Physiol Rev 88: 421– 449, 2008;
doi:10.1152/physrev.00041.2005.
Ca2⫹-Operated Transcriptional Networks: Molecular
Mechanisms and In Vivo Models
BRITT MELLSTRÖM, MAGALI SAVIGNAC, ROSA GOMEZ-VILLAFUERTES, AND JOSE R. NARANJO
Centro Nacional de Biotecnologı́a, Consejo Superior Investigaciones Científicas, Madrid, Spain
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Mellström B, Savignac M, Gomez-Villafuertes R, Naranjo JR. Ca2⫹-Operated Transcriptional Networks: Molecular Mechanisms and In Vivo Models. Physiol Rev 88: 421– 449, 2008; doi:10.1152/physrev.00041.2005.—Calcium
is the most universal signal used by living organisms to convey information to many different cellular processes. In
this review we present well-known and recently identified proteins that sense and decode the calcium signal and are
key elements in the nucleus to regulate the activity of various transcriptional networks. When possible, the review
also presents in vivo models in which the genes encoding these calcium sensors-transducers have been modified, to
emphasize the critical role of these Ca2⫹-operated mechanisms in many physiological functions.
I. INTRODUCTION: THE ENCODED
CALCIUM SIGNAL
For the last 25 years, great effort has been devoted to
understanding and characterizing the molecular mechanisms used by cells to transform a cytosolic Ca2⫹ signal
into specific, finely controlled changes in gene expression. Several earlier reviews have addressed the variety of
regulatory mechanisms that participate in Ca2⫹-dependent gene expression in neurons (76, 208, 321) and other
cells (27, 45, 179). Recent discoveries have added new
elements to the “nuclear Ca2⫹ toolkit” and, just as important, new interactions have been reported between players that use Ca2⫹ to tune the function of different transcriptional networks. Furthermore, the spectacular rise of
recently developed genetically modified animal models
illustrates the universal, though selective, and crucial role
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of the calcium signal in the living animal. Advances in the
understanding of the role of the calcium signal in regulating gene expression patterns in other organisms, mainly
worms, yeast, and plants, have been recently reviewed
(19, 68, 333) and are not discussed here.
Since the central protagonist in this review is the
calcium signal, this introduction will comment on three
major characteristics of the calcium signal that determine
its final physiological role in the control of transcriptional
networks: the specific temporal dynamics of the signal,
the subcellular microdomains in which the signal is generated, and the nature of the calcium signal inside the
nucleus.
In most cells, excitable and nonexcitable, stimulation
of cell-surface receptors generates oscillations in intracellular free calcium concentration ([Ca2⫹]i) of variable amplitude and frequency. The oscillatory nature of the cal-
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I. Introduction: The Encoded Calcium Signal
II. The Calcium Toolkit for Posttranslational Modifications
A. Ca2⫹/kinase-regulated transcription pathways
B. Ca2⫹/phosphatase-regulated transcription pathways
III. Calcium-Dependent Transcriptional Networks
A. The CREB/CBP/TORC pathway
B. The MEF-2 crossroad of Ca2⫹ regulation
C. The NFAT family of transcription factors
D. The DREAM/KChIP family of Ca2⫹-sensitive transcriptional repressors
E. The NF-␬B /I-␬B couple
F. Novel mechanisms associated with Ca2⫹-dependent gene expression
IV. Calcium-Dependent Protein-Protein Interactions That Modulate Gene Expression
A. Ca2⫹ sensors in the nucleus
B. Ca2⫹-dependent changes in chromatin structure
V. Exemplifying the Complexity of Calcium-Dependent Gene Expression: The Brain-Derived
Neurotrophic Factor Compendium
VI. Summary and Future Directions
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entry, at least two completely different molecular pathways can be discriminated, conferring acute or long-lasting neuroprotection. Acute survival induced by Ca2⫹ entry through synaptic NMDA channels is thus not mediated
by CREB-dependent transcriptional activity, but is exclusively related to the activation of the phosphatidylinositol
(PI) 3-kinase/Akt pathway. Conversely, in the same study,
the authors demonstrate that long-lasting activity-dependent neuroprotection requires CREB family activation
and the elevation in nuclear Ca2⫹ or in nuclear Ca2⫹/
calmodulin signaling.
In nonexcitable cells, the first Ca2⫹ entry pathway
identified was termed store-operated Ca2⫹ entry (SOCE),
since it is stimulated in response to depletion of Ca2⫹
from intracellular Ca2⫹ stores in the endoplasmic reticulum (ER). SOCE is mediated via the activation of specific
plasma membrane channels, termed store-operated calcium (SOC) channels, which are ubiquitously expressed
in all cell types. However, and somewhat uniquely, the
biophysical characteristics of the channel are different in
various cell types. The first SOC channel to be identified,
the calcium-release-activated calcium (CRAC) channel,
mediates a highly Ca2⫹-selective calcium current detected
in T lymphocytes (9, 230). The molecular entity and the
mechanisms that operate the activation of CRAC channels have remained elusive over the years that followed
their functional identification (101, 180). Until recently,
members of the mammalian TRP family of channels
(named after the homologous Drosophila transient receptor potential channel) were considered to be good candidates for forming the CRAC channel (reviewed in Refs.
179, 237). However, TRP channels do not recapitulate the
expected biophysical properties of CRAC currents in
transfection experiments (247). Concerning the mechanisms for the activation of these currents, several theories
were proposed including a direct conformational coupling with inositol trisphosphate (IP3) receptors (146, 159,
161, 195) or the involvement of a diffusive calcium influx
factor (CIF) (252, 291).
Recently, several proteins that are essential for CRAC
channel activity in Drosophila and in mammals have been
identified, including the ER Ca2⫹ sensor Stim1 (186, 260)
and the transmembrane protein Orai1/CRACM1, which is a
pore subunit of the CRAC channel and forms the Ca2⫹selectivity filter of the channel (93, 249, 315, 334, 340).
Transient overexpression of either Stim1 or Orai1 alone
results in little or no increase in store-operated Ca2⫹
entry, while cotransfection of both proteins results in an
increased store-operated Ca2⫹-selective current (241). In
basal conditions, the Stim1 protein is located in the lumen
of the ER, where it senses Ca2⫹ levels. After store depletion, Stim1 relocalizes into preexisting and newly formed
regions of junctional ER lying within 10 –25 nm of the
plasma membrane, while Orai1 accumulates at sites in the
plasma membrane (PM) directly opposite to Stim1 (186,
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cium signal was from the beginning understood as a code
to explain the different biological activities that it triggered in different cell systems. In a pioneering work,
Lewis and colleagues (85) demonstrated that the oscillatory nature of the Ca2⫹ signal was in itself sufficient to
enhance the nuclear detection of low-amplitude stimuli,
and to reduce the effective Ca2⫹ threshold for activating
transcription factors, while for high level of stimulation
oscillations did not further increase the response (85). In
trying to decipher the encoded information, it was soon
obvious that frequency rather than amplitude was the
important property of the oscillation for selective activation of one but not other transcriptional networks. Thus
the Lewis and the Tsien groups showed in parallel that
rapid oscillations stimulated nuclear factor of activated
T cells (NFAT) and NF-␬B-dependent transcription,
whereas infrequent oscillations activated only NF-␬B (85,
181). This effect of oscillation frequency has a physiological correlate in the differential inducibility at rapid and
slow oscillations of interleukin (IL)-2 and IL-8, respectively (85), and it was clearly associated with the specific
dynamics of posttranslational modifications and nuclear
accumulation of these two nuclear effectors, fast and very
transient for NFAT and much slower for NF-␬B (reviewed
in 129a).
