Trends in Neurosciences
ReviewCaMKII regulation in information processing and storage
Introduction
CaMKII has sparked the imagination of neuroscientists since its discovery 1, 2. It is highly expressed in brain and is further enriched at excitatory synapses and their postsynaptic densities (PSDs). Moreover, its stimulation by Ca2+/CaM can also generate Ca2+-independent autonomous activity that outlasts this initial stimulus 2, 3, 4. Thus, CaMKII is ideally poised to mediate the induction and maintenance of synaptic plasticity underlying learning and memory. Indeed, CaMKII can mediate LTP of excitatory synapse strength 5, 6, 7, 8, 9, both by increasing the number of synaptic AMPA receptors (AMPARs) 10, 11, 12 and their conductance 13, 14, 15, 16 (see also 17, 18, 19, 20, 21). Furthermore, knockout mice of CaMKIIα, the major isoform in brain, were the first transgenic animals with a behavioral phenotype in learning and memory [22].
Over 25 years of research has firmly connected CaMKII with LTP of excitatory synapses (Table 1), however, recent findings have expanded this traditional view: CaMKII is also required for postsynaptic mechanisms induced by excitatory LTD-stimuli, both for depressing excitatory synapses [23] and for potentiating inhibitory synapses 24, 25. Further complicating the matter, at least some of the LTP- and LTD-mechanisms require CaMKII autophosphorylation at T286 25, 26, 27. Thus, the spatial and temporal control of CaMKII regulation in neurons has gained much renewed significance [28]. Despite recent advances on the regulation and structure of CaMKII 29, 30, 31, 32, 33, both areas still pose many unsolved riddles. Here, we discuss our current understanding of CaMKII regulation mechanisms in the context of the kinase structure and their role in synaptic functions, with a focus on the CaMKIIα isoform. Although presynaptic [34], pathological [35], cerebellar [36], and non-neuronal [30] functions of CaMKII are emerging, our discussion here is largely restricted to postsynaptic CaMKII mechanisms in hippocampal pyramidal neurons (where the functions of specific CaMKII regulation mechanisms in information processing and storage are understood best).
Section snippets
CaMKII isoforms, variants, subunits and holoenzymes
Four homologous CaMKII isoforms (α, β, γ, and δ) are encoded by separate genes, with alternative splicing in their variable linker domain generating additional diversity [2] (Figure 1a). Splicing can affect targeting and regulation. For instance, the minor splice variant αB contains a nuclear localization signal [37], and the developmental variant βe lacks the F-actin binding found for the major β isoform [38]. Additionally, variants with shorter linkers (such as the major α isoform) appear to
Stimulated and autonomous CaMKII activity
Activity of each CaMKII subunit is stimulated individually by direct binding of Ca2+/CaM to their regulatory domains (Figure 1c–e and Figure 3a) 1, 2. Autophosphorylation at T286 within the regulatory domain transforms CaMKII from one of the lowest to one of the highest affinity CaM binders within the cell [57]. This autophosphorylation also generates autonomous (Ca2+-independent) kinase activity. However, contrary to common perception, such autonomous CaMKII is not fully active, but can
Frequency detection by T286 autophosphorylation
The holoenzyme assembly (Figure 1b) has at least one profound effect on CaMKII regulation: T286 autophosphorylation occurs as an inter-subunit reaction within the holoenzyme, which makes it independent of the CaMKII concentration [2]. Importantly, Ca2+/CaM-binding has a dual role in this reaction: it is required not only for activation of the subunit acting as the kinase, but also for making T286 accessible on the neighboring subunit acting as the substrate 82, 83 (Figure 3a). Indeed, this
Function of T286 autophosphorylation in processing of information
A long-standing hypothesis proposed a function for CaMKII stimulation in LTP induction and for CaMKII autonomy in LTP maintenance. Indeed, maintaining the kinase activity that induced LTP 5, 6 should then also be sufficient to maintain the potentiated state, and this intuitive view is supported by experiments that introduced active CaMKII into postsynaptic neurons [90] and by T286A mutant mice [26]. However, recent studies reported that autonomous CaMKII is not fully active [29] and that CaMKII
The CaMKII/NMDAR complex in storage of synaptic information
The tatCN21 inhibitor interferes not only with CaMKII activity, but also with binding to the NMDAR subunit GluN2B [73]. However, in contrast to inhibition of phosphorylation of regular substrates, inhibition of GluN2B binding is competitive and likely occurs with a higher IC50 [73]. Indeed, transient tatCN21 application persistently disrupts the CaMKII/NMDAR complex in hippocampal slices, but only at higher concentrations (20 μM) and not at the lower concentrations (5 μM) sufficient to block LTP
