A spatial model of autophosphorylation of Ca2+/calmodulin-dependent protein kinase II in a glutamatergic spine reveals dynamics of kinase activation in the first several seconds after a complex synaptic stimulus

Abstract

AbstractLong-term potentiation (LTP) is a biochemical process in excitatory glutamatergic synapses in the Central Nervous System (CNS). It is initiated by a bout of synaptic activation that is strong enough to contribute to production of an action potential in the axon of the postsynaptic neuron, and it results in an increase in the size of postsynaptic depolarization during subsequent activity. The first step leading to LTP is activation and autophosphorylation of an abundant postsynaptic enzyme, Ca2+/calmodulin-dependent protein kinase II (CaMKII). We use simulation of activation of CaMKII holoenzymes in a realistic spatial model of a spine synapse, created in MCell4, to test three hypotheses about how the autophosphorylation response of CaMKII is shaped during a repeated high-frequency stimulus. First, the simulation results indicate that autophosphorylation of CaMKII does not constitute a bistable switch under biologically realistic conditions. Instead, prolonged autophosphorylation of CaMKII may contribute to a biochemical “kinetic proof-reading” mechanism that controls induction of synaptic plasticity. Second, concentration of CaMKII near the postsynaptic membrane increases the local concentration of kinase activity. However, neither localization nor “Ca2+-calmodulin-trapping (CaM-trapping)” increase the proportion of autophosphorylated subunits in holoenzymes after a complex stimulus, as previously hypothesized. Finally, we show that, as hypothesized, the amplitude of autophosphorylation in the first 30 seconds after a stimulus is extremely sensitive to the level and location of PP1 activity when PP1 is present in biologically accurate amounts. We further show that prolonged steric hindrance of dephosphorylation of CaMKII, caused by CaM-trapping, can increase the amplitude of autophosphorylation after a complex stimulus. These simulation results sharpen our quantitative understanding of the early events leading to LTP at excitatory synapses.Author SummaryNeurons in the brain are interconnected in an organized fashion by synapses that transmit neuronal activity from one neuron to another. Most of the billions of neurons in the brain have about 10,000 synapses spread over the neuronal membrane. Information is stored in the brain when the ability of specific synapses to pass along neuronal activity is strengthened resulting in formation of new networks. The increase in strength of a synapse is tightly controlled by the frequency and amplitude of its activity, and by neurohormonal signals, which, in combination, can cause long-lasting biochemical changes at the synapse that underlie learning and memory. Defects in these biochemical pathways cause mental and neurological diseases. To develop treatments, we need to understand the precise choreography of these critical biochemical changes. However, the tiny size of the synaptic compartment makes precise measurements of the biochemical reactions impossible. We have used computer simulation techniques and information gathered from experiments on purified synaptic proteins to simulate, within a single synapse, the choreography of the first biochemical step in synaptic strengthening: activation of the enzyme Ca2+/ calmodulin-dependent protein kinase II. Our results provide insights that can be used in future studies to develop treatments for neuronal diseases.