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A Dynamic Model of Interactions of Ca2+, Calmodulin, and Catalytic Subunits of Ca2+/Calmodulin-Dependent Protein Kinase II 1. 2. 2¤ 2 Shirley Pepke , Tamara Kinzer-Ursem , Stefan Mihalas , Mary B. Kennedy * 1 Center for Advanced Computing Research, California Institute of Technology, Pasadena, California, United States of America, 2 Division of Biology, California Institute of Technology, Pasadena, California, United States of America Abstract During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D- aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+ influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play