It was long hypothesized that the site of Ca2⫹ entry
determined the biological outcome of Ca2⫹ signaling (84,
121). In neurons, calcium flux through N-methyl-D-aspartate (NMDA) receptors or L-type calcium channels is a
potent inducer of CREB phosphorylation and brain-derived neurotrophic factor (BDNF) expression. Ca2⫹ entry
following glutamate bath application only slightly activates CREB and does not trigger BDNF expression (120,
279, 300). The apparent controversy was solved by Bading
and co-workers (122), who showed conclusively that
Ca2⫹ entry through extrasynaptic NMDA receptors opposes the increase in CREB phosphorylation and the induction of BDNF expression triggered by Ca2⫹ input
through synaptic NMDA channels. Thus expression of
BDNF in neurons is regulated by at least two different
Ca2⫹ pools, each one associated with specific signaling
cascades that lead to opposite biological effects. The
mechanism(s) by which extrasynaptic Ca2⫹ shuts off
CREB activation is not fully understood, but the action of
a glutamate-regulated protein phosphatase 1 (PP1) able to
specifically dephosphorylate Ser133CREB was shown in
hippocampal neurons (268). This finding is consistent
with previous reports (29, 119) and with the proposed role
of PP1 in synaptic plasticity (7). How PP1 is specifically
activated by extrasynaptic NMDA receptor stimulation
and the cellular compartment where it dephosphorylates
CREB are questions that remain to be elucidated.
In a recent follow-up report, Hardingham and coworkers (236) added further complexity to the calcium
signal by showing that within the synaptic site of calcium
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223). The major mechanism by which the signal is
restricted to the apical part of the cell is sequestration
of Ca2⫹ by active mitochondria that localize in a “belt”
around the granular region (155, 288, 307). These mitochondria accumulate Ca2⫹ during agonist-evoked Ca2⫹
elevations (238).
Control of the activity of specific transcriptional networks by Ca2⫹ is regulated by cytosolic and/or nuclear
mechanisms that decode the calcium signal specificities
in terms of frequency and spatial properties. The regulation of Ca2⫹-dependent transcriptional networks does
naturally demand the intervention of nuclear Ca2⫹, but
existence of mechanisms that control free calcium concentration within this organelle independently of the cytoplasm remains to this day an unresolved question. A
frequently proposed view is that calcium diffuses freely
from the cytosol into the nucleus, and back, through
nuclear pores (187). However, this view is challenged by
a number of observations that support the alternative
concept of independent nuclear Ca2⫹ homeostasis (81,
191 for a comprehensive review, but also a number of
other specific contributions 197, 240; see Ref. 269). According to the alternative concept, the nuclear pores
could be somehow gated and restrict the transient of Ca2⫹
under given physiological situations. About this, we could
quote a number of observations, in diverse cell types, that
have shown attenuation of cytosolic Ca2⫹ transients at
the nuclear envelop, and the demonstration of singlechannel currents in patch-clamped nuclear envelop containing dozens of nuclear pores. The idea of an independently regulated nuclear calcium compartment is conceptually important, as it would imply the existence of
similarly independent regulatory mechanisms for the release of this calcium. More importantly, it would also
allow us to consider calcium microdomains within the
nucleus that would confer additional specificity to calcium effects on chromatin structure and gene expression.
In a recent study that extends previous work by other
laboratories (97, 103, 118), Nathanson’s group (88) identified a nucleoplasmic reticulum that is continuous with
the ER and the nuclear envelope. Like the ER, the nucleoplasmic reticulum expresses IP3Rs that mediate small
calcium signals in localized subnuclear microdomains.
This calcium signal then triggers the translocation of nuclear protein kinase C (PKC)-␥ to the nuclear envelope in
the vicinity of this domain (88). Interestingly, the mechanism can be preferentially triggered by growth factors
such as hepatocyte growth factor and involves nuclear
translocation of the growth factor receptor, induction of
nuclear calcium signals, and the translocation of PKC-␥ to
the nuclear envelope without cytosolic PKC redistribution (88). It is presently not known whether increases in
nuclear calcium control transcriptional networks through
general mechanisms (see below) or if the specific localization of the signal in subnuclear compartments requires
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260, 341). There, Stim1 interacts with Orai1 (193, 210,
327). Taken together, these data suggest a model in which
the elementary unit of CRAC is represented by ER-PM
junctions (192). A similar coupling between the sarcoplasmic reticulum and the plasma membrane was previously
described in skeletal and cardiac muscle directing excitation/contraction (299). While in the skeletal muscle
there is a direct coordinated bidirectional interaction between plasma membrane L-type Ca2⫹ channels (LTCC)
and the ryanodine receptor (RyR) in sarcoplasmic reticulum (221), in cardiac muscle calmodulin and Ca2⫹- and
calmodulin-dependent protein kinase (CaMK) are required
to functionally couple LTCC and RyR during cardiac excitation-contraction coupling (328).
The mechanism that regulates CRAC channels has
been further advanced by the recent identification of
Golli, a negative regulator of the CRAC activation pathway (92). Golli-deficient T cells show enhanced calcium
entry after TCR stimulation, while golli⫺/⫺ oligodendrocytes show altered Ca2⫹ transients that are associated
with hypomyelinization in the visual cortex and optic
nerve (148). Myristoylation-dependent membrane association of Golli is essential for its inhibitory action after
calcium influx in T cells (92).
Following the discovery of the Stim1 and Orai1 proteins, the potential role of TRP channels in calcium fluxes
has been reevaluated, and an emerging role for TRP channels has been disclosed. Thus it has been shown that
TRPC1 interacts with Stim1 in a store depletion-dependent manner and that Stim1 is required for the coupling
between TRPC1 and type II IP3 receptor (IP3R) in platelets (188). Furthermore, it has also been shown that the
structural features of Stim1 that are essential for Stim1dependent activation of CRAC channels are identical to
those involved in the binding and activation of TRPC1 in
Jurkat T cells (137). Recent evidence showing that the
formation of a TRPC1-Stim1-Orai1 ternary complex is
essential for the generation of ISOC currents in salivary
gland cells suggests a common molecular basis for CRAC
in T lymphocytes and SOC in other cells (9, 230).
An additional important point, specific to exocrine
cells, is the polarized/asymmetric nature of Ca2⫹ handling. Exocrine acinar cells are polarized, and it was
therefore of interest to investigate whether Ca2⫹ extrusion has a uniform rate across both faces of the cell or
whether there is preferential extrusion in one direction. It
has been shown that in acinar cells the basal part is
designed for Ca2⫹ uptake from the extracellular fluid into
the ER, while the apical part is specialized for Ca2⫹
release from the ER to stimulate the formation of primary
fluid and enzyme secretion into the acinar lumen (243). It
is therefore favorable for the cells to restrict Ca2⫹ elevations to the apical/granular region. The signal is initiated
at the apical pole (303) due to preferential localization
of Ca2⫹ release channels in this part of the cell (176,
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different mechanisms, such as localized changes at dinucleotide repeats in the DNA structure (83).
II. THE CALCIUM TOOLKIT FOR
POSTTRANSLATIONAL MODIFICATIONS
A. Ca2ⴙ/Kinase-Regulated Transcription Pathways
Several kinases are important mediators of calciumdependent gene expression since, in one way or another,
their activity is regulated by changes in calcium levels and
their substrates are molecules that regulate gene expression. Among the kinases, our focus will be on two major
groups, the CaMKs and the “conventional” PKC isoenzymes. A summary of the different Ca2⫹-dependent kinases, their regulation, and specificities is portrayed in
this section (Fig. 1). For a more detailed description, see
monographic reviews (62, 139, 212, 239).
1. CaMKs
The CaMKs (CaMKI, CaMKII, and CaMKIV) are serine/
threonine protein kinases with an NH2-terminal catalytic
2⫹
FIG. 1. Molecular mechanisms of Ca -dependent transcription: activity-dependent kinases.
Representation of the main transcriptional networks regulated by Ca2⫹/calmodulin (CaM)-dependent protein kinases (CaMKs) and “conventional” Ca2⫹/diacylglycerol (DAG)-dependent
protein kinase C isoenzymes (PKC). For details
about how these kinases regulate Ca2⫹-dependent transcription, see section IIA in the text.
