Calmodulin in neurotransmitter release and synaptic function

Calmodulin is a major Ca2+-binding protein in the brain that may regulate many of the neuronal functions of Ca2+. Calmodulin was characterized in preparations of presynaptic cytoplasm and highly enriched synaptic vesicles fractions. Calmodulin regulated the Ca2+-stimulated phosphorylation of several proteins in synaptic vesicle, synaptic membrane, synaptic junction, and postsynaptic density fractions. Depolarization-dependent Ca2+ influx stimulated the phosphorylation of several synaptic proteins in whole synaptosomes, synaptic vesicles, and synaptic junctions in intact synaptosomes. Evidence is presented to demonstrate that Ca2+-calmodulin-regulated synaptic protein phosphorylation plays a role in regulating neurotransmitter release in intact synaptosome and isolated vesicle preparations. Synaptic vesicle and synaptic membrane interactions in isolated systems were mediated by Ca2+ and calmodulin, and occurred under conditions that simultaneously stimulated neurotransmitter release and protein phosphorylation. Ca2+ and calmodulin stimulated the activity of a synaptic tubulin kinase system that was shown to be a distinct enzyme system from the cyclic AMP protein kinases. The calmodulin-regulated phosphorylation of tubulin was found to cause marked alterations in the properties of tubulin, resulting in the formation of insoluble tubulin fibrils. The possible role of the tubulin kinase in converting the Ca2+ signal into a motor force at the synapse and may regulate the effects of Ca2+ on neurotransmitter release and many other aspects of synaptic activity.