Copper activates TrkB in cortical neurons in a metalloproteinase-dependent manner

Copper (Cu) is an endogenous metal that is physiologically essential in the brain and that, like zinc (Zn), may be synaptically released in certain regions. Previously, we demonstrated that Zn activates TrkB in cultured cortical neurons in a metalloproteinase (MP)-dependent manner. To determine whether Cu has similar properties, we exposed cortical cultures for 15 min to various metals and performed Western blots to detect tyrosine-phosphorylated TrkB (p-Trk). Whereas Cd, Mn, Fe(II), and Fe(III) had no effect on the level of p-Trk, 10 microM of Cu in phosphate-containing (Hanks' balanced salt solution) or 10 nM in phosphate-lacking salt solution (control salt solution), increased levels of p-Trk. Cu also activated extracellular signal-regulated kinase 1/2 and Src tyrosine kinase, signaling molecules activated downstream of TrkB. Cu decreased levels of probrain-derived neurotrophic factor (pro-BDNF) in cells but increased levels of pro- and mature BDNF in the media. Addition of MP inhibitors completely blocked the Cu-induced increases in pro-BDNF and BDNF as well as TrkB activation, indicating that MP mediates most of the Cu effect. Furthermore, Cu increased the activity of matrix metalloproteinase 2 (MMP2) and MMP9 in cortical neurons. These findings indicate that, like Zn, Cu activates MPs, releases pro-BDNF from cells, and phosphorylates TrsB. Because Cu, like Zn, is released in certain brain areas with neuronal activity, metal-triggered TrkB activation may occur in both Cu- and Zn-containing synapses.