sequence of events essential for hSERT occlusion and discovered that TM1b and TM6a move remarkably independently of each other.…”

Screening of SERT and p11 mRNA Levels in Airline Pilots: A Translational Approach

“…To our knowledge, this is the first work to report high mRNA levels of SERT and p11 in PBMC from airline pilots. Both genes are related to depression ( 16 , 19 ) and play key roles in the functioning and regulation of the serotonergic system ( 35 , 36 ). A dysfunctional serotonergic system leads to abnormal neurotransmission and the development of psychiatric disorders.…”

A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain

“…Sodium binding is the first step of the transport cycle, because the high extracellular NaCl concentration leads to fast binding. The outward-facing state is stabilized by sodium binding and the affinity of the substrate increases strongly with the presence of Na + ( Keshet et al, 1995 ; Mager et al, 1996 ; Lu and Hilgemann, 1999a ; Lu and Hilgemann, 1999b ; Kanner, 2003 ; Szollosi and Stockner, 2021 ; Szollosi and Stockner, 2022 ).…”