MINIREVIEW
Cellular Signaling through Multifunctional Ca2+/Calmodulin-dependent Protein Kinase II*

Thomas R. SoderlingDagger, Bill Chang, and Debra Brickey

From the Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201



    INTRODUCTION
TOP
INTRODUCTION
Structure and Regulation
Sensor of Cellular Ca2+...
Subcellular Localization and...
Activation and Synthesis of...
Neuronal Substrates of CaM-KII
Concluding Remarks
REFERENCES

Ca2+/CaM-dependent protein kinase II (CaM-KII)1 is a ubiquitously expressed protein kinase that transduces elevated Ca2+ signals in cells to a number of target proteins ranging from ion channels to transcriptional activators. CaM-KII has a unique holoenzyme structure and autoregulatory properties that allow it to give a prolonged response to transient Ca2+ signals and to sense cellular Ca2+ oscillations. In neurons CaM-KII is highly expressed and localized with certain subcellular structures. Upon activation it can translocate to excitatory synapses where it regulates a number of proteins involved in synaptic transmission and its downstream signaling pathways.

Elevated intracellular free calcium (Ca2+i), in response to agonist stimulation or cell depolarization, is highly regulated and involves influx through voltage- and ligand-gated Ca2+-permeable ion channels, release from intracellular stores through ryanodine- and inositol 1,4,5-trisphosphate-sensitive channels, sequestration by Ca2+ pumps and exchangers, and signaling through specific Ca2+ transducer proteins (1). Changes in intracellular calcium can display variable responses ranging from highly localized, transient elevations within subcellular structures (e.g. a dendritic spine of a neuron) to Ca2+ waves that spread throughout the cell including the nucleus. The most ubiquitous calcium-sensing protein is calmodulin (CaM), which contains four "EF" hand motifs with high specificity for binding Ca2+. The Ca2+/CaM complex interacts with and modulates the functionality of a large number of proteins (2) including several Ser/Thr protein kinases (CaM-Ks). This review, which is part of a series on Ca2+/CaM-dependent protein kinases and phosphatase, will consider one member of this family, the multifunctional CaM-KII. The CaM-KII family is encoded by four genes (alpha , beta , gamma , and delta ) that also exhibit alternative splicing. The gamma  and delta  isoforms are expressed in most tissues, whereas the alpha  and beta  isoforms are most prominent in neural tissues and comprise up to 2% of total protein in hippocampus. This review will focus on selected advances over the past 5 years, especially for neuronal CaM-KII, and readers are referred to an earlier comprehensive review for general background information (3).


    Structure and Regulation
TOP
INTRODUCTION
Structure and Regulation
Sensor of Cellular Ca2+...
Subcellular Localization and...
Activation and Synthesis of...
Neuronal Substrates of CaM-KII
Concluding Remarks
REFERENCES

The various CaM kinase II subunits are comprised of an N-terminal catalytic region, a central regulatory domain containing an autoinhibitory domain (AID) and Ca2+/CaM binding motif, a variable sequence, and the C-terminal subunit association domain (4) (Fig. 1A). The holoenzyme is an oligomeric protein comprised of twelve 50-60-kDa subunits arranged as two stacked hexameric rings (5, 6). The C-terminal association domains form the central core of each ring with the N-terminal catalytic domains projecting outward (Fig. 1B). In the absence of bound Ca2+/CaM, the CaM-KII is maintained in an inactive conformation because of an interaction of the AID with the catalytic domain of its own subunit. Three distinct molecular models, based on structure/function studies, have been presented for how the AID might suppress catalytic activity (7-9), but definitive proof from a crystal structure has yet to be obtained. The Ca2+/CaM complex binds to a sequence that partially overlaps the AID (Fig. 1A), presumably causing a conformational change and thereby disrupting interaction of the AID with the catalytic domain and producing kinase activation. Interestingly, the sensitivity of CaM-KII to activation by Ca2+/CaM depends on the subunit composition of the holoenzyme (10).



