<P> The classic transporter proteins use transmembrane ion gradients and electrical potential to transport neurotransmitter across the membrane of the presynaptic neuron . Typical neurotransmitter sodium symport (NSS) transporters, which are Na and Cl ion dependent, take advantage of both Na and Cl gradients, inwardly directed across the membrane . The ions flow down their concentration gradients, in many cases leading to transmembrane charge movement that is enhanced by the membrane potential . These forces pull the neurotransmitter substrate into the cell, even against its own concentration gradient . At a molecular level, Na ions stabilize amino acid binding at the substrate site and also hold the transporter in an outward - open conformation that allows substrate binding . The role of the Cl ion in the symport mechanism has been proposed to be for stabilizing the charge of the symported Na . </P> <P> After ion and substrate binding have taken place, some conformational change must occur . From the conformational differences between the structure of TMs 1 - 5 and that of TMs 6 - 10, and from the identification of a substrate permeation pathway between the binding site of SERT and the cytoplasm, a mechanism for conformational change was proposed in which a four - helix bundle composed of TMs 1, 2, 6 and 7 changes its orientation within the rest of the protein . A structure of LeuT in the inward - open conformation subsequently demonstrated that the major component of the conformational change represents movement of the bundle relative to the rest of the protein . </P> <P> The main objective of a reuptake inhibitor is to substantially decrease the rate by which neurotransmitters are reabsorbed into the presynaptic neuron, increasing the concentration of neurotransmitter in the synapse . This increases neurotransmitter binding to pre - and postsynaptic neurotransmitter receptors . Depending on the neuronal system in question, a reuptake inhibitor can have drastic effects on cognition and behavior . Non-competitive inhibition of the bacterial homologue LeuT by tricyclic antidepressants resulted from binding of these inhibitors in the extracellular permeation pathway . However, the competitive nature of serotonin transport inhibition by antidepressants suggests that in neurotransmitter transporters, they bind in a site overlapping the substrate site . </P> <P> Horschitz et al. examined reuptake inhibitor selectivity among the rat serotonin reuptake protein (SERT) expressed in human embryonic kidney cells (HEK - SERT). They presented SERT with varying doses of either citalopram (an SSRI) or desipramine (an inhibitor of norepinephrine reuptake protein, NET). By examining the dose - response curves (using a normal medium as control), they were able to quantify that citalopram acted on SERT as an SSRI, and that desipramine had no effect on SERT . In a separate experiment, Horschitz et al. exposed HEK - SERT with citalopram on a long - term basis . They noticed that long - term exposure led to a down - regulation of binding sites . These results suggest some mechanism for long - term changes in the pre-synaptic neuron after drug therapy . Horschitz et al. found that after removing citalopram from the system, normal levels of SERT binding site expression returned . </P>

What kind of transport mechanisms are used for reabsorption