Sodium Binding Stabilizes the Outward-Open State of SERT by Limiting Bundle Domain Motions.

Dániel Szöllősi,Thomas Stockner

doi:10.3390/cells11020255

Abstract

The human serotonin transporter (hSERT) removes the neurotransmitter serotonin from the synaptic cleft by reuptake into the presynaptic nerve terminal. A number of neurologic diseases are associated with dysfunction of the hSERT, and several medications for their treatment are hSERT blockers, including citalopram, fluoxetine, and paroxetine. The substrate transport is energized by the high concentration of external NaCl. We showed through molecular dynamics simulations that the binding of NaCl stabilized the hSERT in the substrate-binding competent conformation, which was characterized by an open access path to the substrate-binding site through the outer vestibule. Importantly, the binding of NaCl reduced the dynamics of the hSERT by decreasing the internal fluctuations of the bundle domain as well as the movement of the bundle domain relative to the scaffold domain. In contrast, the presence of only the bound chloride ion did not reduce the high domain mobility of the apo state.

Highlights

The physiological function of the human serotonin transporter is the reuptake of serotonin from the synaptic cleft into the presynaptic nerve terminal, thereby regulating the physiologically important concentration of the neurotransmitter serotonin
Structures of human serotonin transporter (hSERT) have been solved in the presence of inhibitors in three conformations [3,4], which are interpreted as representing the outward-open, the outward-occluded, and the inward-open states
These structures reveal that hSERT transitions between these states through the movement of the mobile bundle domain (consisting of transmembrane helix (TMH) 1, 2, 6, and 7) relative to the scaffold domain (TMH3, 4, 8, and 9), which anchors the transporter in the cellular membrane

Summary

Introduction

The physiological function of the human serotonin transporter (hSERT) is the reuptake of serotonin from the synaptic cleft into the presynaptic nerve terminal, thereby regulating the physiologically important concentration of the neurotransmitter serotonin. Structures of hSERT have been solved in the presence of inhibitors in three conformations [3,4], which are interpreted as representing the outward-open, the outward-occluded, and the inward-open states. These structures reveal that hSERT transitions between these states through the movement of the mobile bundle domain (consisting of transmembrane helix (TMH) 1, 2, 6, and 7) relative to the scaffold domain (TMH3, 4, 8, and 9), which anchors the transporter in the cellular membrane. The hSERT returns to the outward-facing state with either a bound potassium ion or a proton [5,6]

Methods

Results

Conclusion