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The first known and best described set of mechanisms by which changes in the intracellular concentration
of free calcium can affect gene expression is the activation of several kinases and phosphatases. Both in the
cytosol and the nucleus, they introduce posttranslational
modifications on appropriate molecules in the transcriptional machinery, resulting in modified expression of specific single genes or in readjustments of the activity of
entire transcriptional networks.
domain and a COOH-terminal regulatory domain. The
regulatory domain includes the Ca2⫹/calmodulin (CaM)
binding domain, which overlaps with an autoinhibitory
domain such that autoinhibition is relieved upon Ca2⫹/
CaM binding. In addition, CaMKII has an association domain that permits CaMKII to form multimeric structures,
whereas CaMKI and CaMKIV are monomeric enzymes.
These kinases are all regulated by phosphorylation, although through different mechanisms. Whereas CaMKI
and CaMKIV are phosphorylated by two Ca2⫹/CaM-dependent protein kinase kinases (CaMKK␣ and -␤), CaMKII
binds Ca2⫹/CaM and autophosphorylates at Thr-286. After
phosphorylation, phosphoCaMKII shows a 1,000-fold increased affinity for CaM and becomes partially Ca2⫹/CaM
independent (reviewed in Ref. 134). In addition, CaMKII
activity can also be regulated by proteins that have domains homologous to the CaMKII autoinhibitory domain
(114), i.e., the NMDA NR2B subunit (23) or the Drosophila ether-a-go-go (Eag) potassium channel (294). In most
cases, these interactions require prior autophosphorylation at Thr-286 to occur, and once in place, the enzymatic
activity becomes also Ca2⫹/CaM independent. The fact
that kinase activity is preserved for some time after the
initial stimulus has ended led to proposals that CaMKII
might serve as a memory molecule at synapses and may
underlie long-term changes in synaptic activity (reviewed
in Ref. 113). The enzyme activity may terminate through
the action of specific phosphatases and/or through other
autophosphorylation events as is the case of CaMKII, in
which autophosphorylation at Thr residues 305 and 306
blocks binding to CaM and inhibits activity of the kinase.
Four genes encode CaMKII isoenzymes. Of them, ␣ and ␤
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thymocytes and defective Ca2⫹-dependent cytokine gene
transcription in CD4⫹ T cells (12, 251) as well as reduced
male and female fertility due to defective spermatogenesis and impaired follicular development and ovulation,
respectively (325, 326).
Nevertheless, the phenotype does not necessarily
result from the lack of action on nuclear transcriptional
effectors but could as well be related to the lack of
phosphorylation of other substrates. Whereas phenotypic changes in neurons and memory CD4⫹ T cells are
clearly associated with impaired CREB phosphorylation in mutant mice, CRE-dependent transcription is
perfectly normal in germ cells of CaMKIV⫺/⫺ mice,
suggesting that CaMKIV might use other targets in this
cell type (325, 326).
2. Ca2⫹-dependent PKC isoenzymes
To date, 11 closely related PKC isoenzymes have
been described and classified into three subfamilies based
on their domain structure and ability to respond to Ca2⫹
and DAG (226). The “conventional” PKC isoforms (␣, ␤I,
␤II, and ␥) are regulated by DAG, which binds the C1
domain, and by Ca2⫹, which binds the C2 domain. In
contrast, the “novel” PKC isoforms (␦, ␧, ␩, and ␪) are not
regulated by Ca2⫹ but respond to DAG. The molecular
structure of the novel PKC isoforms is similar to that of
the classical isoforms except for differences in the Ca2⫹
binding domain. The third group of PKC isoforms includes the “atypical” PKC isoforms (␨, ␭/␫, and ␮), which
are regulated neither by DAG nor Ca2⫹.
Elevated concentrations of intracellular Ca2⫹ activate conventional PKC isoforms, recruiting the enzyme to
the inner leaflet of the plasma membrane or the nuclear
envelope within minutes. This process has been associated with changes in gene expression by two different
mechanisms: 1) the first involves activation of IKK and
nuclear translocation of activated NF-␬B to activate cytokine gene expression and T-cell proliferation (123, 309).
The initial finding identified PKC-␪ as responsible for the
effect (183, 295). Ca2⫹-dependent conventional PKC ␣and ␤-isoforms were shown to activate NF-␬B transcription as well (267, 290). A later study identified PKC-␣
action upstream of PKC-␪ to activate the IKK complex and
NF-␬B in T lymphocytes following TCR activation (310).
2) The second mechanism of Ca2⫹/PKC-mediated gene
expression relates to increased nuclear activity of histone
acetyltransferases (HAT). This mechanism has been described in epidermal cells where calcium induces epidermal cell differentiation and expression of several keratinocyte differentiation markers such as involucrin, filaggrin,
loricrin, and transglutaminase (82). The process involves
a dramatic increase in nuclear HAT activity and the specific acetylation of a subset of nuclear proteins. Calciuminduced HAT activity in epidermal cells is associated with
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are expressed preferentially in neuronal tissue, while ␥
and ␦ are expressed in somatic cells (140). Another important distinction between CaMKs is their subcellular distribution. While at least one CaMKII isoform is predominantly a
nuclear enzyme and CaMKIV is largely nuclear, CaMKI is
exclusively cytosolic.
Among other substrates, CaMKs have been associated with activity-dependent direct phosphorylation of
several transcription factors including CREB, CBP, and
Ets-1, and to the nuclear translocation of NF-␬B. In addition, a recent report associates CaMK’s activity with the
activity-dependent redistribution of SMRT, a corepressor
protein related to transcriptional control through hormone receptors. Thus nuclear export of SMRT follows the
nuclear extrusion of class II histone deacetylases (HDAC)
and the process is blocked by the CaMKKK inhibitors
N-62 and Sto-609 (205). Whether this is a direct mechanism remains to be clarified. It is conceptually important,
however, since it could explain the Ca2⫹-dependent potentiation of hormonal effects without direct intervention
at the level of nuclear hormone receptors.
With such a pleiotropic role in the regulation of gene
expression, it could be expected that genetic manipulation of CaMKs results in profound phenotypic changes. In
the case of CaMKII␣, which is highly expressed in the
forebrain, genetic ablation results in deficient hippocampal long-term potentiation (LTP) (280), abnormal fear
response and aggressive behavior (52), increased ischemia-induced neuronal damage (319), and deficient plasticity in the primary visual cortex (109). Outside the brain,
expression of a calcium-independent CaMKII␥ mutant in
T cells results in increased percentage of peripheral T cells
with an antigen-dependent memory phenotype through a
mechanism that involves NF-␬B activation (39). In keeping with a wider distribution of CaMKIV expression, removal of this gene results in strong phenotypic changes in
the central nervous system (CNS) and in the periphery.
Thus CaMKIV⫺/⫺ mice are deficient in two forms of synaptic plasticity: LTP in hippocampal CA1 neurons and a
late phase of long-term depression in cerebellar Purkinje
neurons (129). Despite impaired LTP and CREB activation, CaMKIV/Gr-deficient mice exhibit no obvious deficits in spatial learning and memory, although emotional
memory, which is associated with CREB activation in
amygdala and cortex, is significantly reduced (320). Moreover, CaMKIV null mice display locomotor defects consistent with a significant reduction in the number of mature Purkinje neurons and an immature development of
Purkinje cells (258). Use of CaMKIV inhibitors or expression of a kinase-dead CaMKIV mutant blocks Ca2⫹-induced dendritic growth in cortical neurons, an effect that
is strictly dependent on CREB phosphorylation (257).
Outside the CNS, CaMKIV is highly expressed in the immune system and reproductive organs. Genetic deletion
of the enzyme results in impaired positive selection in
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B. Ca2ⴙ/Phosphatase-Regulated
Transcription Pathways
As important as phosphorylation events, Ca2⫹-dependent dephosphorylation of specific residues in key proteins within a given transcriptional network also induces
drastic changes in the activity of the network. Interestingly, activity-dependent phosphorylation and dephosphorylation are in some occasions coupled events that act
on a particular protein or even on a particular phosphoresidue. In those cases, the specificities of the calcium
signal to activate the two events alternatively require a
fine tuning that so far is not well understood. Two major
phosphatases, calcineurin, also termed protein phosphatase 2B (PP2B), and PP1, will be discussed in detail in this
section. A summary of the different transcriptional networks regulated by these Ca2⫹-dependent phosphatases
is shown in Figure 2.
