The norepinephrine transporter (NET), the first of the monoamine transporters to be cloned in humans, transports NE from the synaptic cleft back into the neuron (Pacholczyk et al. 1991). Like other monoamine transporters, NET comprises 12 putative transmembrane domains, and autoradiography with various NE reuptake inhibitors has been used to determine the brain distribution of NET. A high level of NET is found in the LC, with moderate to high levels found in the dentate gyrus, raphe nuclei, and hippocampus (Tejani-Butt and Ordway 1992; Tejani-Butt et al. 1990). This pattern of expression is consistent with the NE innervation to these structures. The NET is expressed mainly on NE terminals, as demonstrated by a drastic reduction in labeling following NE destruction with the neurotoxin 6-hydroxydopamine or DSP-4 (Tejani-Butt and Ordway 1992; Tejani-Butt et al. 1990).
The NET is dependent on extracellular Na+ to mediate NE reuptake and the effectiveness of NE reuptake inhibitors in inhibiting NE reuptake (Bruss et al. 1997, 1999; Harder and Bonisch 1985). The uptake of NE is CI" dependent, meaning that the electrogenic process of NE transport is Na+ and CI" driven (Harder and Bonisch 1985). In addition to the electrogenic process, the NET demonstrates properties of a channel-like pore, in that it can transport NE showing an infinite stoichiometry that can be blocked by cocaine and desipramine (Galli et al. 1995, 1996). A number of studies suggest that NET can be regulated by diverse stimuli, neuronal activity, and peptide hormones, as well as protein kinases. Indeed, studies have shown that all monoaminergic transporters (5-HTT, DAT, and NET) are rapidly regulated by direct or receptor-mediated activation of cellular kinases, particularly PKC (Bauman et al. 2000). PKC activation results in an activity-dependent transporter phosphorylation and sequestration. Protein phosphatase-l/2A (PP-1/PP-2A) inhibitors, such as okadaic acid and calyculin A, also promote monoaminergic transporter phosphorylation and functional downregulation (Bauman et al. 2000). These phenomena that occur beyond the receptor level may well be important in the long-term actions of psychotropic drugs known to regulate protein kinases (G. Chen et al. 1999; Manji and Lenox 1999).
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