Crystal structures of transmembrane transport proteins belonging to the important families of neurotransmitter-sodium symporters reveal how they transport neurotransmitters across membranes. Substrate-induced structural conformations of gated neurotransmitter-sodium symporters have been in the focus of research, however, a key question concerning the mechanism of Na+ ion coupling remained unanswered. Homology models of human glial transporter subtypes of the major inhibitory neurotransmitter gamma-aminobutyric acid were built. In accordance with selectivity data for subtype 2 vs. 3, docking and molecular dynamics calculations suggest similar orthosteric substrate (inhibitor) conformations and binding crevices but distinguishable allosteric Zn2+ ion binding rnotifs. Considering the occluded conformational states of glial human gamma-aminobutyric acid transporter subtypes, we found major semi-extended and minor ring-like conformations of zwitterionic gamma-aminobutyric acid in complex with Na+ ion. The existence of the minor ring-like conformation of gamma-aminobutyric acid in complex with Na+ ion may be attributed to the strengthening of the intramolecular H-bond by the electrostatic effect of Na+ ion. Coupling substrate uptake into cells with the thermodynamically favorable Na+ ion movement through substrate-Na+ ion complex formation may be a mechanistic principle featuring transmembrane neurotransmitter-sodium symporter proteins. (C) 2009 Elsevier Inc. All rights reserved.