Calcium/calmodulin-dependent protein kinase II and synaptic plasticity
Introduction
Influx of calcium ions (Ca2+) through ligand- and voltage-gated calcium channels in the plasma membrane, together with Ca2+ release from endoplasmic reticulum stores, results in complex calcium signals (reviewed by Sabatini et al. and Franks and Sejnowski 1., 2.). Information can be conveyed by the spatial localization, amplitude, duration, and frequency of individual calcium transients. Ca2+ modulates virtually all neuronal functions, ultimately providing short- and long-term regulation of synaptic properties and determining normal and diseased brain functions. Ca2+/calmodulin-dependent protein kinase II (CaMKII), a multifunctional serine/threonine kinase found in essentially all neuronal compartments, is prominent among the Ca2+-sensitive processes that underlie these responses. The unique regulatory properties of CaMKII make it an ideal ‘interpreter’ of the diversity of Ca2+ signals. Here, we discuss CaMKII structure and regulation but focus on the roles of dendritic CaMKII in synaptic plasticity.
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Structure
CaMKIIα and CaMKIIβ are the two major isoforms of CaMKII expressed in the brain. Both isoforms contain amino-terminal catalytic (≈260 amino acids) and regulatory (≈40 amino acids) domains that are about 90% identical. The variable size of the carboxy-terminal domain (180–240 amino acids) arises from alternative mRNA splicing (Figure 1a). Carboxy-terminal domains assemble subunits into homo- or heteromeric holoenzymes consisting of a stacked pair of hexameric subunit rings, as revealed by
Calcium/calmodulin-dependent protein kinase II subcellular localization
CaMKII was identified as a major PSD protein two decades ago. CaMKII is specifically localized to the cytoplasmic face of isolated PSDs at a mean distance of 25 nm from the synaptic cleft, and in a highly ordered array of tower-like structures [10•]. Individual PSDs contain highly variable levels of CaMKII [10•], probably reflecting dynamic regulation of CaMKII association with PSDs in vivo. This dynamic association was revealed in real time by overexpression of green fluorescent protein
Turnover of calcium/calmodulin-dependent protein kinase II
Long-term potentiation (LTP) induction in the hippocampal CA1 region elevates total dendritic CaMKIIα protein levels by an NMDA receptor- and mitogen activated protein (MAP)-kinase-dependent mechanism 21., 22.. Recently, high levels of synaptic activity were shown to upregulate CaMKIIα expression and downregulate CaMKIIβ expression in cultured hippocampal neurons [23•]. High levels of synaptic activity also upregulate CaMKIIα levels in PSDs from cultured cortical neurons, but with a parallel
Plasticity of synaptic transmission
CaMKII activity and Thr286 autophosphorylation are essential for normal NMDA receptor-dependent forms of LTP in the hippocampal CA1 region and hippocampus-dependent behaviors, such as spatial learning and memory 31., 32., 33., and also for plasticity in other central nervous system regions 34., 35.•, 36., 37.. Hippocampal LTP involves enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid -type glutamate receptors (AMPA receptors) by two mechanisms: phosphorylation of GluR1
Plasticity of dendritic morphology
CaMKIIβ splice variants predominate in early brain development, and it was recently demonstrated that CaMKIIβ, but not CaMKIIα, promotes motility of filopodia and neuritic branches in developing hippocampal neuron cultures, which results in enhanced arborization. These morphological changes appear to require direct association of CaMKIIβ with F-actin, a property not shared by CaMKIIα [12•]. CaMKIIα is expressed later during neuronal development and stabilizes dendritic arbor structure [71].
Conclusions and future directions
Many years have been devoted to unraveling the role of CaMKII in synaptic plasticity. These studies have revealed complex mechanisms that control CaMKII activity with exquisite spatial and temporal specificity and regulate the surface expression and activity of AMPA-type glutamate receptors (Figure 2). However, the mechanisms and roles of enhanced dendritic synthesis of CaMKIIα, and CaMKII-dependent morphological changes are only beginning to be understood. Much remains unknown about the
Update
Two recent papers provide new information about the role of CaMKII in different forms of synaptic plasticity. Rodrigues et al. [83•] demonstrate that fear conditioning increases CaMKII autophosphorylation at Thr286 in dendritic spines of lateral amygdala synapses and that a CaMKII inhibitor impairs the acquisition of fear conditioning, as well as LTP at thalamic input synapses. Ninan and Arancio [84] present evidence for a novel presynaptic role for CaMKII in synaptic plasticity in cultured
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
Work in the authors’ laboratory is supported by National Institutes of Health grants (RO1-MH63232, RO1-NS37508, and PO1-NS044282). AM Brown was supported by a National Institutes of Health Training Grant (T32-GM08554). We thank L Carmody, AJ Robison, E Norman and E Weeber (Vanderbilt University) for comments on drafts of this article. The journal policy to focus on recent advances (since 2002) within tight space constraints made it impossible to adequately discuss and cite all relevant primary
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