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Glycine Transporter 2 (GlyT2) inhibitors have shown considerable potential as analgesics for the treatment of neuropathic pain but also display considerable side effects. One potential source of side effects is irreversible inhibition. In this study, we have characterized the mechanism of ORG25543 inhibition of GlyT2 by first considering three potential ligand binding sites on GlyT2—the substrate site, the vestibule allosteric site and the lipid allosteric site. The three sites were tested using a combination of molecular dynamics simulations and analysis of the inhibition of glycine transport of a series point mutated GlyT2 using electrophysiological methods. We demonstrate that the lipid allosteric site on GlyT2 is the most likely binding site for ORG25543. We also demonstrate that cholesterol derived from the cell membrane can form specific interactions with inhibitor‐bound transporters to form an allosteric network of regulatory sites. These observations will guide the future design of GlyT2 inhibitors with the objective of minimising on‐target side effects and improving the therapeutic window for the treatment of patients suffering from neuropathic pain. [ABSTRACT FROM AUTHOR]

Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, and its precise control is vital to maintain normal brain function and to prevent excitotoxicity.sup.1. The removal of extracellular glutamate is achieved by plasma-membrane-bound transporters, which couple glutamate transport to sodium, potassium and pH gradients using an elevator mechanism.sup.2-5. Glutamate transporters also conduct chloride ions by means of a channel-like process that is thermodynamically uncoupled from transport.sup.6-8. However, the molecular mechanisms that enable these dual-function transporters to carry out two seemingly contradictory roles are unknown. Here we report the cryo-electron microscopy structure of a glutamate transporter homologue in an open-channel state, which reveals an aqueous cavity that is formed during the glutamate transport cycle. The functional properties of this cavity, combined with molecular dynamics simulations, reveal it to be an aqueous-accessible chloride permeation pathway that is gated by two hydrophobic regions and is conserved across mammalian and archaeal glutamate transporters. Our findings provide insight into the mechanism by which glutamate transporters support their dual function, and add information that will assist in mapping the complete transport cycle shared by the solute carrier 1A transporter family. Glutamate transporters conduct chloride ions through an aqueous channel with hydrophobic gates that forms during the glutamate transport cycle., Author(s): Ichia Chen [sup.1] , Shashank Pant [sup.2] [sup.3] [sup.4] , Qianyi Wu [sup.1] , Rosemary J. Cater [sup.1] [sup.7] , Meghna Sobti [sup.5] [sup.6] , Robert J. Vandenberg [sup.1] [...]

We examined how affective (AC), normative (NC), perceived sacrifice (PS), and few alternatives (FA) commitments combine to form profiles and determine turnover intention and turnover. We theorized that three mechanisms account for how profiles operate, i.e., the degree to which membership is internally regulated, the perceived desirability and ease of movement, and the within-person contextual effects among profiles. In a sample of 712 University alumni, we found evidence of six profiles of commitment, reflecting different combinations of commitment forms. The AC Dominant, AC-NC Dominant, and Committed profiles displayed lower turnover intention than the Continuance Dominant and Not Committed profiles. Moreover, the Continuance Dominant profile and the profiles in which AC was high displayed lower turnover rates than the Not Committed profile. We discuss the implications of these findings for the understanding of drivers operating within commitment profiles. (Contains 1 figure and 5 tables.)

The effectiveness of an intervention depends on its dose and on moderators of dose, which usually are not studied. The purpose of the study is to determine whether goal setting and theory-based moderators of goal setting had dose relations with increases in goal-related physical activity during a successful workplace intervention. A group-randomized 12-week intervention that included personal goal setting was implemented in fall 2005, with a multiracial/ethnic sample of employees at 16 geographically diverse worksites. Here, we examined dose-related variables in the cohort of participants (N = 664) from the 8 worksites randomized to the intervention. Participants in the intervention exceeded 9000 daily pedometer steps and 300 weekly minutes of moderate-to-vigorous physical activity (MVPA) during the last 6 weeks of the study, which approximated or exceeded current public health guidelines. Linear growth modeling indicated that participants who set higher goals and sustained higher levels of self-efficacy, commitment and intention about attaining their goals had greater increases in pedometer steps and MVPA. The relation between change in participants' satisfaction with current physical activity and increases in physical activity was mediated by increases in self-set goals. The results show a dose relation of increased physical activity with changes in goal setting, satisfaction, self-efficacy, commitment and intention, consistent with goal-setting theory. (Contains 1 table and 8 figures.)

In the current career climate characterized by change and turbulence, employees may demonstrate limited organizational commitment to their employers. Rousseau (1998) suggests that two key ways to elicit loyalty from employees today are to reinforce perceptions of organizational membership and demonstrate organizational care and support for employees. Based on her conceptual framework, we examined the separate and synergistic effects of three valued aspects of the work environment--management communication, opportunity for learning, and work schedule flexibility--on organizational commitment. With 1770 full-time and 273 part-time workers of a large national retailer, we found that all three variables had positive main effects on organizational commitment. Also, they three-way interacted to affect part-time workers' organizational commitment. The implications of these findings for research on organizational commitment and on comparisons of full-time and part-time workers are discussed.