A spatial model of autophosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) predicts that the lifetime of phospho-CaMKII after induction of synaptic plasticity is greatly prolonged by CaM-trapping.

Abstract

Activation of N-methyl-D-aspartate-type glutamate receptors (NMDARs) at synapses in the CNS triggers changes in synaptic strength that underlie memory formation in response to strong synaptic stimuli. The primary target of Ca2+ flowing through NMDARs is Ca2+/calmodulin dependent protein kinase II (CaMKII) which forms dodecameric holoenzymes that are highly concentrated at the postsynaptic site. Activation of CaMKII is necessary to trigger long-term potentiation of synaptic strength (LTP), and is prolonged by autophosphorylation of subunits within the holoenzyme. Here we use MCell4, an agent-based, stochastic, modeling platform to model CaMKII holoenzymes placed within a realistic spine geometry. We show how two mechanisms of regulation of CaMKII, 'Ca2+-calmodulin-trapping (CaM-trapping)' and dephosphorylation by protein phosphatase-1 (PP1) shape the autophosphorylation response during a repeated high-frequency stimulus. Our simulation results suggest that autophosphorylation of CaMKII does not constitute a bistable switch. Instead, prolonged but temporary, autophosphorylation of CaMKII may contribute to a biochemical-network-based 'kinetic proof-reading' mechanism that controls the induction of synaptic plasticity.

Role of Post-Transcriptional Regulation in Learning and Memory in Mammals

“…The mechanisms underlying LTP are fundamental for the highest cognitive functions, such as the processes of learning and memory. Among other things, a correlation has been reported between the synaptic strength and the volume of the dendritic spines that constitute the post-synaptic elements [ 31 , 32 , 33 , 34 , 35 , 36 ]. Modifications of the dendritic spines are, in turn, bound to the remodeling of the actin cytoskeleton, a complex event which also depends on the modification of the number and activity of actin-binding proteins able to regulate G-actin polymerization.…”

“…It is also important to consider that learning and memory are, for most, bound to neurotransmission from glutamatergic neurons; in this case, due to the involvement of the N-methyl-D-aspartate-type glutamate receptors (NMDARs), post-synaptic elements undergo a significant afflux of calcium ions, which can bind and activate the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII). It has indeed been found that the generation of LTP is also CaMKII-dependent [ 36 , 38 ].…”