Neuronal functions critically depend on the maintenance of cell copper (Cu) homeostasis, but a full knowledge of the regulatory mechanisms has not been reached yet. Cu excess/deficiency is known to activate in vitro a transcriptional response, mainly involving the oxidative stress genes, but the effects on the kinetics of cell Cu import are largely unexplored. It's currently accepted that the integral membrane protein Ctr1 functions as the major Cu importer, but our previous studies demonstrated in a neuron-like cell model the involvement of the surface prion protein (PrP^C) in driving cell Cu internalization. This work focused on the adaptive response of a rat neuroblastoma cell line (B104) subjected to an inadequate Cu supply, with special attention to PrP^C role. Preliminarily, the health condition of Cu-depleted cells was investigated by metabolic assays (i.e. oxygen consumption rate), then the transcriptional response (Cu import proteins; CCS, Atox1 and Cox17 chaperons; ATP7A efflux pump) was analyzed by RT-PCR, and the more relevant results confirmed by proteomic studies. Remarkably, an increase in PrP^C expression was detected in Cu-depleted cultures, associated to an enhanced cell Cu uptake activity, measured by a fluorimetric technique. This finding evidenced the importance of PrP^C as a cell Cu importer under ion deficiency. Work is in progress to accurately quantify its contribution in Cu transport processes using PrP^C knocked-down neuroblastoma cell models.