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Fig. 1.   Structure of CaM-KII. A, CaM-KII subunit domain organization. All of the isoforms and alternative splice variants of CaM-KII have a similar overall subunit organization with an N-terminal catalytic domain, a central regulatory region with overlapping autoinhibitory (AID) and CaM-binding (CaM) domains, a variable region (V) with inserts or deletions, and a C-terminal subunit association region. The color coding corresponds with the domain organization of the holoenzyme in B. B, holoenzyme structure. CaM-KII alpha  holoenzyme consists of a gear-shaped body ~140 Å in diameter with a height of 100 Å and contains 12 subunits arranged in two sets of six subunits that form stacked hexagonally shaped rings. The central structure is comprised of the association domains (green), and the footlike protrusions (aqua blue) contain the catalytic and regulatory domains. This top view of reconstructed CaM-KII, based on three-dimensional electron microscopy, is reproduced with permission from Kolodziej et al. (5).

Upon activation by Ca2+/CaM binding, the kinase undergoes an immediate autophosphorylation on Thr-286 (numbering will be based on the alpha  isoform) (3). This autophosphorylation occurs within the oligomeric complex (i.e. intramolecular) but between adjacent subunits (intersubunit) that have bound Ca2+/CaM (11, 12). An interesting consequence of the oligomeric structure of CaM-KII discussed above is that it would restrict intramolecular autophosphorylation of Thr-286 within each of the two hexameric rings. This rapid autophosphorylation on Thr-286 has two important regulatory consequences. 1) The subsequent dissociation rate for Ca2+/CaM upon removal of Ca2+ is decreased by several orders of magnitude (13), and 2) even after full dissociation of Ca2+/CaM, the kinase retains partial activity (i.e. Ca2+/CaM-independent or constitutive activity). Presumably the complex holoenzyme structure of CaM-KII (see Fig. 1B) endows the kinase with this unique regulatory property. Thus, transient elevation of intracellular Ca2+ can give a prolonged response through the constitutive activity of autophosphorylated CaM-KII, and this property appears to be critical for certain physiological functions of CaM-KII as discussed later.


    Sensor of Cellular Ca2+ Oscillations
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INTRODUCTION
Structure and Regulation
Sensor of Cellular Ca2+...
Subcellular Localization and...
Activation and Synthesis of...
Neuronal Substrates of CaM-KII
Concluding Remarks
REFERENCES

The efficiency of synaptic transmission between neurons can be modulated, a process known as synaptic plasticity. At excitatory synapses using glutamate as neurotransmitter, synaptic plasticity such as long term potentiation (LTP) is triggered by increased Ca2+ in postsynaptic spines (14) and is dependent on the frequency of afferent stimulation (15). How is the frequency of Ca2+i oscillations in the postsynaptic spine decoded? CaM-KII has been touted as a decoding mechanism (Fig. 2) because of its unique activation properties as discussed above and its localization in dendritic spines in an organelle called the postsynaptic density (PSD) (16). The magnitude of constitutive CaM-KII activity because of autophosphorylation of Thr-286 on adjacent subunits in the oligomeric holoenzyme should depend on the duration, amplitude, and frequency of elevated Ca2+i, and a recent in vitro study (17) shows this to be the case. The abilities of CaM-KII to decode the frequency of synaptic stimulation and to give a prolonged readout beyond the initial stimulus are two characteristics required for a molecule involved in generation of synaptic plasticity.