1. Calcineurin-regulated gene expression
Calcineurin is a Ca2⫹/calmodulin-activated serine/
threonine phosphatase, with a catalytic A subunit that
binds calmodulin and a regulatory B subunit that binds
calcium. Calcineurin conveys cytosolic Ca2⫹ signals to
the nucleus, regulating the activity of at least three important transcription pathways involving NFAT, TORC,
and myocyte enhancer factor-2 (MEF-2) proteins (for reviews, see Refs. 27, 30, 64, 255; see also sect. III) that
control responses in the immune, nervous, and cardiovascular systems. Calcineurin may also interfere with gene
expression through regulation of the intracellular concentration of free calcium by dephosphorylating phospholamban (219), the endogenous regulator of the SERCA2a
calcium pump, ryanodine receptors (53), as well as the
IP3R1 (43).
Three genes encode the catalytic subunit of calcineurin in mammalian cells: CnA␣, CnA␤, and CnA␥.
Genetic ablation of CnA␣ or CnA␤ results in specific
alterations of T-cell function, suggesting that the absence
of one gene is not fully compensated by the others (37,
2⫹
FIG. 2. Molecular mechanisms of Ca -dependent transcription: activity-dependent phosphatases. Representation of the main transcriptional networks regulated by Ca2⫹/CaM-dependent protein phosphatases calcineurin and
protein phosphatase 1 (PP1). For details about
how these phosphatases regulate Ca2⫹-dependent transcription, see section IIB in the text.
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CBP and P/CAF transcriptional coactivators, but only
overexpression of P/CAF mimics the activation of the
involucrin promoter and the specific nuclear acetylation.
The effect of calcium on HAT activity is almost completely blocked by specific PKC inhibitors at concentrations that block only Ca2⫹/DAG-dependent “conventional” PKC isoenzymes, suggesting that “conventional”
PKC isoforms may phosphorylate P/CAF to direct epidermal cell differentiation (154). Calcium-induced involucrin
expression nevertheless seems to require a calcium-dependent tyrosine phosphorylation of PKC-␦ (78).
Genetic ablation of the different “conventional” PKCs
rendered a variety of phenotypes, suggesting diversified
hierarchy in different biological functions. Thus PKC-␣⫺/⫺
mice showed cardiac hypercontractility, which protects
against heart failure induced by pressure overload and
rescues cardiomyopathy associated with overexpression
of protein phosphatase 1 (35). B cells from PKC-␤-deficient mice develop an immunodeficient phenotype that is
related to their inability to activate IKK, degrade I-␬B, and
upregulate NF-␬B-mediated induction of the prosurvival
protein Bcl-xL (267, 290). Finally, mice deficient in PKC-␥
have a modified LTP of synaptic transmission in the hippocampus (1), and Purkinje cells show aberrant innervation from climbing fibers, while other aspects of the cerebellum including the morphology and excitatory synaptic transmission appear normal (152).
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(Csp-1), MCIP-1, and Adapt78, is the protein product of
the RCAN-1 gene previously known as DSCR1 because it
is localized in the Down’s syndrome critical region (90, 98,
261). RCAN-1 is highly expressed in the CNS, immune
system, heart, and skeletal muscle and was shown to
interact physically and functionally with CnA, inhibiting
both NFAT and MEF-2 signaling pathways (reviewed in
Ref. 263). It has been proposed that RCAN-1 expression is
regulated through a calcineurin-dependent mechanism
that involves a cluster of NFAT binding sites in the promoter (reviewed in Ref. 263), indicating that RCAN-1
could function as a feedback inhibitor of calcineurin.
Furthermore, it was demonstrated that glycogen synthase
kinase-3 (GSK-3)-mediated phosphorylation of RCAN-1 reverses its effect on calcineurin signaling (127) and that
RCAN-1 is repressed by the basic helix loop helix (bHLH)
protein Hes-1 after Notch1 activation (198). On the other
hand, RCAN-2, also known as Csp-2, MCIP-2, and ZAKI-4, is
not regulated by calcium, but its expression in striated muscle is absolutely dependent on thyroid hormone levels (332).
Work with RCAN⫺/⫺ or RCAN transgenic mice indicates that RCAN-mediated inhibition of calcineurin activity may represent a superimposed control of the
calcium signal by finely tuning the calcineurin response
to the calcium signal. Thus a high-threshold gene, such
as Fas ligand (87), is kept silent under moderate TCR
stimulation (265), and cardiac hypertrophy is blocked
after calcineurin stimulation without repression of the
induction of B-type natriuretic peptide (BNP), a lowthreshold calcineurin target gene in the heart (128).
RCAN-1⫺/⫺ mice show premature cell death of Th1
lymphocytes during TCR-mediated proliferation due to
aberrant expression of Fas ligand and enhanced responses in several models of cardiac hypertrophy (reviewed in Ref. 313). Conversely, targeted overexpression
of RCAN-1, Cain/Cabin-1, or AKAP-79 in myocytes inhibits
cardiac hypertrophy and preserves the systolic function
(72, 128, 262).
Calsarcins, a family of calcineurin-interacting proteins expressed specifically in striated muscle, also inhibit
calcineurin (96). Calsarcin-1-deficient mice show an excess of slow muscle fibers and develop exaggerated hypertrophy in response to mechanical stress, which is associated with marked activation of a cardiac fetal gene
program (95). The fact that calsarcin-1-deficient mice
show induction of the fetal gene program but not cardiac
hypertrophy in basal conditions and do not respond to
other hypertrophic stimuli such as chronic isoproterenol
administration or exercise, supports the concept that the
calcineurin response to a given calcium signal is tuned to
different thresholds by the specific action of calcineurin
inhibitors that modulate the physiological or pathological
response (265).
Recently, an endogenous inhibitor of calcineurin,
named Carabin, functions as a true feedback inhibitor
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339). In support of distinct roles for the three proteins,
lack of CnA␣ results in deficient T-cell response, while
absence of CnA␤ has profound effects on T-cell development, with fewer CD4/CD8 single positive cells and defective proliferative response. Furthermore, CnA␤-deficient mice show impaired cardiac hypertrophic response
following pressure overload or isoproterenol infusion
(38). The molecular basis of the functional specificity
difference between ␣- and ␤-isoforms is not fully understood, although it could be related to differential expression or distinct ability to interact with endogenous inhibitors. Thus the specific regulation of the CnA␤ promoter
by NFAT/GATA4 complexes was recently described
(229), and several classes of endogenous inhibitors of
calcineurin activity have been identified (see below).
Compared with other mechanisms of Ca2⫹-dependent gene regulation, calcineurin has a particularly high
affinity for Ca2⫹/calmodulin and is at least one order of
magnitude more sensitive to Ca2⫹/calmodulin than is
CaMKII. As a consequence, calcineurin responds to sustained, low-amplitude calcium transients, whereas CaMKdependent gene expression is used preferentially in response to transient, high-amplitude calcium spikes (84,
304). It was shown, however, that adequate calcium levels
for calcineurin effects on gene expression may require
calreticulin-mediated supply from the endoplasmic reticulum; embryonic lethality in calreticulin deficient mice is
thus reversed by cardiac-specific overexpression of calcineurin (194). Furthermore, overexpression of activated
calcineurin is associated with an intermediate phase of
LTP in CA1 neurons of the hippocampus (324) and with
defective long-term memory, evident in both a spatial task
and a visual recognition task (199). Conversely, transient
inhibition of calcineurin facilitates LTP, enhancing learning and strengthening short- and long-term memory in
several hippocampal-dependent spatial and nonspatial
tasks (199). Taken together, these data are consistent
with the idea that endogenous calcineurin restrains LTP
and memory. On the other hand, calcineurin B mutant
mice have defects in axonal outgrowth but die at E10.0
due to failure to correctly pattern the developing vascular
system (110).
