Neurotransmitter transporters: molecular function of important drug targets

doi:10.1016/j.tips.2006.05.003

Trends in Pharmacological Sciences

Volume 27, Issue 7, July 2006, Pages 375-383

https://doi.org/10.1016/j.tips.2006.05.003 Get rights and content

The concentration of neurotransmitters in the extracellular space is tightly controlled by distinct classes of membrane transport proteins. This review focuses on the molecular function of two major classes of neurotransmitter transporter that are present in the cell membrane of neurons and/or glial cells: the solute carrier (SLC)1 transporter family, which includes the transporters that mediate the Na⁺-dependent uptake of glutamate, and the SLC6 transporter family, which includes the transporters that mediate the Na⁺-dependent uptake of dopamine, 5-HT, norepinephrine, glycine and GABA. Recent research has provided substantial insight into the structure and function of these transporters. In particular, the recent crystallizations of bacterial homologs are of the utmost importance, enabling the first reliable structural models of the mammalian neurotransmitter transporters to be generated. These models should be an important tool for developing specific drugs that, through selective interaction with transporters, could improve the treatment of serious neurological and psychiatric disorders.

Section snippets

The different classes of neurotransmitter transporter

The transmembrane transport of neurotransmitters is of fundamental importance for proper signaling between neurons. The transport processes are mediated by distinct classes of membrane transport protein that have key roles in controlling the neurotransmitter concentration in the synaptic cleft. Overall, these transporters can be classed as intracellular vesicular transporters that are responsible for sequestering transmitters from the cytoplasm into synaptic vesicles, and plasma membrane

Tertiary and quaternary structure

All neurotransmitter transporters are polytopic membrane proteins that mediate ion-coupled secondary active transport of their substrate across the membrane; hence, both the SLC1 and the SLC6 transporters operate as Na⁺-dependent co-transporters that use the transmembrane Na⁺ gradient to couple ‘downhill’ transport of Na⁺ with ‘uphill’ transport (i.e. against a concentration gradient) of their substrate from the extracellular to the intracellular environment 2, 3. There are, however, clear

Neurotransmitter transporters as drug targets

It is well established that neurotransmitter transporters have roles in several neurological and psychiatric diseases. This is directly supported by several examples of naturally occurring mutations in the transporter genes that cause or increase the risk of developing certain diseases. Examples include an inactivating mutation in EAAT2 that is linked to amyotrophic lateral sclerosis (ALS) [32], an inactivating mutation in the norepinephrine transporter (NET) that is linked to severe

Concluding remarks

The recently solved structures of the bacterial homologs of mammalian neurotransmitter transporters, Glt_Ph and LeuT_Aa, represent a huge leap forward in terms of the understanding of how plasma membrane transporters operate at the molecular level. Furthermore, they open a new avenue of research aimed at clarifying the molecular mechanisms that are responsible for the action of the large number of drugs acting at mammalian transporters. Until now, knowledge of these mechanisms has been

Acknowledgements

We thank the Alfred Benzon Foundation for providing financial support to the recent symposium in Copenhagen, Denmark, on the structure, function and regulation of neurotransmitter transporters.

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Trends in Pharmacological Sciences

Neurotransmitter transporters: molecular function of important drug targets

Section snippets

The different classes of neurotransmitter transporter

Tertiary and quaternary structure

Neurotransmitter transporters as drug targets

Concluding remarks

Acknowledgements

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