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Fig. 2.   Ca2+ frequency decoding mechanism by CaM-KII autophosphorylation. This figure illustrates under conditions where CaM is limiting relative to CaM-KII (depicted for simplicity as a decamer) three Ca2+ spikes at a frequency and amplitude such that not all Ca2+/CaM has dissociated from CaM-KII after the first spike. The magnitude and duration of each spike allows three subunits of CaM-KII to bind Ca2+/CaM (blue). During the first spike, by chance, no adjacent subunits bind CaM; therefore, no Thr-286 autophosphorylation occurs, and at the end of the spike the Ca2+/CaM rapidly dissociates. The second spike occurs at a frequency when one nonphosphorylated subunit still has bound Ca2+/CaM, increasing the probability that a proximal subunit would bind one of the three additional Ca2+/CaM and undergo intersubunit autophosphorylation (P). Between the second and third Ca2+ spikes, Ca2+/CaM dissociates more slowly from autophosphorylated subunits (solid purple line) than from nonphosphorylated subunits (dashed orange line). During the third Ca2+ spike additional adjacent subunits autophosphorylate. The constitutive activity of the CaM-KII holoenzyme is the summation of the autophosphorylated subunits (blue), which in turn depends on the magnitude, frequency, and duration of the Ca2+ spikes. This figure was kindly donated by Dr. Howard Schulman of Stanford University.



    Subcellular Localization and Translocation
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INTRODUCTION
Structure and Regulation
Sensor of Cellular Ca2+...
Subcellular Localization and...
Activation and Synthesis of...
Neuronal Substrates of CaM-KII
Concluding Remarks
REFERENCES

In many cells CaM-KII is largely soluble and widely distributed throughout the cell, but discrete subcellular pools of CaM-KII have recently become recognized. Localization of signaling enzymes close to their substrates has, in general, important regulatory consequences (18), especially for broad specificity enzymes such as CaM-KII. Thus, characterization of mechanisms for subcellular localization of CaM-KII and its physiological roles are intense areas of investigation.

Alternative splice variants of alpha , delta , and gamma  isoforms contain a nuclear localization signal (19, 20), and nuclear CaM-KII is likely to play a role in Ca2+-mediated transcriptional regulation of genes such as brain-derived neurotrophic factor (21) and atrial natriuretic factor (22) through phosphorylation of transcription factors including CCAAT/enhancer-binding protein (C/EBP) (23, 24). It is intriguing that CaM kinases I and IV can phosphorylate a Ser adjacent to the nuclear localization signal and prevent nuclear localization of the CaM-KII, but whether this occurs physiologically is uncertain (25). CaM-KI exhibits broad cellular distribution and is largely cytoplasmic, whereas CaM-KIV has a rather restricted tissue distribution and exists as both cytosolic and nuclear isoforms (26). CaM-KII may also exert negative effects on transcription through phosphorylation of the transcription factor CREB. Surprisingly, although the activation site (Ser-133) in CREB can be efficiently phosphorylated by CaM-KII, it simultaneously phosphorylates another site (Ser-142) that exerts a dominant negative role (27). Thus, it is possible that nuclear CaM-KII can inhibit CREB-dependent transcription meditated by kinases such as PKA, but this needs to be verified under physiological conditions. Ca2+-stimulated gene transcription through CREB is mediated in part by CaM-KIV (28, 29).

Anchoring proteins that localize PKA (18) and protein kinase C (30) close to physiological substrates have been well characterized, and recent studies indicate a similar regulatory scheme for CaM-KII. An anchoring protein, alpha KAP, has recently been identified that localizes skeletal muscle CaM-KII to the sarcoplasmic reticulum. This unique protein contains a hydrophobic N terminus fused to the C-terminal association domain of CaM-KII (31). The C-terminal association domain of alpha KAP can form heteromers with the full-length CaM-KII subunit, and the hydrophobic N terminus of alpha KAP directs the resulting kinase complex to the sarcoplasmic reticulum membrane (32). Likely substrates for CaM-KII in the sarcoplasmic reticulum include the ryanodine receptor (33), phospholamban (34), and the Ca2+-ATPase pump (35).

