The norepinephrine transporter (NET) terminates noradrenergic signals by clearing released NE from extracellular synapses. Stimulation of presynaptic receptors regulates activity of NET via second messengers and kinase/ phosphatase linked pathways that modulate surface trafficking and alter catalytic activity. Stimulation of M3 acetylcholine receptors induces internalization of NET via protein kinase C dependent pathways (Apparsundaram et al. 1998). Further clarification of these pathways may suggest candidates for novel therapeutics as well as identify mechanisms that may be altered in disease states. Recently, we conducted immunoprecipitation (IP) of NET from a stably transfected neuroblastoma (CAD cells) and analyzed the proteins co-immunoprecipitated with NET by LC-MS/MS (Sung et al., 2003, SFN). In the analysis, we identified multiple peptides related to ubiquitin (Ub) system among other NET associated proteins. These proteins include the E3 ligase Nedd-4, E2 conjugating and E1 activating enzymes, sug...