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Received for publication January 20, 2005.
Revised April 20, 2005.
Accepted for publication May 11, 2005.
The role of norepinephrine (NE) in attention, memory, affect, stress, heart rate and blood pressure implicate NE in psychiatric and cardiovascular disease. The norepinephrine transporter (NET) mediates reuptake of released catecholamines, thus playing a role in the limitation of signaling strength, in the central and peripheral nervous systems. Nonsynonymous single nucleotide polymorphisms (SNPs) in the human NET (hNET) gene that influence transporter function can contribute to disease, such as the nonfunctional transporter, A457P, identified in Orthostatic Intolerance. Here, we examine additional amino acid variants that have been identified, but not characterized, in populations that include cardiovascular phenotypes. Variant hNETs were expressed in COS-7 cells and assayed for protein expression and trafficking using cell-surface biotinylation and Western blot analysis, transport of radiolabeled substrate, antagonist interaction and regulation through protein kinase C(PKC) linked-pathways by the phorbol ester, 
-PMA. We observed functional perturbations in 6 out of the 10 mutants studied. Several variants were defective in trafficking and transport with the most dramatic effect observed for A369P, which was completely devoid of the fully glycosylated form of transporter protein, was retained intracellularly and lacked any transport activity. Furthermore, A369P and another trafficking variant, N292T, impeded surface expression of hNET when coexpressed. F528C, demonstrated increased transport and, remarkably, exhibited both insensitivity to down-regulation by PKC and a decrease in potency for the tricyclic antidepressant desipramine. These findings reveal functional deficits likely to compromise NE signaling in SNP carriers in the population and also identify key regions of NET contributing to transporter biosynthesis, activity and regulation.
Key words:
Adrenergic, Protein Kinase C, Biogenic Amine, Anti-depressants
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