FRIBIOFYS project coordinated by Niels Chr. Danbolt

Dynamic 3-D modelling of the synaptic environment:
The roles of transporters in controlling receptor activation and water transport

Prevention and cure of neurological diseases are hampered by a lack of knowledge of the underlying pathogenetic mechanisms which involve a complex system of transporter proteins. The primary objective of this proposal is to uncover how transporters limit activation of brain neurotransmitter receptors. To achieve this, it is not sufficient to generate qualitative data on transporter and receptor localizations. It is necessary to determine the numbers of the various protein molecules at different locations within and around synapses. Then this information must be analyzed using super computer simulation of eurotransmitter diffusion in dynamic 3-D models of cubes of brain tissue. The models must take into account protein densities, localizations, affinities, and other relevant properties like ion channel conductances and associated water transport. We will start producing these models, and also to provide the quantitative data (molecules per square micrometer cell
membrane) needed to model the roles of all the transporter proteins with affinity for. One transgenic mouse line will be produced to address an important questions related to the model: the functional importance of glutamate transporter EAAT2 in synaptic terminals. This project combines expertise in computer simulation, brain ultrastructure, membrane protein purification, molecular biology, water transport and electrophysiology in order to achieve the ambitious goal.

Partners

Jan G. Bjaalie
The University of Oslo
j.g.bjaalie@medisin.uio.no

Morten Dæhlen
The University of Oslo
mortend@ifi.uio.no

Stefan Krauss
The National Hospital
stefan.krauss@medisin.uio.no

Dimitri Rusakov
UCL Institute of Neurology
d.rusakov@ion.ucl.ac.uk