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Review
. 2019 Aug 7;103(3):380-394.
doi: 10.1016/j.neuron.2019.05.033.

CaM Kinase: Still Inspiring at 40

K Ulrich Bayer  1 , Howard Schulman  2
Affiliations
Review

CaM Kinase: Still Inspiring at 40

K Ulrich Bayer et al. Neuron. .

Abstract

The Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) was touted as a memory molecule, even before its involvement in long-term potentiation (LTP) was shown. The enzyme has not disappointed, with subsequent demonstrations of remarkable structural and regulatory properties. Its neuronal functions now extend to long-term depression (LTD), and last year saw the first direct evidence for memory storage by CaMKII. Although CaMKII may have taken the spotlight, it is a member of a large family of diverse and interesting CaM kinases. Our aim is to place CaMKII in context of the other CaM kinases and then review certain aspects of this kinase that are of current interest.

Keywords: CaMKII; DAPK; LTD; LTP; calmodulin; memory; synapse.

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Figures

Figure 1.
Figure 1.. The CaMK family
(A) The CaMKII family tree within the human kinome (based on (Manning et al., 2002)). Also indicated are the different CaMK subfamilies as well as the classification of some CaM-regulated kinases that are not part of the CaMK family. (B) Examples of CaMK domain organization: CaMKII, CaMKI, DAPK1, DAPK3, and Trio in schematic representation. DAPK3 and Trio are examples of CaMKs without CaM binding regulatory domain; DAPK1 and Trio are examples of CaMKs with complex domain structure. CaMKII contains a unique association domain that mediates 12meric holoenzyme assemblies (see Figure 3).
Figure 2.
Figure 2.
The CaMKII kinase and regulatory domains, with regulatory phosphorylation sites indicated in red; sites for other posttranslational modifications in black. (A) Structure of the kinase and regulatory domains of CaMKII, compared to CaMKI and DAPK1. In CaMKII, the substrate binding “S-site” is indicated in orange; the nearby “T-site” that interacts with T286 of the regulatory domain in the basal state (and with GluN2B upon activation) is indicated in yellow. (B) Amino acid sequence of the CaMKII regulatory domain, with sites of posttranslational modification by phosphorylation, oxidation/nitrosylation and GlcNacylation indicated. (C) Structural transition of the CaMKII regulatory structure in response to Ca2+/CaM binding (Rellos et al., 2010). The arrow is for orientation and for comparison to the sequence in panel C.
Figure 3.
Figure 3.
The CaMKII holoenzyme structure based on EM tomography (Myers et al., 2017). (A) A pseudoatomic model of the CaMKII holoenzyme in the preferred average conformation. (B) Image analysis of individual CaMKII holoenzymes shows that the CaMKII association domain assemblies are very static, but that the kinase domain positioning is highly flexible; as a result, essentially no individual holoenzyme is in the average conformation shown in panel A. (C) While a crystal structure has suggested an additional compact conformation (in which the CaM binding region is not accessible), most of the holoenzymes are in an activation-competent extended conformation, both in vitro and within cells. (D) While most CaMKII holoenzymes are 12meric, a minority can be found in a 14meric conformation, which may represent a transition state that enables subunit exchange.
Figure 4.
Figure 4.. CaMKII autonomy generated by T286 autophosphorylation: mechanism, frequency detection, and spike counting
(A) CaMKII autophosphorylation at T286 occurs primarily within holoenzymes and exclusively as a reaction between two subunits. Ca2+/CaM stimulates the process and has to be bound to the subunit that is being phosphorylated, in order to make T286 accessible (compare also Figure 2B). Therefore, the reaction can only occur in presence of Ca2+/CaM, and making CaMKII autonomous can only substitute for the function of Ca2+/CaM in activating one kinase subunit, but not for the substrate-directed function. (B) The dual role of CaM in T286 autophosphorylation enables frequency detection. During submaximal Ca2+-spikes, some CaM molecules bind to some subunits of a CaMKII holoenzyme, and then dissociate during the spike interval, and so on. However, at higher frequencies (with spike intervals in the range of the CaM dissociation time) additional CaM molecules accumulate before all of the initial CaM molecules have dissociated. This increases the chance of CaM binding to neighboring subunits and thereby the autophosphorylation at T286. Panels A and B are derived from a previous review (Coultrap and Bayer, 2012). (C) T286 phosphorylation can be induced at lower Ca2+-spike frequencies, but then takes longer time (and more spikes) to reach the same level. (Adapted from (De Koninck and Schulman, 1998). (D) Spikes of glutamate uncaging are integrated by CaMKII within hippocampal neurons in a T286-dependent manner, as measured using a FRET sensor of CaMKlI activity. (Adapted from (Chang et al., 2017).
