The key goal of NeuroTrans is to establish a framework for understanding Neurotransmitter:Sodium Symporters (NSS) that creates a direct link between the fundamental structural, biochemical and biophysical principles at the molecular level and the mode(s) of action of novel psychoactive substances, but also also of disease causing mutations. To achieve this ambitious goal, NeuroTrans has defined the following work-packages:
WP1: Determining transporter structures and gaining insight into complex formationTo characterize ligand bound complexes and derive structural and mechanistic insights by determining GABA transporter structures.
WP2: Characterizing electrophysiological ligand binding and substrate transportTo characterize the electrogenic events associated with transport (binding, translocation, release). Novel technologies for electrophysiological recordings will be developed by Nanion to significantly improve instrument sensitivity and throughput in vesicular and cellular recordings.
WP3: Dynamic, thermodynamic and mechanistic insights into substrate binding and transportTo obtain dynamic, kinetic, thermodynamic, structural, and mechanics insight into the processes of substrate binding and transport with improved temporal and spatial resolution. NanoTemper will develop novel technologies for efficient measurements of thermodynamic and kinetics parameters in vesicles and cells.
WP4: Mode of action of Novel Psychoactive Substances (NPS)To identify the mode of action of Novel Psychoactive Substances (NPS). The development of new microfluidic devices by Elvesys for cell based measurements and the integration with the novel technology by Nanion and NanoTemper will boost throughput by orders of magnitude and significantly decrease the time-lag between initial discovery and complete characterization to provide policy makers and regulatory bodies with information on a useful time-scale.
WP5: Molecular determinants of novel disease causing mutationsTo assess the molecular determinants of novel disease causing mutations associated with neuropsychiatric disorders discovered in large population screens. We will dissect and model how discrete molecular perturbations caused by such mutations mechanistically elicit discrete changes in transporter function that in turn can translate into disease-relevant dysregulation of neurotransmitter homeostasis.