Competitive tuning: Competition's role in setting the frequency-dependence of Ca2+-dependent proteins

A number of neurological disorders arise from perturbations in biochemical signaling and protein complex formation within neurons. Normally, proteins form networks that when activated produce persistent changes in a synapse’s molecular composition. In hippocampal neurons, calcium ion (Ca2+) flux through N-methyl-D-aspartate (NMDA) receptors activates Ca2+/calmodulin signal transduction networks that either increase or decrease the strength of the neuronal synapse, phenomena known as long-term potentiation (LTP) or long-term depression (LTD), respectively. The calcium-sensor calmodulin (CaM) acts as a common activator of the networks responsible for both LTP and LTD. This is possible, in part, because CaM binding proteins are “tuned” to different Ca2+ flux signals by their unique binding and activation dynamics. Computational modeling is used to describe the binding and activation dynamics of Ca2+/CaM signal transduction and can be used to guide focused experimental studies. Although CaM binds over 100 proteins, practical limitations cause many models to include only one or two CaM-activated proteins. In this work, we view Ca2+/CaM as a limiting resource in the signal transduction pathway owing to its low abundance relative to its binding partners. With this view, we investigate the effect of competitive binding on the dynamics of CaM binding partner activation. Using an explicit model of Ca2+, CaM, and seven highly-expressed hippocampal CaM binding proteins, we find that competition for CaM binding serves as a tuning mechanism: the presence of competitors shifts and sharpens the Ca2+ frequency-dependence of CaM binding proteins. Notably, we find that simulated competition may be sufficient to recreate the in vivo frequency dependence of the CaM-dependent phosphatase calcineurin. Additionally, competition alone (without feedback mechanisms or spatial parameters) could replicate counter-intuitive experimental observations of decreased activation of Ca2+/CaM-dependent protein kinase II in knockout models of neurogranin. We conclude that competitive tuning could be an important dynamic process underlying synaptic plasticity.Author summary: Learning and memory formation are likely associated with dynamic fluctuations in the connective strength of neuronal synapses. These fluctuations, called synaptic plasticity, are regulated by calcium ion (Ca2+) influx through ion channels localized to the post-synaptic membrane. Within the post-synapse, the dominant Ca2+ sensor protein, calmodulin (CaM), may activate a variety of downstream binding partners, each contributing to synaptic plasticity outcomes. The conditions at which certain binding partners most strongly activate are increasingly studied using computational models. Nearly all computational studies describe these binding partners in combinations of only one or two CaM binding proteins. In contrast, we combine seven well-studied CaM binding partners into a single model wherein they simultaneously compete for access to CaM. Our dynamic model suggests that competition narrows the window of conditions for optimal activation of some binding partners, mimicking the Ca2+-frequency dependence of some proteins in vivo. Further characterization of CaM-dependent signaling dynamics in neuronal synapses may benefit our understanding of learning and memory formation. Furthermore, we propose that competitive binding may be another framework, alongside feedback and feed-forward loops, signaling motifs, and spatial localization, that can be applied to other signal transduction networks, particularly second messenger cascades, to explain the dynamical behavior of protein activation.