Moreover, the x-ray structure of a transport-inactive Drosophila melanogaster DAT (dDAT) in complex with nortriptyline shows the antidepressant bound at the central site 9, 31. Mutagenesis, chemical modification, binding and transport studies have implicated the central or S1 binding site in DAT, akin to the leucine and tryptophan site in LeuT, as the binding site occupied by DA, amphetamines, cocaine and antidepressants 25, 26, 30. Widely prescribed antidepressants specifically inhibit serotonin and noradrenaline uptake and typically have weaker affinities towards DAT 28, 29. On the other hand, the Erythroxylon coca leaf-derived alkaloid, cocaine, as well as synthetic cocaine derivatives are competitive inhibitors of DAT and enhance extracellular DA concentrations by locking the transporter in a transport inactive conformation 14, 25– 27. On the one hand, the amphetamines – potent and widely abused psychostimulants – are DAT substrates that enhance synaptic levels of DA both by competing with DA transport by DAT and by inducing the release of DA from synaptic vesicles into the cytoplasm, from where DA is then effluxed through DAT into the synaptic space 18– 24. Congruent with the multifaceted roles of DA in the nervous system, perturbation of dopaminergic signaling by disruption of native DAT function has profound consequences 15– 17. To drive the vectorial ‘uphill’ movement of extracellular DA into presynaptic cells, DAT couples substrate transport to pre-existing sodium and chloride transmembrane gradients. The dopamine transporter (DAT) 14 removes DA from synaptic and perisynaptic spaces, thus extinguishing its action at G-protein coupled DA receptors. Due to variations in amino acid sequences 12, however, the biogenic amine transporters possess distinct yet overlapping pharmacological ‘fingerprints’ 13. Experimental and computational studies have shown that the DA, serotonin (SERT) and norepinephrine (NET) transporters harbor a conserved structural fold 9, 10, first seen in the structure of LeuT 11. Biogenic amines play profound roles in the development and function of the nervous system, as well as in animal behavior and activity, thus NSSs are central to normal neurophysiology and are the targets of a spectrum of therapeutic and illicit agents, from antidepressants and antianxiety medications to cocaine and amphetamines 8. Signals by the biogenic amine neurotransmitters – dopamine (DA) 1, serotonin 2 and noradrenaline 3 - at chemical synapses are terminated by the cognate neurotransmitter sodium symporters (NSSs) 4– 7.
0 kommentar(er)
