BDNF, NT-3 and NGF induce distinct new Ca2+ channel synthesis in developing hippocampal neurons

Neurotrophins exert short‐ and long‐term effects on synaptic transmission. The mechanism underlying these forms of synaptic plasticity is unknown although it is likely that intracellular Ca2+ and presynaptic Ca2+ channels play a critical role. Here we show that BDNF, NGF and NT‐3 (10–100 ng/mL) exhibit a selective long‐term up‐regulation of voltage‐gated Ca2+ current densities in developing hippocampal neurons of 6–20 days in culture. NGF and NT‐3 appear more effective in up‐regulating L‐currents, while BDNF predominantly acts on non‐L‐currents (N, P/Q and R). The effects of the three neurotrophins were time‐ and dose‐dependent. The EC50 was comparable for BDNF, NGF and NT‐3 (10–16 ng/mL) while the time of half‐maximal activation was significantly longer for NGF compared to BDNF (58 vs. 25 h). Despite the increased Ca2+ current density, the neurotrophins did not alter the voltage‐dependence of channel activation, the kinetics parameters or the elementary properties of Ca2+ channels (single‐channel conductance, probability of opening and mean open time). Neurotrophin effects were completely abolished by coincubation with the nonspecific Trk‐receptor inhibitor K252a, the protein synthesis blocker anisomycin and the MAP‐kinase inhibitor PD98059, while cotreatment with the PLC‐γ blocker, U73122, was without effect. Immunocytochemistry and Western blotting revealed that neurotrophins induced an increased MAP‐kinase phosphorylation and its translocation to the nucleus. The present findings suggest that on a long time scale different neurotrophins can selectively up‐regulate different Ca2+ channels. The action is mediated by Trk‐receptors/MAP‐kinase pathways and induces an increased density of newly available Ca2+ channels with unaltered gating activity.