NEUROTROPHINS STIMULATE PHOSPHORYLATION OF SYNAPSIN-I BY MAP KINASE AND REGULATE SYNAPSIN-I ACTIN INTERACTIONS

The ability of neurotrophins to modulate the survival and differentiat ion of neuronal populations involves the Trk/MAP (mitogen-activated pr otein kinase) kinase signaling pathway, More recently, neurotrophins h ave also been shown to regulate synaptic transmission, The synapsins a re a family of neuron-specific phosphoproteins that play a role in reg ulation of neurotransmitter release, in axonal elongation, and in form ation and maintenance of synaptic contacts, We report here that synaps in I is a downstream effector for the neurotrophin/Trk/MAP kinase casc ade, Using purified components, we show that MAP kinase stoichiometric ally phosphorylated synapsin I at three sites (Ser-62, Ser-67, and Ser -549). Phosphorylation of these sites was detected in rat brain homoge nates, in cultured cerebrocortical neurons, and in isolated presynapti c terminals, Brain-derived neurotrophic factor and nerve growth factor upregulated phosphorylation of synapsin I at MAP kinase-dependent sit es in intact cerebrocortical neurons and PC12 cells, respectively, whi le KCI-induced depolarization of cultured neurons decreased the phosph orylation state at these sites, MAP kinase-dependent phosphorylation o f synapsin I significantly reduced its ability to promote G-actin poly merization and to bundle actin filaments, The results suggest that MAP kinase-dependent phosphorylation of synapsin I may contribute to the modulation of synaptic plasticity by neurotrophins and by other signal ing pathways that converge at the level of MAP kinase activation.