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regulating glycine availability at NMDA receptors has warranted attempts to develop high-afi nity
inhibitors of GlyT1 as a novel class of antipsychotic drugs, i.e., blockade of the GlyT1 is envisioned
to increase synaptic levels of glycine ensuring saturation of the glycine-B (GlyB) site at the NMDA
receptor at which glycine acts as an obligatory coagonist. Importantly, a derivative of sarcosine
[3-(4-l uorophenyl)-3-(4¢-phenylpheroxy)]propylsarcosine (NFPS) has been shown to potentiate
NMDA receptor-sensitive activity and to produce an antipsychotic-like behavioral proi le in rats.
Several GlyT1 and GlyT2 inhibitors have now been described; however, little is known about their
mode of interaction with the transporters.
14.5 CONCLUSION
The SLC6 neurotransmitter transporters represent a prototypical class of ion-coupled membrane
transporters capable of utilizing the transmembrane Na + gradient to couple “downhill” transport of
Na + with “uphill” transport (against a concentration gradient) of their substrate from the extracellular
to the intracellular environment. The transporters play key roles in regulating synaptic transmission in
the brain by rapidly sequestering transmitters such as dopamine, norepinephrine, serotonin, GABA,
and glycine away from the extracellular space. Moreover, they are targets for a wide variety of drugs
including antidepressants, antiepileptics, and psychostimulants as well as they are subject to current
drug discovery efforts. Only recently, high-resolution structural information became available for this
class of transporters through crystallization of the bacterial homologue, LeuT Aa . For the i rst time,
this permitted insight into the tertiary structure of this family of transporters. The structure serves
as an important framework for future studies aimed at deciphering the precise molecular details and
dynamics of the transport process. The structure also serves as an important template for delineating
the molecular determinants for drug binding to SLC6 neurotransmitter transporters. The i rst experi-
mentally validated computational models of drug binding have now been published and provided the
i rst insight into the exact molecular basis for drug action at these important proteins.
FURTHER READINGS
Beuming, T., Kniazeff, J., Bergman, M. L., Shi, L., Gracia, L., Raniszewska, K., Newman, A. H., Javitch, J. A.,
Weinstein, H., Gether, U., and Loland, C. J. 2008. The binding sites for cocaine and dopamine in the
dopamine transporter are overlapping. Nat. Neurosci . 11: 780-789.
Gether, U., Andersen, P. H., Larsson, O. M., and Schousboe, A. 2006. Neurotransmitter transporters: Molecular
function of important drug targets. Trends Pharmacol. Sci . 27: 375-383.
Kniazeff, J., Shi, L., Loland, C. J., Javitch, J. A., Weinstein, H., and Gether, U. 2008. An intracellular inter-
action network regulates conformational transitions in the dopamine transporter. J. Biol. Chem . 283:
17691-17701.
Reith, M. E. A. 2002. Neurotransmitter Transporters: Structure, Function, and Regulation , 2nd edn. Humana
Press, Totawa, NJ.
Singh, S. K., Yamashita, A., and Gouaux, E. 2007. Antidepressant binding site in a bacterial homologue of
neurotransmitter transporters. Nature 448: 952-956.
Yamashita, A., Singh, S. K., Kawate, T., Jin, Y., and Gouaux, E. 2005. Crystal structure of a bacterial homo-
logue of Na + /Cl -dependent neurotransmitter transporters. Nature 437: 215-223.
Yernool, D., Boudker, O., Jin, Y., and Gouaux, E. 2004. Structure of a glutamate transporter homologue from
Pyrococcus horikoshii . Nature 431: 811-818.
Zomot, E., Bendahan, A., Quick, M., Zhao, Y., Javitch, J. A., and Kanner, B. I. 2007. Mechanism of chloride
interaction with neurotransmitter:sodium symporters. Nature 449: 726-730.
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