CaMKII, the synaptic tag, and other structural functions related to LTP
As LTP maintenance requires synthesis of new proteins that selectively strengthen only activated synapses but not their neighbors [21], some synaptic tag must enable differentiation between these synapses. Strong evidence indicates that CaMKII activation is required for this tagging 104, 105, 106. CaMKII may induce structural changes that create the tag, be part of the tag itself, or both. CaMKII can induce structural changes by regulating the synaptic scaffolding proteins PSD95 107, 108 and
Beyond LTP: CaMKII functions in LTD-related mechanisms
Glutamatergic LTD-stimuli cause depression of excitatory glutamatergic synapses and potentiation of inhibitory GABAergic synapses in the same postsynaptic neurons, and CaMKII has recently been implicated in the regulation of both events 23, 24. The specific CaMKII-mediated downstream signaling steps are currently unclear, but phosphorylation of the AMPAR subunit GluA1 at S567 is an attractive candidate for depressing glutamatergic synapses: phosphorylation of S567 in loop 1 directly reduces
CaMKII in global communication between different synapses and receptor systems
CaMKII can communicate the input information of glutamatergic LTD-stimuli to inhibitory synapses, both by increased CaMKII localization to these synapses and by increased GABAA receptor surface expression [25]. CaMKII can also communicate input information by serotonin, dopamine, and Wnt signaling pathways to glutamatergic synapses. Specifically, CaMKII can mediate 5-HT1A receptor induced suppression of NMDAR function [129], D4-type dopamine receptor-induced bidirectional regulation of AMPARs
Directing neuronal plasticity by spatiotemporal regulation of CaMKII?
Traditionally, significant CaMKII T286 phosphorylation (and thus autonomy) was thought to be induced specifically by LTP-stimuli, and then to persist for hours (Figure 5). Such a view is supported by experimental evidence 139, 140, 141, however, may need to be reassessed in light of recent studies. For instance, a live-imaging study [28] that used a fluorescence resonance energy transfer (FRET)-based sensor [142] to visualize CaMKII activity in individual spines found that LTP-stimuli induced a
Concluding remarks
Although we now know many details about CaMKII, both regarding its complex regulation and its various neuronal functions, there is undoubtedly still much to be learned in both areas (Box 1). The most significant advances will likely come from tying together specific regulation mechanisms with specific signaling functions. This will require further elucidating the specific aspects of the complex regulation of CaMKII activity and localization that are engaged in response to different neuronal
Disclosure statement
The University of Colorado is currently seeking patent protection for tatCN21, its derivatives, and uses.
Acknowledgments
We thank Drs Howard Schulman and Matt Kennedy for critical reading of the manuscript and helpful comments. We also thank Drs Howard Schulman, Luke Chao, and John Kuriyan for providing CaMKII holoenzyme models. Our research was supported by a National Institutes of Health grant (R01 NS052644).
References (147)
Quantitative estimates of the cytoplasmic, PSD, and NMDAR-bound pools of CaMKII in dendritic spines
Brain Res.
(2011)CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin
Neuron
(2010)- et al.
Posttranslational regulation of AMPA receptor trafficking and function
Curr. Opin. Neurobiol.
(2012) - et al.
The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits
Neuron
(2011) - et al.
Regulation of AMPA receptor trafficking and synaptic plasticity
Curr. Opin. Neurobiol.
(2012) - et al.
Postsynaptic signaling during plasticity of dendritic spines
Trends Neurosci.
(2012) CaMKII autonomy is substrate-dependent and further stimulated by Ca2+/calmodulin
J. Biol. Chem.
(2010)A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation
Cell
(2008)A mechanism for tunable autoinhibition in the structure of a human Ca2+/calmodulin- dependent kinase II holoenzyme
Cell
(2011)Functional implications of the subunit composition of neuronal CaM kinase II
J. Biol. Chem.
(1999)
Developmental expression of the CaM kinase II isoforms: ubiquitous gamma- and delta-CaM kinase II are the early isoforms and most abundant in the developing nervous system
Brain Res. Mol. Brain Res.
SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation
Neuron
Oligomeric structure of alpha-calmodulin-dependent protein kinase II
J. Mol. Biol.
Crystal structure of a tetradecameric assembly of the association domain of Ca2+/calmodulin-dependent kinase II
Mol. Cell
Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation
Neuron
Dendritic protein synthesis, synaptic plasticity, and memory
Cell
Spatially restricting gene expression by local translation at synapses
Trends Neurosci.
