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Ulrik Gether "Molecular function of cocaine-sensitive neurotransmitter transporters."

Abstract :

The dopamine transporter (DAT) belongs to the SLC6 (solute carrier 6) gene family of Na+/Cl- dependent transporters.
It is situated in the presynaptic membrane and mediates rapid reuptake of dopamine from the synaptic cleft. Alteration in dopaminergic signaling and thereby DAT function is tightly coupled to the development of major neurological and psychiatric diseases including schizophrenia, bipolar disorder, psychosis, ADHD (Attention Deficit Hyperactivity Disorder), Tourette’s syndrome and Parkinsons’ disease. The DAT is moreover the principle target for widely abused psychostimulants, such as cocaine and amphetamines. Until recently, little was known about the tertiary structure of Na+/Cl- dependent transporters; however, a high-resolution structure has now been obtained for a bacterial homolog allowing for the first time generation of believable structural models of the DAT and related transporters.
The long-term goal of our research is to understand the molecular and cellular mechanisms governing the activity and availability of Na+/Cl- dependent neurotransmitter transporters in the synaptic membrane. By the combined use of molecular modeling, site-directed mutagenesis, cysteine reactivity assays and fluorescence techniques we are currently trying to define the structural basis for conformational transitions in the transport cycle as well as we aim at characterize the structural basis for the action cocaine and related pcychostimulants at the DAT. In parallel we attempt to characterize the role of cellular protein-protein interaction for DAT function. Specifically, we have searched for novel interaction partners and employed both proteomics based techniques and classical yeast two hybrid screens. In this way we have identified a number of proteins that might be important for regulating DAT function. This includes Ca2+/Calmodulin dependent kinase IIα (CaMKIIα that was found to bind to the DAT C-terminus. Our data suggest that CaMKIIα binding to the DAT C-terminus facilitates phosphorylation of the DAT N-terminus and thereby mediates amphetamine-induced dopamine efflux. This represents a yet unknown mechanism for how amphetamines exert their action on the human brain and should prove important for future efforts directed towards the discovery of new treatments against amphetamine addiction.

Selected publications

June 2006 / Neurotransmitter transporters: molecular function of important drug targets. : Gether U, Andersen PH, Larsson OM, Schousboe A.
Trends Pharmacol Sci.
June 2006 /Phosphorylation of the norepinephrine transporter at threonine 258 and serine 259 is linked to protein kinase C-mediated transporter internalization.: Jayanthi LD, Annamalai B, Samuvel DJ, Gether U, Ramamoorthy S.
J Biol Chem.
May 2006 /Zn2+ modulation of neurotransmitter transporters. : Norgaard-Nielsen K, Gether U.
Handb Exp Pharmacol.

May 2006 /Regulation of Dopamine Transporter Trafficking by Intracellular Amphetamine. : Kahlig KM, Lute BJ, Wei Y, Loland CJ, Gether U, Javitch JA, Galli A. Mol Pharmacol.

Laurent Groc