Investigating the Mechanism of Sodium Binding to SERT Using Direct Simulations.

Dániel Szöllősi,Thomas Stockner

doi:10.3389/fncel.2021.673782

Dániel Szöllősi, Thomas Stockner

Open Access

https://doi.org/10.3389/fncel.2021.673782

Copy DOI

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.

Highlights

The function of the serotonin transporter (SERT) is to terminate neurotransmission by reuptake of serotonin (5HT) from the synapse into the pre-synaptic nerve terminal
The binding and co-transport of extracellular sodium into the cell and the movement downhill its electrochemical gradient is the primary determinant for driving the transport cycle of SERT (Chen et al, 2004)
Stabilization of substrate in the S1 was linked to NA1, as in LeuT the substrate interacts directly with the sodium ion in NA1 (Yamashita et al, 2005; Grouleff et al, 2015; Coleman et al, 2019), while in the monoamine transporters, the sodium ion in NA1 positions the sidechain of the adjacent aspartate (D98 in SERT) to interact with the amino groups of the substrate (Wang et al, 2015; Coleman et al, 2016, 2019)

Summary

Introduction

The function of the serotonin transporter (SERT) is to terminate neurotransmission by reuptake of serotonin (5HT) from the synapse into the pre-synaptic nerve terminal. Drugs of abuse like cocaine or amphetamine interfere with normal SERT function and lead to depletion of the 5HT pools in the pre-synaptic nerve terminal (Hilber et al, 2005). The substrate binding site (labeled S1) is located in the center of the transporter, halfway through the membrane. The transport cycle leading to 5HT uptake is initiated by binding of substrate and co-transported ions to the outward-open conformation. Full assembly of the transport complex consisting of bound ions and 5HT leads first to 5HT occlusion in the substrate binding site S1, followed by a transition to the inward-open conformation from which substrate

Objectives

Methods

Results

Conclusion