Structure and Gating Dynamics of Na+/Cl– Coupled Neurotransmitter Transporters

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.

Crystal structure of a YeeE/YedE family protein engaged in thiosulfate uptake

“…YeeE appears to be a sophisticated structure evolved for thiosulfate uptake that can allow the thiosulfate transport by minimal structural changes of the LA–LD loop at the constrict site, at the center, while maintaining membrane permeability. Notably, in this proposed model, YeeE does not require large conformational changes in the surrounding transmembrane helices (as demonstrated by the MD simulation), compared with those of other transporter proteins, such as conformational transitions between inward- and outward-facing forms ( 16 – 18 ) and “rocking bundle” motions of LeuT ( 19 ). If the S─H─S hydrogen bond is critical for the thiosulfate transport activity, then YeeE would be structurally unable to transport sulfates in the same manner because of the unexposed sulfur atom of sulfate ( Fig.…”

A guide to plasma membrane solute carrier proteins

“…As an example, the crystal structure of vSGLT, the sodium/glucose cotransporter from Vibrio parahaemolyticus, has been determined, providing insight on the mechanism of similar proteins like SLC5A1 (which has 32% sequence similarity) [48]. Similarly, the high-resolution atomic structure of a bacterial amino acid transporter has further provided structural context for how the SLC6 family of proteins transports its substrates [49,50]. However, one of the major limitations of using bacterial transporters as a method to elucidate the structure and function of human transporters is that these crystalized bacterial proteins can lack the longer cytoplasmic tails that play a significant role in transporter activity and specificity [51].…”

Homozygous in‐frame variant of SCL6A3 causes dopamine transporter deficiency syndrome in a consanguineous family

“…Thus, we conjectured that the variant can impose its effects by altering the Zn 2+ ‐binding site. However, this should be evaluated by functional analysis (Joseph, Pidathala, Mallela, & Penmatsa, 2019).…”