Molecular basis for substrate discrimination by glycine transporters.
Glycine is an inhibitory neurotransmitter in the spinal cord and brain stem, where it acts on strychnine-sensitive glycine receptors, and is also an excitatory neurotransmitter throughout the brain and spinal cord, where it acts on the N-methyl-d-aspartate family of receptors. There are two Na(+)/Cl(-)-dependent glycine transporters, GLYT1 and GLYT2, which control extracellular glycine concentrations and these transporters show differences in substrate selectivity and blocker sensitivity. A bacterial Na(+)-dependent leucine transporter (LeuT(Aa)) has recently been crystallized and its structure determined. When the amino acid residues within the leucine binding site of LeuT(Aa) are aligned with residues of the two glycine transporters there are a number of identical residues and also some key differences. In this report, we demonstrate that the LeuT(Aa) structure represents a good working model of the Na(+)/Cl(-)-dependent neurotransmitters and that differences in substrate selectivity can be attributed to a single difference of a glycine residue in transmembrane domain 6 of GLYT1 for a serine residue at the corresponding position of GLYT2.
Vandenberg
Robert J
RJ
Department of Pharmacology, Institute for Biomedical Research, University of Sydney, New South Wales, Australia.
Shaddick
Kim
K
Ju
Pengchu
P
D000818:Animals; D004594:Electrophysiology; D005260:Female; D005998:Glycine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D014982:Xenopus laevis / Q000378:metabolism
D050487:Glycine Plasma Membrane Transport Proteins; D010446:Peptide Fragments; C493271:SLC6A5 protein, human; C493268:SLC6A9 protein, human; D012694:Serine; D005998:Glycine