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Removal of neurotransmitter from the synaptic cleft is accomplished by a class of transporter called Neurotransmitter/sodium symporters (NSSs). These couple the uptake of neurotransmitter (including dopamine, GABA, serotonin, noradrenaline) with sodium ions. They’re the target of pharmaceutical interventions, particularly antidepressants (serotonin and noradrenaline reuptake inhibitors, collectively SNRIs), as well as being behind the basis of action of psychostimulants such as cocaine and amphetamines.

As with many complex proteins, NSSs have prokaryotic orthologues that are easier to study and understand, but that can give us valuable information about their eukaryotic counterparts.

But sometimes we run into trouble.

LeuT is a leucine-transporting NSS orthologue, and there’s some controversy over whether it binds two, or just one, leucine molecule. This is important because determining the mechanism depends on knowing how many molecules of substrate the transporter binds. Leucine is an amino acid—rather large as such things go, but tiny compared with the transporter—and counting how many are bound to at any one time is reasonably non-trivial. The crystal structure of LeuT only had a single leucine substrate molecule, but the authors said the second one had been replaced by a molecular of octylglucoside, a detergent used to keep membrane proteins happy and stable while crystallographers are mucking around with them (and the source of much amusement in my previous life).

A recent paper in Nature (incidentally, from the same lab as published the structure) seemed to nail the problem (one leucine only, Vasili) and was recommended by Gary Rudnick at Yale. But today we’ve published a dissent by Louis De Felice at Virginia Commonwealth University.

Louis says that the conflicting data “require further explanation and experimentation,” which probably means we’re not going to see the end of this one for a while.

Piscitelli, C., Krishnamurthy, H., & Gouaux, E. (2010). Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site Nature, 468 (7327), 1129-1132 DOI: 10.1038/nature09581