Calcineurin activity is regulated by its interaction
with several endogenous proteins. The first inhibitor identified, AKAP79 (A-kinase anchoring protein-79), serves as
a scaffold protein that anchors calcineurin to the membrane together with protein kinases A or C (160). Other
inhibitors, such as Cabin1/Cain, A238L, and RCS (regulator of calmodulin signaling), function by blocking calcineurin binding to physiological substrates (170, 216,
250, 293), or by mimicking the interaction of calcineurin
with its regulatory subunit calcineurin B as is the case of
the CHP/p22 protein (184). More recently, a family of
regulators of calcineurin (RCAN)-1 to -3 has been described (70, 157). RCAN-1, also known as calcipressin-1
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2. PP1-regulated gene expression
The calcium/calcineurin-dependent type 1 serine/
threonine protein phosphatase (PP1) holoenzyme consists of a highly conserved catalytic subunit and one or
more regulatory subunits. Evidence accumulated in recent years indicates that PP1 activity is modulated largely
by its interaction with ⬃70 different auxiliary proteins
that target the enzyme to distinct subcellular compartments, conferring substrate specificity (21, 138). A subset
of these interacting proteins are inhibitory proteins that
block the catalytic activity of PP1. These include PP1
inhibitors 1 and 2, DARPP-32 (220, 331), as well as PNUTS
and NIPP-1, two inhibitory subunits of PP1 that direct the
nuclear targeting and retention of the enzyme, regulating
PP1 nuclear activity (8, 178). Binding to PP1 and inhibition of its activity are regulated by PKA phosphorylation
in both cases (28, 156), while calcineurin dephosphorylates inhibitor-1 blocking its activity which results in PP1
activation (89). PNUTS also binds to chromatin and enhances in vitro chromosome decondensation in a PP1dependent manner (171). Dephosphorylation of inhibitor
1 by other non-calcium-dependent phosphatases like
PP2A should result in calcium-independent PP1 activation (89).
A major role of PP1 activity in the nucleus is to
dephosphorylate the transcription factor CREB (44) and
terminate CREB-dependent gene expression. The mechanism involves the specific interaction of PP1 with HDAC1,
which in turn recruits the phosphatase to the proximity of
phosphoCREB, allowing its dephosphorylation (44). Conditional overexpression of PP1 protein inhibitor-1 in mice
prolongs CREB phosphorylation and improves performance in an object recognition task (102). Strikingly, the
improvement was observed only when mice were exposed to a protocol of distributed training with brief
intertrial intervals, suggesting that the interference with
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the decay of CREB phosphorylation specifically mimicked the improved acquisition associated with long intertrial protocols (102). Furthermore, conditional inhibition of PP1 activity during training also improved the
information retention for up to 6 wk after intensive training in the water maze test, supporting an active role of
PP1 in memory decline. Overexpression of PP1 protein
inhibitor-1 also resulted in extended autophosphorylation
of CaMKII at Thr-286, a finding previously observed
in vitro after local application of thiophosphorylated inhibitor-1 and associated with improved LTP at the Schaffer collateral-CA1 synapse (33).
III. CALCIUM-DEPENDENT
TRANSCRIPTIONAL NETWORKS
A number of nuclear effectors whose action is regulated by changes in intracellular Ca2⫹ have been described over the years. The growing list includes proteins,
which are targets of calcium-dependent posttranslational
modifications as well as others, whose nuclear activity or
presence is regulated by the interaction with Ca2⫹ or
calcium binding proteins. This section reviews recent developments on the diversity of molecular mechanisms
governing these calcium-sensitive transcriptional networks.
A. The CREB/CBP/TORC Pathway
It has long been accepted that Ca2⫹- and cAMPdependent pathways that control gene expression share
many common players and points of cross-talk. Indeed,
the accepted view involves several coincident steps, including the phosphorylation at Ser-133 of DNA-bound
CREB dimers and recruitment of the coactivator paralogs
CBP/p300 to trigger transcription of CRE-containing target genes (reviewed in Ref. 204). Recent studies have
added new players and provided new steps into the process, some of which are strictly dependent on changes in
intracellular Ca2⫹ levels.
Binding of CREB as a dimer to the canonical CRE site
(TGAGCTCA) has been considered the default start of the
process. Work in Goodman’s laboratory using chromatin
immunoprecipitation and in vivo genomic footprinting
assays showed, however, that occupancy of CRE sites is
regulated in a cell-specific manner and that the ability of
CREB dimers to bind to a particular CRE represents an
important component of gene regulation (48). In addition,
core promoter configuration, including the presence of a
TATA box motif and the vicinity to, and methylation state
of consensus cAMP response elements near the promoter,
are key factors in deciding the proportion of CREB target
genes that will respond to cAMP in a given cell type (61,
342). Thus, before CREB is phosphorylated in response to
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since its expression is upregulated after TCR stimulation
and calcium entry (235). Carabin induction is sensitive to
inhibitors of calcineurin, indicating that Carabin constitutes part of a negative regulatory loop for the intracellular TCR signaling pathway. Knockdown of Carabin by
short interfering RNA led to a significant enhancement of
IL-2 production by antigen-specific T cells in vitro and
in vivo (235).
The most significant and best-characterized mechanisms by which calcineurin influences transcriptional networks involves dephosphorylation of NFAT and TORC
and the activation of MEF-2 proteins (30, 65, 201, 274,
336). While in the first case the effect of calcineurin is a
direct enzymatic action on NFAT and TORC proteins, in
the second case, calcineurin regulates the activity of
MEF-2 transcription factors by three different mechanisms that are discussed in detail in section IIIB.
Ca2⫹-REGULATED GENE EXPRESSION
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TORCs, for transducers of regulated CREB activity, that
enhances CRE-dependent transcription via a phosphorylation-independent interaction with the bZIP DNA binding/dimerization domain of CREB. TORC recruitment
does not appear to modulate CREB DNA binding activity,
but rather enhances the interaction between the glutamine-rich transactivation domain of CREB and the
TAFII130 protein, a component of the TFIID complex,
following TORC recruitment to the promoter (61, 145).
The three TORC family members share an NH2-terminal coiled-coil domain that associates as a tetramer
with the bZIP domain of CREB. Contrary to CBP, expression levels of TORC proteins are very low in the cell. In
basal unstimulated conditions, TORC proteins are localized mainly in the cytosol, which makes it difficult to
understand their crucial role as limiting factors for CREB
transcription. Later studies from the two laboratories involved in the identification of TORC proteins defined a
“signaling module” that mediates calcium- and cAMPdependent, phosphorylation-independent activation of
the CREB transcription factor. The pathway involves the
calcium-regulated phosphatase calcineurin and the Ser/
Thr kinase SIK2, both of which associate with TORC2 in
pancreatic islet cells. Under resting conditions, TORC2 is
sequestered in the cytoplasm via a phosphorylation-dependent interaction with 14-3-3 proteins. Following glucose and gut hormone stimulation, calcium influx increases calcineurin activity triggering TORC2 dephosphorylation, its release from the interaction with 14-3-3
proteins, and its nuclear translocation. Concomitant stimulation of the cAMP pathway after glucose and hormone
action inhibits SIK2 kinase activity, reducing TORC2
phosphorylation. Through this mechanism, the concerted
action of a phosphatase/kinase module connects two signaling pathways in response to nutrient and hormonal
cues (30, 274). In a recent report, Montminy’s group
shows that hormonal- and energy-sensing pathways converge on the coactivator TORC2 to modulate glucose
output. Under fasting conditions or after glucagon administration, TORC2 thus translocates to the nucleus and
enhances CREB-dependent transcription. Conversely, signals that activate the energy-sensing kinase AMPK inhibit
hepatic gluconeogenesis by promoting TORC2 phosphorylation and nuclear export. These results suggest that
fasting hyperglycemia associated with elevated gluconeogenesis in type 2 diabetes could potentially be treated
with compounds that enhance TORC2 phosphorylation
(162). A key role for TORC proteins in muscle cells has
been described to induce the expression of PGC-1␣, a
master regulator of mitochondrial biogenesis and energy
metabolism (329).
