Modulation of the nitric oxide pathway by copper in glial cells

The action of copper on the nitric oxide (NO) pathway was investigated in r at C6 glioma cells expressing both inducible and constitutive NO synthase ( NOS) isoforms, The inducible NOS-II-mediated NO synthesis (i.e., nitrite pr oduction induced by LPS plus IFN gamma) was found to be increased upon copp er uptake by cells, this effect being attributable to NOS-II mRNA transcrip tional over-expression. On the other hand, the constitutive neuronal isofor m (NOS-I) was inhibited after copper uptake, as revealed by the decrease of basal intracellular cGMP levels in C6 cells. Consistently, in vitro experi ments showed that copper selectively blocked the catalytic activity of NOS- I, but not of NOS-II, The observed modulation of NOS isoforms by copper in C6 cells is in line with the previous hypothesis that selective inhibition of NOS-I leads to enhanced NO production through transcriptional activation of NOS-II. (C) 2000 Academic Press.