Abstract
Neurotransmitters released at the neural synapse through vesicle exocytosis are spatiotemporally controlled by the action of neurotransmitter transporters. Integral membrane proteins of the solute carrier 6 (SLC6) family are involved in the sodium and chloride coupled uptake of biogenic amine neurotransmitters including dopamine, serotonin, noradrenaline and inhibitory neurotransmitters including glycine and γ-amino butyric acid. This ion-coupled symport works through a well-orchestrated gating of substrate through alternating-access, which is mediated through movements of helices that resemble a rocking-bundle. A large array of commercially prescribed drugs and psychostimulants selectively target neurotransmitter transporters thereby modulating their levels in the synaptic space. Drug-induced changes in the synaptic neurotransmitter levels can be used to treat depression or neuropathic pain whereas in some instances prolonged usage can lead to habituation. Earlier structural studies of bacterial neurotransmitter transporter homolog LeuT and recent structure elucidation of the Drosophila dopamine transporter (dDAT) and human serotonin transporter (hSERT) have yielded a wealth of information in understanding the transport and inhibition mechanism of neurotransmitter transporters. Computational studies based on the structures of dDAT and hSERT have shed light on the dynamics of varied components of these molecular gates in affecting the uphill transport of neurotransmitters. This review seeks to address structural dynamics of neurotransmitter transporters at the extracellular and intracellular gates and the effect of inhibitors on the ligand-binding pocket. We also delve into the effect of additional factors including lipids and cytosolic domains that influence the translocation of neurotransmitters across the membrane.
Highlights
Chemical neurotransmission between neurons involves the exocytic release of neurotransmitters that activate downstream ligand-gated ion channels and metabotropic receptors (Jessell and Kandel, 1993)
A majority of neurotransmitter transporters belong to the solute carrier 6 (SLC6) family (Broer and Gether, 2012) that includes dopamine (DA), norepinephrine (NE), serotonin (5HT), glycine and Neurotransmitter Transporter Structure and Dynamics γ-amino butyric acid (GABA) transporters (Figure 1)
The disordered stretch of TM1 continues to form the floor of the binding pocket F43, which in case of the human serotonin transporter (hSERT) is a tyrosine (Y95) that undergoes a massive shift of 6 Å in the Cα position and 12.5 Å in the position of the phenyl group during the conformation change leading to the inward-open (Io) state
Summary
Chemical neurotransmission between neurons involves the exocytic release of neurotransmitters that activate downstream ligand-gated ion channels and metabotropic receptors (Jessell and Kandel, 1993). The disordered stretch of TM1 continues to form the floor of the binding pocket F43, which in case of the hSERT is a tyrosine (Y95) that undergoes a massive shift of 6 Å in the Cα position and 12.5 Å in the position of the phenyl group during the conformation change leading to the inward-open (Io) state This movement facilitates solvent access to the binding site and these changes are discussed in detail in the subsequent section dealing with the intracellular gate dynamics. The inward movement of the F319 side chain by about 100◦, closes the solvent access of the extracellular vestibule to the substratebinding pocket (Figure 4) While this movement is consistently observed within LeuT and the substrate analog bound structure of dDAT, the ibogaine bound outward occluded (Oocc) structure of hSERT does not exhibit any such movement of the side chain, F335. These interactions are lost during the opening of the cytosolic gate that lead to a massive movement resembling a “trapdoor,” that swings the TM1a out by 40◦ to TABLE 1 | Intracellular interacting partners of neurotransmitter transporters
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