Finally, also in line with the phosphorylation-independent regulation of CREB activity, a Ca2⫹-dependent
interaction between transcriptional repressor DREAM
and CREB or phosphoCREB regulates the accessibility of
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a given stimulus in a particular cell type, genetic and
epigenetic factors determine whether that cell will respond to the stimulus with an upregulation of CRE transcription just by allowing or preventing the CREB-controlled machinery to approach the specific promoter.
Evidence has accumulated showing that Ser-133
CREB phosphorylation can occur through several kinases
including PKA, PKC, mitogen-activated protein kinases
(MAPKs; ERK and p38), CaMK, and CaMKK. As mentioned above, Ca2⫹/calcineurin-dependent activation of
PP1 terminates CREB activation and stops CRE-dependent transcription (44). Both processes have been reviewed extensively (77, 108, 204).
CBP/p300 recruitment to Ser-133 phosphoCREB is
favored by signaling-dependent modifications of CBP by
several kinases, including Ca2⫹- and CaMKIV-dependent
phosphorylation of CBP at Ser-301, e.g., following NMDA
receptor activation in cultured hippocampal neurons
(135, 143). Nevertheless, serine to alanine mutation of residue 301 attenuates but does not block CREB/CBP-dependent transactivation, indicating that additional CaMKIV
phosphorylation sites, particularly in the COOH terminal,
or other kinases, including CaMKII, may as well participate in activity-dependent CBP induction. The Ca2⫹-dependent phosphorylation of CBP is thus an additional
check-point controlling CREB/CBP-dependent transcription, although the mechanism by which phosphorylation
of CBP affects its transactivating properties is not known.
An intriguing possibility is that Ca2⫹-dependent CBP
phosphorylation modifies its HAT activity, as previously
shown for the P/CAF protein (154). In support of this
mechanism, impaired chromatin acetylation in heterozygous CBP⫹/⫺ mice or after inducible expression in the
forebrain of a mutant form of CBP that lacks HAT activity,
CBP(HAT⫺/⫺), is related to long-term memory impairment that is reversed by pharmacological inhibition of
histone deacetylases (5, 166). Overexpression of constitutively active CREB or treatment with rolipram, a phosphodiesterase-4 inhibitor that enhances CREB activation,
partially rescues this phenotype (5, 34).
Nonetheless, CREB phosphorylation alone is not a
reliable predictor of target gene activation, and additional
CREB regulatory partners are required for recruitment of
the transcriptional apparatus to the promoter. It has been
shown that calcium signals destabilize the CREB-CBP
complex through secondary phosphorylation events on
CREB (164) and that the DNA binding/dimerization domain (bZIP) in CREB mediates transcriptional response
to both calcium influx and cAMP (278). In this case, the
bZIP appears to contribute significantly to induction of
CREB activity in response to membrane depolarizing signals, implicating this domain in CREB association with a
calcium-regulated coactivator. Indeed, search for proteins
able to interact with CREB and to induce CREB activity
identified a conserved family of coactivators, designated
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CBP to the KID domain in CREB, and so compromises
CRE transcription (174). This mechanism, which is described in detail later in this review, constitutes together
with the Ca2⫹-dependent modulation by TORC proteins a
new possibility to module CREB activity independently of
its phosphorylation state.
B. The MEF-2 Crossroad of Ca2ⴙ Regulation
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The MEF-2 family of myogenic transcription factors
(MEF-2A to D) is an important determinant in muscle
differentiation and T-cell activation through the transcriptional control of specific target genes (31, 336). It was
found that MEF-2A and MEF-2C are highly expressed also
in postmitotic neurons of the cerebellum and the cerebral
cortex, respectively, and that MEF-2 expression is essential for the survival of these neurons (200). Transcriptional actions of MEF-2 proteins are regulated by a variety
of mechanisms. In resting conditions, MEF-2 proteins are
bound to DNA as part of a repressor complex that includes histone deacetylases and calmodulin binding proteins among others (189). HDAC4 and -5 interact with the
so-called MEF-2 domain, located next to the MADS box in
the NH2 terminal of MEF-2 proteins (189, 215, 318), resulting in the repression of MEF-2 transcriptional activation, e.g., of the c-jun promoter (318). MEF-2B and -D are
normally sequestered by cabin1 (190) or the MEF-2 interacting transcriptional repressor (MITR) (285) in multiprotein complexes together with HDAC1. Cabin1 recruits
chromatin-modifying enzymes, both histone deacetylases
and a histone methyltransferase to repress MEF2 transcriptional activity (149, 162). As a result, transcription of
target genes like nur77 is also repressed (337), and myoblast differentiation is blocked (190). HDAC4, cabin1, and
MITR are Ca2⫹-CaM binding proteins that bind calmodulin with the same domain responsible for binding of
MEF-2 proteins (337, 338). Thus activity-dependent increase in nuclear Ca2⫹/CaM complexes after stimulation
releases MEF-2 proteins from the repressor complex (337,
338). This Ca2⫹-dependent mechanism is partially counteracted in the case of MEF-2D by increased cAMP levels
(26). In addition, Ca2⫹-dependent phosphorylation of the
MEF-2 domain by CaMKI and CaMKIV disrupts HDACmediated repression and releases MEF-2 (189, 190). Both
CaMKI and CaMKIV can phosphorylate HDAC4 and -5,
creating a phosphodomain that binds to 14-3-3 proteins
and mediates shuttling of HDACs from the nucleus to
the cytosol as well as releases repression from MEF-2
(205, 206). Noteworthy, a negative-feedback loop between MEF-2 proteins and HDAC9 has been recently
disclosed by showing that HDAC9 is a direct transcriptional target of MEF-2 in myocytes, where HDAC9 associates with MEF2 proteins to suppress their transcriptional activity (117).
Activation of nonrepressed MEF-2 proteins is also a
Ca2⫹-dependent process, for which two major mechanisms have been proposed. First, as shown in cerebellar
neurons by Greenberg’s group, calcium influx through
voltage-sensitive calcium channels triggers activation of
MKK6-p38 MAPK resulting in the phosphorylation of Ser387 located in the transactivation domain of MEF-2C
(202). Second, the Ca2⫹/CaM-dependent phosphatase calcineurin activates MEF-2 through a posttranscriptional
mechanism that either increases its DNA binding activity
in cerebellar granules (201) or triggers interaction of
MEF-2 and NFAT proteins and recruitment of CBP to
these complexes in T lymphocytes (32, 336). Ca2⫹/CaMdependent signaling thus prevents formation of the MEF2/HDAC complexes, induces nuclear export of class II
HDACs, activates MEF-2-dependent transcription, and as
a result stimulates cytokine expression, myogenesis, and
neuronal survival. An integrated view of different Ca2⫹dependent mechanisms regulating MEF-2 transcriptional
activity is shown in Figure 3.
Abrogation of MEF-2C by homologous recombination in mice leads to early embryonic lethality at E9.5
due to cardiac defects (182). Specifically, mutant mice
lacking the MEF-2C gene show a severely hypoplastic
right ventricular chamber and outflow tract, suggesting
that these cardiogenic regulatory factors may act in a
common pathway for development of the anterior heart
field and its derivatives. It was recently shown that expression of the BOP nucleoprotein in the developing heart
depends on the direct MEF-2C binding to a MEF-2-response element in the Bop promoter. Consistent with this,
mice deficient in the BOP transcriptional activity reproduce the MEF-2C⫺/⫺ phenotype. MEF-2C is thus necessary and sufficient to recapitulate endogenous BOP expression in the anterior heart field and its cardiac derivatives during mouse development. The Bop promoter also
directs transcription in the skeletal muscle lineage, but
only cardiac expression is dependent on MEF-2C. These
findings identify Bop as an essential downstream effector
gene of MEF-2C in the developing heart and reveal a
transcriptional cascade involved in development of the
anterior heart field and its derivatives (246).