In brain, there is evidence for colocalization of the CaM-KII beta  isoform with the cytoskeleton. Upon stimulation of the Ca2+-permeable NMDA-R ion channel in hippocampal neurons, CaM-KII appears to dissociate from F-actin and undergo translocation to membranous fractions including the PSD (36). The PSD, a complex of postsynaptic membrane proteins involved in mediating and modulating synaptic transmission, is held together and to the cytoskeleton through anchoring proteins of the PDZ/SAP family (16, 37). CaM-KII is a major constituent of the PSD where it is anchored in part through the protein densin-180 (38). This interaction of CaM-KII with densin-180 does not appear to depend on the activation state of the kinase. In contrast, additional CaM-KII can associate with the PSD through interaction with the NMDA-type glutamate-gated ion channel, but this translocation appears to require activation of the kinase and its autophosphorylation on Thr-286 (39, 40). Translocation to the PSD occurs in hippocampal slices upon treatments that activate CaM-KII, and it promotes the phosphorylation of CaM-KII substrates in the PSD such as the AMPA-R (39, 41). The anchoring interaction appears to occur between the catalytic domain of CaM-KII and residues 1290-1309 in the cytosolic tail of the NR2B subunit of the NMDA-R (42). Translocation would localize CaM-KII at a critical site of Ca2+ influx into the dendritic spine because the NMDA channel has considerable Ca2+ permeability, and its activation is required for several types of synaptic plasticity. In addition to localizing CaM-KII to a site of Ca2+ influx, this translocation also situates the activated kinase in close proximity to several very important neuronal substrates (Fig. 3) as discussed below.



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Fig. 3.   Neuronal substrates of CaM-KII at the PSD. An excitatory synapse is depicted with presynaptic release of the neurotransmitter glutamate (red triangles), which interacts with two types of ionotropic receptors, NMDA-R (orange) and AMPA-R (purple). Ca2+ influx through the NMDA-R activates postsynaptic CaM-KII, which autophosphorylates on Thr-286 and translocates to the PSD (reaction 1), in part through binding to the NMDA-R. PSD-associated CaM-KII phosphorylates and enhances (+) or inhibits (-) several PSD substrates including the AMPA-R (reaction 2), nNOS (reaction 3), SynGAP (reaction 4), and DLG/SAP (reaction 5). All of these CaM-KII substrates may be important in signaling events that regulate synaptic plasticity. Reprinted from Current Opinion in Neurobiology, T. R. Soderling (2000) CaM-kinases: modulators of synaptic plasticity. Vol. 10, pp. 375-380, with permission from Elsevier Science. MAPK, mitogen-activated protein kinase; EPSC, excitatory postsynaptic current.



    Activation and Synthesis of CaM-KII in Neurons
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INTRODUCTION
Structure and Regulation
Sensor of Cellular Ca2+...
Subcellular Localization and...
Activation and Synthesis of...
Neuronal Substrates of CaM-KII
Concluding Remarks
REFERENCES

There is considerable evidence that activation of CaM-KII in pyramidal neurons of region CA1 in hippocampus is intimately involved in the phenomena of LTP (43, 44). LTP is touted as a cellular model of learning and memory because it represents a neuron-specific mechanism for increasing the efficacy of synaptic transmission (45). Induction of LTP, through activation of the NMDA-R, in hippocampus triggers CaM-KII autophosphorylation on Thr-286 and formation of its constitutively active form (46-48) (Fig. 3). Maintaining the constitutive activity of CaM-KII for at least 1 h during LTP requires inhibition of protein phosphatase 1, which can dephosphorylate Thr-286 (49), through PKA-mediated phosphorylation of the protein phosphatase 1 inhibitor (50). Induction of LTP by multiple tetanic stimuli results in global activation of CaM-KII throughout apical dendrites and the pyramidal cell somas (48). However, very mild NMDA-R stimulation of cultured neurons can result in very restricted activation of CaM-KII within individual dendritic spines (51).

