Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6

Abstract

The SLC6 family is a diverse set of transporters that mediate solute translocation across cell plasma membranes by coupling solute transport to the cotransport of sodium and chloride down their electrochemical gradients. These transporters probably have 12 transmembrane domains, with cytoplasmic N- and C-terminal tails, and at least some may function as homo-oligomers. Family members include the transporters for the inhibitory neurotransmitters GABA and glycine, the aminergic transmitters norepinephrine, serotonin, and dopamine, the osmolytes betaine and taurine, the amino acid proline, and the metabolic compound creatine. In addition, this family includes a system B(0+) cationic and neutral amino acid transporter, and two transporters for which the solutes are unknown. In general, SLC6 transporters act to regulate the level of extracellular solute concentrations. In the central and the peripheral nervous system, these transporters can regulate signaling among neurons, are the sites of action of various drugs of abuse, and naturally occurring mutations in several of these proteins are associated with a variety of neurological disorders. For example, transgenic animals lacking specific aminergic transporters show profoundly disturbed behavioral phenotypes and probably represent excellent systems for investigating psychiatric disease. SLC6 transporters are also found in many non-neural tissues, including kidney, intestine, and testis, consistent with their diverse physiological roles. Transporters in this family represent attractive therapeutic targets because they are subject to multiple forms of regulation by many different signaling cascades, and because a number of pharmacological agents have been identified that act specifically on these proteins.

Ancestry and progeny of nutrient amino acid transporters

“…Metazoan Na ϩ -dependent and -independent carrier systems transporting amino acids comprise B 0,ϩ , LAT1, LAT2, and TAT secondary transporters and ATP-binding cassette (ABC) pumps. Mammalian Na ϩ -driven B 0,ϩ amino acid systems deriving from initially characterized SLC6A14 members in Homo sapiens may contribute to primary transapical uptake of phenylalanine (2). Nevertheless, these transporters belong to a glycine-proline phylogenetic cluster within the sodium-neurotransmitter symporter family (SNF) and have a relatively low selectivity for phenylalanine and several other essential amino acids: I EC50 ϭ 6 M Ͼ L 12 Ͼ M 14 ϾF 17 Ͼ other amino acids (3).…”

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).…”

High Selectivity of the γ-Aminobutyric Acid Transporter 2 (GAT-2, SLC6A13) Revealed by Structure-based Approach

“…The solute carrier 6 family (SLC6) 5 consists of 20 Na ϩ -and Cl Ϫ -dependent membrane transporters that regulate a variety of biological activities such as neurotransmission and metabolism (1). This transporter family can be classified into four groups based on their amino acid sequences: monoamine transporters, GABA transporters, amino acid transporters, and "orphan" transporters that may also transport amino acids (1,2).…”

“…This transporter family can be classified into four groups based on their amino acid sequences: monoamine transporters, GABA transporters, amino acid transporters, and "orphan" transporters that may also transport amino acids (1,2). Mutations in SLC6 members are associated with a wide spectrum of disorders such as obsessive compulsive disorder (serotonin transporter, SLC6A4), obesity (SLC6A14), and orthostatic hypotension (NET, SLC6A2) (2).…”