Although MEF-2C is the only family member shown
to have a role in early heart formation, MEF-2A is the
predominant mef2 gene product expressed in postnatal
cardiac muscle. In accordance with this, most mice lacking MEF-2A die suddenly within the first week of life and
exhibit pronounced dilation of the right ventricle, myofibrillar fragmentation, mitochondrial disorganization, and
activation of a fetal cardiac gene program (224). The few
MEF-2A⫺/⫺ mice that survive to adulthood show a deficiency in cardiac mitochondria and susceptibility to sudden death. These MEF-2A-mutant mouse phenotypes reveal an essential role for MEF-2A in maintenance of mitochondrial content and cytoarchitectural integrity in
Ca2⫹-REGULATED GENE EXPRESSION
431
2⫹
FIG. 3. Multiple Ca -dependent pathways
control MEF-2-dependent transcription. See section IIIB in the text for details.
C. The NFAT Family of Transcription Factors
The NFAT family of transcription factors, NFATc1
to -c4 and NFAT5, also known as TonEBP, are proteins
evolutionarily related to the Rel/NF-␬B family. Dephosphorylation of NFAT proteins by calcineurin exposes
their nuclear localization signal and allows nuclear translocation. Once in the nucleus, NFAT proteins bind DNA,
alone or in complexes with other nucleoproteins, e.g., the
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Fos-Jun heterodimers, to activate transcription of specific
sets of genes depending on the cell type (reviewed in
Refs. 130, 255). The process is terminated by casein kinase I or the sequential action of PKA and GSK-3, constitutive NFAT kinases that rephosphorylate NFAT, exporting the protein back to the cytosol (24, 111). In addition,
MAPKs p38 and JNK are inducible NFAT kinases, which
may couple the termination of the calcineurin cascade
with different signaling pathways, simultaneously conferring an additional specificity since p38 and JNK show
distinct affinities for the different NFAT family members
(57, 333). Encoded in the Down’s syndrome critical region, the dual-specificity tyrosine-phosphorylation regulated kinases (DYRK) 1A and 2 are physiological negative
regulators of NFAT activation and have been implicated
in the regulation of NFAT phosphorylation (15, 116).
DYRK1A, which is localized in the nucleus, acts as a
priming kinase that enables additional phosphorylation of
NFAT by CK1 and GSK-3 leading to NFAT inactivation
(15, 116). DYRK2, which is localized in the cytoplasm,
functions as a “maintenance” kinase that sustains the
phosphorylation state of cytoplasmic NFAT in resting
cells (116).
Selective activation and action of export kinases
therefore explain how individual NFAT proteins might be
differentially regulated in a single cell type in response to
calcium stimulation. The process as a whole is extremely
rapid, giving NFAT proteins the remarkable ability to
sense dynamic changes in intracellular Ca2⫹ levels and
frequencies of Ca2⫹ oscillations (84). Ca2⫹-dependent regulation of the calcineurin/NFAT transcriptional network
encompasses both activation and repression of several
target genes. Gene profiling shows that activation follows
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postnatal cardiac myocytes and show that other MEF-2
isoforms cannot fully support these activities. Surprisingly, MEF-2 transcriptional activity, revealed by the expression of a MEF-2-dependent reporter transgene, is enhanced in the hearts of MEF-2A-mutant mice, reflecting
the transcriptional activation of residual MEF-2D. The
MEF-2A-mutant mouse phenotype clearly differs from
that of MEF-2C mutants, which die at E9.5 from severe
cardiovascular abnormalities. In light of the overlapping
expression patterns and similar DNA-binding activities of
the four vertebrate Mef2 gene products, it is likely that
these proteins have distinct as well as partially redundant
functions.
The generation of conditional MEF-2CloxP/loxP mice recently showed that myocardial-specific removal of MEF-2C
results in viable offspring, demonstrating that whereas
MEF-2C is required for early development of the heart, it
is not necessary for the formation of the heart after looping morphogenesis (316). As MEF-2C is also highly expressed in postmitotic neurons, smooth muscle cells, and
skeletal muscle precursors, MEF-2CloxP/loxP mice could
serve as a useful tool for dissecting the role of MEF-2C in
these various cell types.
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D. The DREAM/KChIP Family of Ca2ⴙ-Sensitive
Transcriptional Repressors
DREAM (downstream responsive element antagonist
modulator), also termed KChIP-3 (potassium channel interacting protein-3) or calsenilin, is a multifunctional protein of the DREAM/KChIP subfamily of calcium sensors
(KChIP-1 to -4) (11, 42, 46). Depending on the cell type
and the physiological conditions, DREAM shows multiple
subcellular localizations, in the nucleus, cytosol, or cell
membrane (Fig. 4). DREAM is widely expressed in the
brain, in particular in sensory neurons where it has a
predominantly nuclear localization (Fig. 4). All four members of the family are structurally and functionally related
(185), and they are coexpressed in many different brain
areas (Fig. 5), as well as in other tissues including the
FIG. 4. Subcellular distribution of DREAM/KChIP3. A: immunocytochemistry with specific antibodies for DREAM showing the preferential nuclear localization of endogenous DREAM protein in freshly isolated mouse sensory neurons. Note absence of staining in the nucleolar
compartment and weak signal in cytoplasm. B: confocal image showing
the preferential membrane localization of the DREAM-EGFP signal after
overexpression together with the interactive protein Kv4.2 potassium
channel. [Adapted from Ruiz-Gomez et al. (264a).]
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the coordinated action of NFAT:AP-1 complexes, whereas
NFAT in the absence of AP-1 recruits corepressors and
silences the expression of genes (196). Indeed, it was
more recently suggested that repression of CDK4 by
NFAT involves the recruitment of histone deacetylases to
a site just 3⬘ of the transcription start site of the CDK4
gene (18).
Genetic ablation of single NFAT genes generally results in mild phenotypes, indicating a certain degree of
redundancy. There are, nevertheless, notable exceptions:
1) mice with a deletion in the NFATc1 gene show impaired formation of cardiac valves and septa, suggesting a
role for calcineurin/NFATc1 in the cardiac endothelium
during cardiac morphogenesis (71, 253) acting together
with GATA5 to control the expression of endothelin-1
(225), and to direct the differentiation of the Th2 response
(330, 335); and 2) deletion of NFATc2 alone moderately
increases cytokine production by Th2 and mast cells (284,
312), whereas for instance, deletion of NFATc3 does not
alter cytokine expression (234). In most cases, however,
prominent phenotypes are observed only when two or
more NFAT proteins are lacking. Deletion of both
NFATc1 and -c2 is thus required for important loss of
cytokine production in T cells (242); deletion of both
NFATc2 and NFATc3 results in preferential Th2 cytokine
production (254). Deletion of both NFATc3 and NFATc4
isoforms results in serious defects in sensory axon projections, which are mimicked by calcineurin inhibition
during embryonic development; these mice die in utero
due to failure of normal vascular patterning. Death is the
result of derepression of the vascular endothelial growth
factor (VEGF) gene, and due to the growth of vesicles into
the nervous system and somites (110, 151). Finally, deletion of three members, NFATc2, -c3, and -c4, is required to
observe striking defects in axonal outgrowth in the central and peripheral nervous systems. Cultured primary
neurons, sensory or commissural, from these triple
knockout mice are unable to respond to neurotrophins or
netrin-1 with efficient axonal outgrowth. These data indicate that the ability of embryonic axons to respond to
growth factors with rapid outgrowth requires activation
of a calcineurin/NFAT pathway, while survival effects are
independent (112). These results are in line with the
aberrant sensory behavior described in Caenorhabditis
elegans bearing a loss-of-function mutation in TAX-6, a
calcineurin catalytic subunit (168). Also indicative of
functional redundancy, overexpression of constitutively
active versions of NFATc1 and NFATc2, in which a large
fraction of the phosphorylated serines have been mutated
to alanines to mimic the dephosphorylated form, elicit a
similar increase in expression of most cytokine genes
(218). Finally, overexpression of a constitutive active
form of NFATc4 results in cardiac hypertrophy and eventual heart failure, a phenotype observed also after expression of activated calcineurin (217).
