BDNF, NT‐3 and NGF induce distinct new Ca 2+ 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 Ca 2+ and presynaptic Ca 2+ 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 Ca 2+ 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 EC 50 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 Ca 2+ current density, the neurotrophins did not alter the voltage‐dependence of channel activation, the kinetics parameters or the elementary properties of Ca 2+ 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 Ca 2+ channels. The action is mediated by Trk‐receptors/MAP‐kinase pathways and induces an increased density of newly available Ca 2+ channels with unaltered gating activity.