Dynamic visualization of local protein synthesis in hippocampal neurons
Neuron
Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines
Cell
Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II
J. Biol. Chem.
Structure of the autoinhibited kinase domain of CaMKII and SAXS analysis of the holoenzyme
Cell
Differential modulation of Ca2+/calmodulin-dependent protein kinase II activity by regulated interactions with N-methyl-D-aspartate receptor NR2B subunits and alpha-actinin
J. Biol. Chem.
Substrate-selective and calcium-independent activation of CaMKII by alpha-actinin
J. Biol. Chem.
Calcium/calmodulin-dependent protein kinase II inhibitor protein: localization of isoforms in rat brain
Neuroscience
Calcium/calmodulin-independent autophosphorylation sites of calcium/calmodulin-dependent protein kinase II. Studies on the effect of phosphorylation of threonine 305/306 and serine 314 on calmodulin binding using synthetic peptides
J. Biol. Chem.
Inhibitory autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase analyzed by site-directed mutagenesis
J. Biol. Chem.
Inactivation of Ca2+/calmodulin-dependent protein kinase II by basal autophosphorylation
J. Biol. Chem.
Chemical quenched flow kinetic studies indicate an intraholoenzyme autophosphorylation mechanism for Ca2+/calmodulin-dependent protein kinase II
J. Biol. Chem.
Regulation of the Ca2+/CaM-responsive pool of CaMKII by scaffold-dependent autophosphorylation
Neuron
Inhibition of phosphatase activity facilitates the formation and maintenance of NMDA-induced calcium/calmodulin-dependent protein kinase II clusters in hippocampal neurons
Neuroscience
Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals
Neuron
Substrate-directed function of calmodulin in autophosphorylation of Ca2+/calmodulin-dependent protein kinase II
J. Biol. Chem.
Activity-driven postsynaptic translocation of CaMKII
Trends Pharmacol. Sci.
Multivalent interactions of calcium/calmodulin-dependent protein kinase II with the postsynaptic density proteins NR2B, densin-180, and alpha-actinin-2
J. Biol. Chem.
NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII
Neuron
Triheteromeric NR1/NR2A/NR2B receptors constitute the major N-methyl-D-aspartate receptor population in adult hippocampal synapses
J. Biol. Chem.
Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor
J. Biol. Chem.
Stimulation of brain membrane protein phosphorylation by calcium and an endogenous heat-stable protein
Nature
Neuronal CA2+/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function
Annu. Rev. Biochem.
Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain
J. Neurosci.
Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP
Science
Deficient hippocampal long-term potentiation in α-calcium-calmodulin kinase II mutant mice
Science
Specificity of protein kinase inhibitor peptides and induction of long-term potentiation
Proc. Natl. Acad. Sci. U.S.A.
CA1 long-term potentiation is diminished but present in hippocampal slices from alpha-CaMKII mutant mice
Learn. Mem.
Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation
Science
Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction
Science
Motor protein-dependent transport of AMPA receptors into spines during long-term potentiation
Nat. Neurosci.
Modulation of AMPA receptor unitary conductance by synaptic activity
Nature
Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors
Proc. Natl. Acad. Sci. U.S.A.
Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating
Nat. Neurosci.
Cited by (254)
Activation of CaMKII/HDAC4 by SDF1 contributes to pulmonary arterial hypertension via stabilization Runx2
2024, European Journal of PharmacologyExperience-Induced Remodeling of the Hippocampal Post-synaptic Proteome and Phosphoproteome
2023, Molecular and Cellular ProteomicsThe role of hippocampal CaMKII in resilience to trauma-related psychopathology
2022, Neurobiology of StressCitation Excerpt :Expression level of CaMKII is much higher in the dorsal hippocampus that the ventral hippocampus (von Ziegler et al., 2022). The α and β isoforms are predominant in the hippocampus (up to 2% of total protein) (Coultrap and Bayer, 2012; Lisman et al., 2012). The α isoform is much more abundant than the β isoform in the forebrain in a ratio of 3:1, and the localization of αCaMK-II is mostly in glutamatergic neurons (Miller and Kennedy, 1985; Mohanan et al., 2022).
Sphingosylphosphorylcholine ameliorates doxorubicin-induced cardiotoxicity in zebrafish and H9c2 cells by reducing excessive mitophagy and mitochondrial dysfunction
2022, Toxicology and Applied Pharmacology