title: Sodium-assisted formation of binding and traverse conformations of the substrate in a neurotransmitter sodium symporter model.
abstract: Therapeutics designed to increase synaptic neurotransmitter levels by inhibiting neurotransmitter sodium symporters (NSSs) classify a strategic approach to treat brain disorders such as depression or epilepsy, however, the critical elementary steps that couple downhill flux of sodium to uphill transport of neurotransmitter are not distinguished as yet. Here we present modelling of NSS member neuronal GAT1 with the substrate &#947;-aminobutyric acid (GABA), the major inhibitory neurotransmitter. GABA binding is simulated with the occluded conformation of GAT1 homodimer in an explicit lipid/water environment. Simulations performed in the 1-10 ns range of time elucidated persistent formation of halfextended minor and H-bridged major GABA conformations, referred to as binding and traverse conformations, respectively. The traverse GABA conformation was further stabilized by GAT1-bound Na(+)(1). We also observed Na(+)(1) translocation to GAT1-bound Cl(-) as well as the appearance of water molecules at GABA and GAT1-bound Na(+)(2), conjecturing causality. Scaling dynamics suggest that the traverse GABA conformation may be valid for developing substrate inhibitors with high efficacy. The potential for this finding is significant with impact not only in pharmacology but wherever understanding of the mechanism of neurotransmitter uptake is valuable.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Simon
authors.forename: Ákos
authors.initials: Á
authors.lastname: Bencsura
authors.forename: László
authors.initials: L
authors.lastname: Héja
authors.forename: Csaba
authors.initials: C
authors.lastname: Magyar
authors.affiliation: Institute of Molecular Pharmacology, Research Centre for Natural Sciences, PO Box 17, H-1525 Budapest, Hungary. kardos.julianna@ttk.mta.hu.
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
mesh_terms: D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D018377:Neurotransmitter Agents / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D021381:Protein Transport / Q000502:physiology; D012964:Sodium / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity / Q000502:physiology; D027981:Symporters / Q000737:chemistry* / Q000378:metabolism
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D026901:Membrane Transport Proteins; D018377:Neurotransmitter Agents; C493413:SLC6A1 protein, human; D027981:Symporters; D012964:Sodium