研究领域

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Molecular Structure-Function Relationships and Regulation of Transporters for Catecholamines and Serotonin The overall theme of Dr Lluka's research is the molecular mechanisms that determine the expression and function of the noradrenaline transporter (NET) and the serotonin transporter (SERT). These transporters are important in the removal of monoamine neurotransmitters from the synapse after neuronal release and also for the removal of catecholamines and serotonin from the circulation, particularly by endothelial cells in the lungs. Drugs that inhibit these transporters include psychostimulants, such as cocaine, and also antidepressants, such as imipramine and fluoxetine (Prozac). * Molecular structure-function relationships of the noradrenaline transporter (NET) In collaboration with Heinz Bönisch's group at the University of Bonn (Germany), we cloned the rat NET. This led to extensive studies into the structural determinants of both the expression in the cell membrane and the function of this transporter. We have used site-directed mutagenesis followed by assays in transfected cells and confocal microscopy to determine the structural and functional effects of amino acid exchanges in the transporter. We have shown that there are distinct binding sites for antidepressants, psychostimulants and substrates (e.g. noradrenaline) on the NET and are investigating the functionally important parts of the NET with a technique called SCAM. The expected outcomes of this area of research are: (i) a much clearer understanding at the molecular level of how antidepressants, psychostimulants and substrates interact with the transporters; (ii) more rational drug design of transporter inhibitors for the therapy of conditions such as depression; (iii) the development of antagonists that block the effects of psychostimulants such as cocaine on the NET without affecting its other functions (including noradrenaline uptake) for use in cocaine abuse rehabilitation programs. * Regulation of transporters for catecholamines and serotonin We have investigated the roles of second messengers, hormones and drugs in the regulation of expression and function of the NET and SERT. We have shown that the expression of the transporters is differentially regulated in different cell types, and this may lead to new strategies for the therapy of depression with fewer side effects. * We are also involved in a number of collaborative projects investigating such aspects as: (i) the inhibition of the NET and SERT by nitric oxide donors that are used as vasodilators; (ii) the effects of antidepressant administration on glutamate transporters in the mouse brain as a model system (iii) the effects of antipsychotic drugs used in schizophrenia on central neuronal structure and connectivity using a rat model