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Elucidating the Mechanism Behind Sodium-Coupled Neurotransmitter Transporters by Reconstitution

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Abstract

Sodium-coupled neurotransmitter transporters play a fundamental role in the termination of synaptic neurotransmission, which makes them a major drug target. The reconstitution of these secondary active transporters into liposomes has shed light on their molecular transport mechanisms. From the earliest days of the reconstitution technique up to today’s single-molecule studies, insights from live functioning transporters have been indispensable for our understanding of their physiological impact. The two classes of sodium-coupled neurotransmitter transporters, the neurotransmitter: sodium symporters and the excitatory amino acid transporters, have vastly different molecular structures, but complementary proteoliposome studies have sought to unravel their ion-dependence and transport kinetics. Furthermore, reconstitution experiments have been used on both protein classes to investigate the role of e.g. the lipid environment, of posttranslational modifications, and of specific amino acid residues in transport. Techniques that allow the detection of transport at a single-vesicle resolution have been developed, and single-molecule studies have started to reveal single transporter kinetics, which will expand our understanding of how transport across the membrane is facilitated at protein level. Here, we review a selection of the results and applications where the reconstitution of the two classes of neurotransmitter transporters has been instrumental.

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Fig. 1

Figure modified from [4] with permission. b Structure of LeuT in outward-occluded conformation with Na+ (purple) and substrate bound (PDB 2A65) and the inward-facing conformation after release of Na+ and substrate (PDB 3TT3). The bundle domain is shown in orange (TM 1 + 2) and blue (TM 6 + 7). c Membrane topology of GltPh monomer. Figure from [20] with permission. d GltPh in the outward facing conformation and the inward-facing conformation with Na+ (purple) and substrate bound. The transport domain is shown in blue and the scaffold domain is shown in wheat. Hairpin loop 1 and 2 are shown in green and red, respectively. Figure from [20] with permission

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Acknowledgements

We would like to thank Daniel Philip Middleton for proofreading the manuscript.

Funding

The work was supported in part by the Lundbeck Foundation (Grant Nos. R344-2020-1020 to C.J.L. and R266-2017-4331 and R276-2018-792 to U.G.), the Independent Research Fund Denmark – Medical Sciences (Grant Nos. 7016-00272 A to C.J.L. and 7016-00325B to U.G.), the Novo Nordic Foundation (Grant No. NNF19OC0058496 to C.J.L.) and the Carlsberg Foundation (Grant No. CF20-0345 to C.J.L.)

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  1. Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Solveig G. Schmidt, Ulrik Gether & Claus J. Loland

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  1. Solveig G. Schmidt
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All authors conceptualized the idea. SGS and CJL drafted the manuscript. All authors revised the manuscript.

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Schmidt, S.G., Gether, U. & Loland, C.J. Elucidating the Mechanism Behind Sodium-Coupled Neurotransmitter Transporters by Reconstitution. Neurochem Res 47, 127–137 (2022). https://doi.org/10.1007/s11064-021-03413-y

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