Bound to be different: neurotransmitter transporters meet their bacterial cousins

Molecular Interventions
L Keith HenryRandy D Blakely

Abstract

The neurotransmitter transporters belonging to the solute carrier 6 (SLC6) family, including the gamma-aminobutyric acid (GAT), norepinephrine (NET), serotonin (SERT) and dopamine (DAT) transporters are extremely important drug targets of great clinical relevance. These Na+, Cl(-)-dependent transporters primarily function following neurotransmission to reset neuronal signaling by transporting neurotransmitter out of the synapse and back into the pre-synaptic neuron. Recent studies have tracked down an elusive binding site for Cl(-) that facilitates neurotransmitter transport using structural differences evident with bacterial family members (e.g., the Aquifex aeolicus leucine transporter LeuT Aa) that lack Cl(-) dependence. Additionally, the crystal structures of antidepressant-bound LeuT Aa reveals a surprising mode of drug interaction that may have relevance for medication development. The study of sequence and structural divergence between LeuT Aa and human SLC6 family transporters can thus inform us as to how and why neurotransmitter transporters evolved a reliance on extracellular Cl(-) to propel the transport cycle; what residue changes and helical rearrangements give rise to recognition of different substrates; and how d...Continue Reading

Citations

Oct 6, 2011·Journal of the American Chemical Society·Jerry C ChangSandra J Rosenthal
Feb 2, 2011·Proceedings of the National Academy of Sciences of the United States of America·Brent J ThompsonRandy D Blakely
Nov 7, 2009·The Journal of Biological Chemistry·Jacob AndersenAnders S Kristensen
Jan 24, 2009·Human Genomics·Lei HeDaniel W Nebert
Apr 24, 2012·British Journal of Pharmacology·Stefan Bröer, Ulrik Gether
Jul 10, 2016·Neuropharmacology·P J KennedyG Clarke
Mar 23, 2010·The Journal of Biological Chemistry·Melissa I Torres-AltoroEric L Barker
Jun 27, 2009·Chemical Communications : Chem Comm·Jacob AndersenKristian Strømgaard
Jul 15, 2011·Pharmacological Reviews·Anders S KristensenUlrik Gether
Nov 4, 2020·Nutrients·Karolina Skonieczna-ŻydeckaWojciech Marlicz

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