N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons

Ca2+ influx controls multiple neuronal functions including neurotransmitter release, protein phosphorylation, gene expression, and synaptic plasticity, Brain L-type Ca2+ channels, which contain either alpha(1C) or alpha(1D) as their pore-forming subunits, are an important source of calcium entry into neurons, alpha(1C) exists in long and short forms, which are differentially phosphorylated, and C-terminal truncation of cute increases its activity approximate to 4-fold in heterologous expression systems, Although most L-type calcium channels in brain are localized in the cell body and proximal dendrites, alpha(1C) subunits in the hippocampus are also present in clusters along the dendrites of neurons, Examination by electron microscopy shows that these clusters of alpha(1C) are localized in the postsynaptic membrane of excitatory synapses, which are known to contain glutamate receptors, Activation of N-methyl-D-asparatate (NMDA)-specific glutamate receptors induced the conversion of the long form of alpha(1C) into the short form by proteolytic removal of the C terminus, Other classes of Ca2+ channel alpha(1) subunits were unaffected, This proteolytic processing reaction required extracellular calcium and was blocked by inhibitors of the calcium-activated protease calpain, indicating that calcium entry through NMDA receptors activated proteolysis of alpha(1C) by calpain, Purified calpain catalyzed conversion of the long form of immunopurified cute to the short form in vitro, consistent with the hypothesis that calpain is responsible for processing of ale in hippocampal neurons, Our results suggest that NMDA receptor-induced processing of the postsynaptic class C L-type Ca2+ channel may persistently increase Ca2+ influx following intense synaptic activity and may influence Ca2+-dependent processes such as protein phosphorylation, synaptic plasticity, and gene expression.