The Family of Na⁺/Cl⁻ Neurotransmitter Transporters

Abstract

Abstract:The termination of neurotransmission is achieved by rapid uptake of the released neurotransmitter by specific high-affinity neurotransmitter transporters. Most of these transporters are encoded by a family of genes (Na~ICI transporters) having a similar membrane topography of 12 transmembrane helices. An evolutionary tree revealed fivedistinct subfamilies: y-aminobutyric acid transporters, monoamine transporters, amino acid transporters, "orphan" transporters, and the recently discovered bacterial transporters. The bacterial transporters that belong to this family may help to develop heterologous expression systems with the aim of solving the threedimensional structure of these membrane proteins. Some of the neurotransmitter transporters have been implicated as important sites for drug action. Monoamine transporters, for example, are targeted by major classes of antidepressants, psychostimulants, and antihypertensive drugs. Localization of individual transporters in specific cells and brain areas is pertinent to understanding their contribution to neurotransmission and their potential as targets for drugs. The most important questions in the field include resolving the mechanism of neurotransmitter transport, the structure of the transporters, and the interaction of each transporter in complex neurological activities.

Functional Defects in the External and Internal Thin Gates of the γ-Aminobutyric Acid (GABA) Transporter GAT-1 Can Compensate Each Other

“…These membrane proteins harness energy from the sodium gradient for the uphill translocation of neurotransmitters into the cells surrounding the synapse. This process decreases the synaptic neurotransmitter concentrations and leads to signal termination (1,2). With the exception of glutamate transporters, the transporters for other neurotransmitters, such as GABA (GAT1-4), serotonin (SERT), dopamine (DAT), 2 norepinephrine (NET), and glycine (GLYT1,2) belong to the neurotransmitter:sodium:symporter (NSS) family, which couple the flux of neurotransmitter not only to that of sodium, but also to that of chloride.…”

The organic osmolytes betaine and proline are transported by a shared system in early preimplantation mouse embryos

“…The requirement for Na þ and Cl À may indicate that the embryonic betaine/ proline transporter is likely a member of the same neurotransmitter transporter (NTT, SLC6) family as GLYT1, since all known mammalian Na þ -and Cl À -dependent transporters of organic compounds lie in this family (Nelson, 1998;Chen et al, 2004;Hoglund et al, 2005). Within this gene family, there are at least two possible candidates for the transport system identified functionally here: the brain proline transporter (PROT; slc6a7) and the intestinal imino acid transporter (IMINO; slc6a20 or XT3S1).…”

“…We focused first on glycine, since early PI embryos were known to transport glycine at a high rate, via the GLYT1 (slc6a9) transporter (Hobbs and Kaye, 1985;Van Winkle et al, 1988), which is a member of the Na þ -and Cl À -dependent neurotransmitter transporter (NTT or SLC6) family (Nelson, 1998;Hoglund et al, 2005). Also, a large amount of glycine is present in the oviduct, with mouse oviductal fluid containing 0.5-3.0 mM glycine (Guerin et al, 1995;Harris et al, 2005) and similarly high amounts in tubal fluid of other mammals.…”

Haplotype architecture of the norepinephrine transporter gene SLC6A2 in four populations

“…The human NET gene (SLC6A2, hCG2025341) is located on chromosome 16q12.2 (Bru¨ss et al 1993) and has 15 exons spanning $48 kb (Po¨rzgen et al 1995(Po¨rzgen et al , 1998. The cDNA sequence encodes a 617-amino acid protein with 12 highly hydrophobic membrane domains and a high level of amino acid identity to other members of the Na + /Cl ) -dependent monoamine transporter family, e.g., HTT(serotonin transporter) and DAT (dopamine transporter) (Nelson 1998;Hahn and Blakely 2002). SLC6A2 has five alternative splice transcripts.…”