Figure 5.
Figure 5.. CaMKII binding to GluN2B: mechanisms and competition with DAPK1
(A) CaMKII binding to GluN2B can be induced by either Ca2+/CaM or T286 phosphorylation alone. However, after the binding is established, no stimulus is required anymore. The binding site on GluN2B is around S1303, overlapping with the proposed DAPK1 binding site. (B) CaMKII and DAPK1 compete for binding to GluN2B in vitro, with CaMKII winning during LTP-type stimuli (high Ca2+-concentrations) and DAPK1 winning during LTD-type stimuli (low Ca2+-concentrations). (Adapted from (Goodell et al., 2017).
Figure 6.
Figure 6.. CaMKII T286 phosphorylation and GluN2B binding in LTP induction versus maintenance.
(A) tatCN21 but not KN93 inhibits autonomous CaMKII. (Adapted from (Vest et al., 2010). (B) tatCN21 (5 μM) blocks LTP induction by high-frequency stimulation (HFS) but does not interfere with its maintenance. (Adapted from (Buard et al., 2010). (C) CaMKII T286 autophosphorylation is more rapidly reversed after LTP than LTD. (As previously reviewed in Coultrap and Bayer, 2012). (D) Higher tatCN21 concentrations (20 pM) that additionally disrupt CaMKII/GluN2B binding persistently reverse LTP maintenance. LTP can be re-established by additional HFS stimulation, indicating complete washout of the drug and slice health (Adapted from (Sanhueza et al., 2011).
Figure 7.
Figure 7.. CaMKII function in memory: erasure by a kinase dead K42M mutant.
(A) Transient viral (HSV) expression of the CaMKII K42M mutant (but not of GFP control) caused erasure of conditioned place avoidance. Rats were placed on a rotating platform that will eventually bring the rat into a shock zone (red), that the rats can identify by spatial cues. Over a course of twelve 10 min trials, rats learn to avoid the shock, as measured by the reduction of shocks received. The memory was retained in a subsequent trial twelve days later, but not after CaMKII K42M expression. (Adapted from (Rossetti et al., 2017). (B) The CaMKII K42M mutation impairs CaMKII binding to GluN2B in vitro in heterologous cells (adapted from (O’Leary et al., 2011); this effect is indirect: K42M prevents the nucleotide binding to CaMKII that positively regulates GluN2B binding. (C) GFP expression in hippocampus after infection with HSV-GFP is transient. However, while this has been shown also for a different GFP-CaMKII mutant, it remains to be formally demonstrated for GFP-CaMKII K42M mutant.
Figure 8.
Figure 8.. CaMKII in LTD: mechanisms that enable roles in opposing forms of plasticity
(A) CaMKII requirement in LTD: Low frequency (LFS)-induced LTP is blocked by CaMKII knockout (KO), T286A mutation, and by acute inhibition (with 5 μM tatCN21; adapted from (Coultrap et al., 2014a). (B) LTP-specific CaMKII targeting to excitatory synapses is mediated by LTD-specific suppression of such targeting by calcineurin-dependent activation of dApKI (adapted from (Goodell et al., 2017). (C) Differential phosphorylation of GluA S567 versus S831, with S567 being an unusual substrate that is equally well phosphorylated by stimulated and autonomous activity, and S831 being a typical substrate that is more readily phosphorylated when additionally stimulated with Ca2+/CaM (adapted from (Coultrap et al., 2014a). Notably, CaMKII prefers an Arg in the −3 position, but this is lacking in both of these substrate sites on GluA1. (D) Both LTP and LTD induce CaMKII T286 phosphorylation, but LTP-stimuli trigger input-specific CaMKII movement to the stimulated excitatory synapses, while LTD-stimuli instead trigger CaMKII movement to inhibitory synapses. At excitatory synapses CaMKII is required for LTP and LTD; at inhibitory synapses, it is at least required for the iLTP that is induced by excitatory LTD.
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