From the Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201
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
( 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).
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
,
,
, and
) that also exhibit alternative splicing. The
and
isoforms are expressed in most tissues, whereas the
and
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
View larger version (21K):
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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 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 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.
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Sensor of Cellular Ca2+ Oscillations |
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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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Subcellular Localization and Translocation |
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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 ,
, and
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, 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
KAP can form heteromers with the full-length CaM-KII subunit, and the hydrophobic N terminus of
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 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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Activation and Synthesis of CaM-KII in Neurons |
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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 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
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
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
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).
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Neuronal Substrates of CaM-KII |
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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 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).
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Concluding Remarks |
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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).
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ACKNOWLEDGEMENTS |
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We thank Drs. James Stoops (University of Texas, Houston) and Howard Schulman (Stanford University) for contributing Figs. 1 and 2, respectively.
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FOOTNOTES |
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* 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."
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
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ABBREVIATIONS |
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The abbreviations used are:
CaM-KII, Ca2+/CaM-dependent protein kinase;
AID, autoinhibitory domain;
AMPA-R, -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;
KAP,
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.
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