Dendrites contain the machinery for localized protein synthesis, and one of the more abundant mRNAs in dendrites encodes the alpha  subunit of CaM-KII. The 3'-untranslated region (UTR) of CaM-KII mRNA is responsible for its dendritic migration (52). Induction of LTP results in a selective increase in dendritic alpha  CaM-KII protein, which is blocked by anisomycin and detected within 5 min, strongly suggestive of localized synthesis (53). How might dendritic synthesis of proteins such as CaM-KII be regulated (54)? The 3'-UTR in the mRNA encoding alpha  CaM-KII contains two cytoplasmic polyadenylation elements (CPEs). These CPEs interact with a CPE-binding protein (CPEB), which is present in hippocampal dendrites and enriched in PSDs. Binding of CPEB to the 3'-UTR of CaM-KII mRNA promotes its polyadenylation, thereby enhancing translation (55). Certain forms of synaptic plasticity in the visual cortex increase polyadenylation of alpha  CaM-KII mRNA with a 1.7-fold increase in CaM-KII protein in isolated synaptoneurosomes (55). The signaling pathway(s) between neural activity and enhanced CPEB-dependent polyadenylation is not known, but phosphorylation of CPEB may be involved (56).


    Neuronal Substrates of CaM-KII
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INTRODUCTION
Structure and Regulation
Sensor of Cellular Ca2+...
Subcellular Localization and...
Activation and Synthesis of...
Neuronal Substrates of CaM-KII
Concluding Remarks
REFERENCES

CaM-KII can phosphorylate a large number of proteins in vitro (3), and recently several substrates that may be involved in synaptic plasticity have been identified (Fig. 3). Numerous studies have documented that activated CaM-KII can phosphorylate the GluR1 subunit of the AMPA-R and enhance its current (43). A recent report documents AMPA-R phosphorylation by CaM-KII during LTP in region CA1 of hippocampus (57). Phosphorylation of Ser-831 in GluR1 by CaM-KII potentiates AMPA-R current by increasing single channel conductance (58). Indeed, about 60% of CA1 neurons that exhibit potentiation during LTP show an increase in unitary conductance (59). Experiments with transgenic mice also support a crucial role of CaM-KII phosphorylation of GluR1 as an important component of CA1 LTP in mature animals. For example, mice lacking GluR1, the AMPA-R subunit phosphorylated by CaM-KII, show a specific deficit in LTP (60). Likewise, a single-site mutation in alpha CaM-KII (T286A) results in a mouse that is deficient in CA1 LTP (61). This subtle mutation does not effect activation of CaM-KII through binding of Ca2+/CaM, but it precludes generation of constitutive activity by autophosphorylation. Thus, CaM-KII phosphorylation of AMPA-Rs with resultant potentiation of current is thought to contribute prominently to LTP at the CA1 synapse of hippocampus (43, 44).

Several other PSD proteins can also be phosphorylated by CaM-KII. Indeed, the NMDA-R that acts as an anchor for activated CaM-KII can be phosphorylated by CaM-KII (62). Although phosphorylation of Ser-1303 in the NR2B subunit has not been reported to directly regulate channel properties, it appears to decrease its binding affinity for CaM-KII (42). Another substrate is a novel Ras-GTPase-activating protein (SynGAP) localized at the PSD of hippocampal neurons through its interaction with PDZ domains of the scaffold proteins PSD-95 and SAP102 (63, 64). SynGAP is phosphorylated and potently inhibited by CaM-KII. This suggests that activation of the NMDA-R, which is also part of the PSD-95 complex, may result in activation of CaM-KII, which in turn phosphorylates and inhibits SynGAP, thereby potentiating activation of the mitogen-activated protein kinase pathway that appears to be important in some forms of synaptic plasticity. Regulation of mitogen-activated protein kinase through CaM-KII-mediated phosphorylation of SynGAP needs to be verified in intact neurons. Another CaM-KII substrate anchored to PSD-95 is neuronal nitric oxide synthase (nNOS). Phosphorylation of nNOS at Ser-847 results in partial inhibition of its activity (65). Nitric oxide, the product of NOS, appears to be an important signaling molecule in brain (66).

