Research objectives and content
In the central nervous system, serotoninergic neurotransmission is terminated by the rapid re-uptake of the neurotransmitter serotonin out of the synaptic cleft back into the presynaptic terminal. This translocation is mediated by a substrate specific protein, the serotonin transporter (SERT). This polypeptide represents the target site of different classes of antidepressants which inhibit serotonin re-uptake and are widely used for the treatment of depression. In addition, SERT is also the target of drugs of abuse such as cocaine or methylenedioxymethamphetamine (MDMA "ecstacy"). However, the molecular basis of the pharmacological effects and interactions of these compounds are only poorly understood. My objective is a contribution to a better understandig of the mode of action of different antidepressants on the function of the serotonin transporter molecule. This includes:
- identification of molecular determinants of antagonist binding sites on SERT (this includes a strategy which directly combines pharmacological analysis of SERT mutants with photo-affinity labelling studies). - long-term regulation of the function of SERT by antidepressants Training content (objective, benefit and expected impact)
Based on my expertises in molecular neurobiology, in the Biochemistry department I will provide training for five graduate researchers and two post-docs in the research group of. Dr.C. Williams in neuronal transporter research wich includes : - transient expression of the human and rat serotonin transporter protein - generation of a stable cell line, permanently expressing the human serotonin transporter - performing site directed mutagenesis of SERT with following pharmacological analysis - synthesis and use of photo-affinity substrate analogoues to identify antagonist binding domains - molecular characterization of a choline transporter in rat liver In addition, the envisaged collaborative project will allow us to apply for future funding to continue our collaboration also beyond this contract.
Links with industry / industrial relevance (22)
The work on the serotonin transporter in Prof. Williams group is part-funded by BioResearch Ireland which promotes the commercial exploitation of the respective studies. Here, the industrial relevance is in rational antidepressant and anti-obesity drug design and the design of drugs of abuse antidotes possibly using the recombinant SERT protein as drug sensor.