In Caenorhabditis elegans wild-type CaM-KII appears necessary for normal trafficking of glutamate receptors from the cell body and its clustering at neuromuscular synapses (67). In both C. elegans (67) and Drosophila (68), expression of constitutively active CaM-KII results in disruption of normal synaptic structure. In Drosophila this appears to be because of phosphorylation of the synaptic clustering protein DLG, a homologue of the mammalian SAP family involved in clustering of glutamate receptors. In mammals CaM-KII may also be involved in trafficking of glutamate receptors through interactions with SAP proteins. When GluR1 is overexpressed in CA1 hippocampal neurons, it translocates to the synapse in response to either activation of CaM-KII or LTP induction (69). This effect of CaM-KII was not because of phosphorylation of Ser-831 in GluR1, but insertion of GluR1 into the synapse was abolished by mutation of its C-terminal PDZ domain interaction site. GluR1 interacts with SAP97 (70), and SAP97 contains the CaM-KII phosphorylation site identified in Drosophila DLG. Thus, prolonged CaM-KII activity might promote recruitment of AMPA-Rs into synapses as predicted by the "silent synapse" hypothesis of LTP (44, 71).


    Concluding Remarks
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INTRODUCTION
Structure and Regulation
Sensor of Cellular Ca2+...
Subcellular Localization and...
Activation and Synthesis of...
Neuronal Substrates of CaM-KII
Concluding Remarks
REFERENCES

CaM-KII has a unique holoenzyme structure that endows it with unusual regulatory properties required for sensing and transducing various types of intracellular Ca2+ signals. Tremendous progress has occurred over the past 5 years in understanding the cellular and subcellular regulation of CaM-KII and in identifying physiological substrates. The latter area has been hampered by the absence of highly specific CaM-KII inhibitors, but recently a naturally occurring CaM-KII inhibitor protein, CaM-KIIN, has been cloned (72). A 27-residue peptide derived from CaM-KIIN retains its high specificity and potency for inhibition of CaM-KII, and this probe should be useful in identifying additional physiological functions of CaM-KII (73).


    ACKNOWLEDGEMENTS

We thank Drs. James Stoops (University of Texas, Houston) and Howard Schulman (Stanford University) for contributing Figs. 1 and 2, respectively.


    FOOTNOTES

* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. This is the third article of four in the "Ca2+-dependent Cell Signaling through Calmodulin-activated Protein Phosphatase and Protein Kinases Minireview Series."

Dagger To whom correspondence should be sent: Vollum Inst., Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201. Tel.: 503-494-6931; Fax: 503-494-4534; E-mail: soderlit@ohsu.edu.

Published, JBC Papers in Press, November 28, 2000, DOI 10.1074/jbc.R000013200


    ABBREVIATIONS

The abbreviations used are: CaM-KII, Ca2+/CaM-dependent protein kinase; AID, autoinhibitory domain; AMPA-R, alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor; CaM, calmodulin; CPE, cytoplasmic polyadenylation element; CPEB, cytoplasmic polyadenylation element-binding protein; CREB, cAMP response element-binding protein; DLG, disc large protein; GluR1, glutamate receptor subunit 1 of AMPA-R; alpha KAP, alpha CaM-KII association protein; LTP, long term potentiation; NMDA-R, N-methyl D-aspartate receptor; nNOS, neuronal nitric oxide synthase; PSD, postsynaptic density; PKA, protein kinase A; PDZ, Psd-Dlg-Zo-1; SAP, synapse-associated protein; SynGAP, synaptic GTPase-activating protein; UTR, untranslated region.


    REFERENCES
TOP
INTRODUCTION
Structure and Regulation
Sensor of Cellular Ca2+...
Subcellular Localization and...
Activation and Synthesis of...
Neuronal Substrates of CaM-KII
Concluding Remarks
REFERENCES


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