Ca2⫹-REGULATED GENE EXPRESSION
433
FIG. 5. Differential expression of DREAM/KChIP mRNA in different brain areas. Analysis was performed by quantitative real-time PCR using
specific TaqMan probes and primers for each of the four KChIPs, 1-4. Coexpression of two or more KChIPs is observed in most areas analyzed.
pressor function is dependent on DREAM/KChIP heterotetramers, EFmDREAM proteins function as dominant
active mutants of endogenous KChIP proteins during
basal or Ca2⫹-induced cell activation (107, 271). A scheme
depicting the mechanism of Ca2⫹-insensitive repression
by EFmDREAM is shown in Figure 6. In addition, derepression of DRE-dependent transcription is regulated by
PKA or PI 3-kinase activation (173, 270). cAMP-dependent
derepression is associated with specific protein-protein
interactions between DREAM and ␣- or ␧-CREM, two
nuclear effectors of the transcriptional actions of cAMP
(173). This interaction requires two leucine-charged resi-
FIG. 6. DREAM-mediated transcriptional repression. A: basal repression of DREAM target
genes upon binding of DREAM/KChIP heterotetramers to the DRE site. B: stimulated derepression of DREAM-mediated repression by different
stimuli including Ca2⫹ (i), DREAM phosphorylation (ii), or the interaction of DREAM with other
nucleoproteins such as ␣CREM (iii). Once
DREAM is detached from the DRE site, trancription of a given target gene will proceed driven by
the specific combination of enhancers (E) and
silencers (S) present in the promoter region.
C: blockage of Ca2⫹-mediated derepression by
the presence of EFmDREAM within the DREAM/
KChIP heterotetramer bound to the DRE site.
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immune system, thyroid gland, and reproductive organs
(11, 42, 46, 271). All four DREAM/KChIP family members
share the unique property to bind as homo- or heterotetramers to a specific site in the DNA, the DRE site, and
repress transcription in a Ca2⫹-dependent manner (46, 66,
185, 232). Mutation within any of the three functional
calcium binding EF-hand motifs in DREAM results in
mutant proteins, EFmDREAMs, that retain the ability to
bind the DRE sequence and to repress transcription, but
are insensitive to calcium and remain bound to the DRE
site during activity-dependent stimulation, blocking Ca2⫹dependent derepression (46). Since DNA binding and re-
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mRNA and protein levels of the sodium/calcium exchanger-3
(NCX3) without modifying the expression of NCX1 and
NCX2. Reduced NCX3 protein levels in cerebellar granules results in increased levels of free cytosolic Ca2⫹,
making transgenic neurons more vulnerable to increased
Ca2⫹ influx following partial opening of voltage-gated
plasma membrane Ca2⫹ channels induced by increasing
K⫹ in the culture medium. Lentiviral-mediated overexpression of the NCX3 exchanger in cerebellar transgenic
granules restores normal Ca2⫹ homeostasis, indicating
that the phenotypic change in these transgenic neurons is
related exclusively to the downregulation of NCX3 by
DREAM (107). DREAM/KChIPs are the only EF-hand calcium sensors so far known to bind specifically to DNA
and directly regulate transcription in a Ca2⫹-dependent
manner. Recently, however, a novel DNA binding protein
called Freud-1 (5⬘ repressor element under dual repression binding protein-1) was reported to bind to the FRE
site in the proximal promoter of the serotonin 1A receptor
gene and to mediate its Ca2⫹-dependent repression (233).
Freud-1 is evolutionarily conserved and has two DM-14
basic repeats, a predicted helix-loop-helix DNA binding
domain, and a C2 region, calcium/phospholipids binding
domain, similar to those found in conventional PKC isoenzymes. An intact C2 domain is required for Freud-1 to
mediate derepression, whereas treatment with inhibitors
of CaM or CaMKs reversed Ca2⫹-mediated Freud-1 inhibition, suggesting an additional regulatory mechanism
that needs further investigation. Freud-1 thus represents a
novel calcium-regulated repressor that, at least in transient transfection experiments, negatively regulates basal
5-HT1A receptor expression.
E. The NF-␬B /I-␬B Couple
NF-␬B is expressed in nearly all cell types and is
implicated in the regulation of numerous genes mediating
immune, inflammatory, and stress responses (for reviews,
see Refs. 104, 147). NF-␬B is a heterodimer of p65 (RelA)
with p50 or p52. This heterodimer is anchored by a group
of proteins termed I␬B, which retain NF-␬B in the cytosol
by masking its nuclear localization signal (25). Following
site-specific I␬B hyperphosphorylation at S32 and S36 by
two I␬B kinases, IKK␣ and IKK␤ (79, 211), the inhibitor
molecule becomes susceptible to site-specific ubiquitination and subsequent degradation by the proteasome complex (36, 273). This releases NF-␬B, allowing nuclear
translocation. In addition, more recent studies in T lymphocytes and neurons identified CaMKII as an activator of
NF-␬B. In response to T-cell receptor (TCR) activation,
nuclear translocation of NF-␬B can be blocked by inhibitors of CaM or CaMK, or mimicked by overexpression of
a constitutively active form of CaMKII (141). In basal
conditions in neurons, the p65:p50 NF-␬B form is selec-
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due rich domains (LCDs) present in DREAM and ␣-/␧CREM (173). The LCD motif was first described in nuclear
coactivators (NCoA-1, p/CIP) and corepressors (NCoR,
SMRT) and has been implicated in protein-protein interactions with nuclear hormone receptors and CBP (136,
172, 308). The presence of functional LCDs within the
DREAM protein may thus allow DREAM to interact with
several other nucleoproteins to regulate transcriptional
events not directly related to the presence of DRE sites.
Indeed, we have reported that a LCD-dependent DREAM/
CREB interaction displaces CREB from CRE sites and
prevents CBP recruitment to phosphoCREB, which results in a reduction of CRE-dependent transcription without direct binding of DREAM to the CRE site (174). The
DREAM-CREB interaction is Ca2⫹ dependent, and Ca2⫹insensitive DREAM mutants (EFmDREAM) also act as
dominant repressors of Ca2⫹-dependent CREB-mediated
transcription (174). In addition, LCD- and Ca2⫹-independent protein-protein interactions between DREAM
and several other nucleoproteins have been reported
(259, 275).
DREAM was identified through its binding to the
DRE in the proximal promoter of the prodynorphin gene
(46, 47). Consistent with a role for DREAM in the regulation of the prodynorphin gene, DREAM⫺/⫺ mice show
upregulation of prodynorphin expression in spinal cord,
which results in a hypoalgesic phenotype (56). Curiously,
genetic ablation of the functionally related neuronal calcium sensor-1 gene in C. elegans results in worms with
defects in learning and memory for isothermal sensitivity
(105). Nevertheless, except for the modified noxious sensitivity and an anomalous response to chronic cannabinoid administration (56), no other phenotypic changes
have been described in DREAM⫺/⫺ mice, supporting the
idea that functional redundancy between members of the
family compensates for the genetic ablation of DREAM/
KChIP-3. To overcome this problem, an EFmDREAM
dominant active mutant was used in conventional transgenesis to block activity-dependent DREAM-KChIP-mediated derepression and to address the analysis of the physiological significance of this group of proteins. In two
recent reports, overexpression of EFmDREAM in T cells
or in neurons has dramatic effects on the response to TCR
engagement or to extracellular depolarizing conditions,
respectively (107, 271). In T lymphocytes, endogenous
DREAM expression is downregulated in response to TCR
stimulation, and overexpression of EFmDREAM results in
reduced proliferative response after polyclonal TCR activation or following an antigen-specific response (271).
The phenotype could be associated with decreased expression of several Th1 and Th2-specific cytokine genes
including IL-2, IL-4, and interferon (IFN)-␥, suggesting
DREAM as a new target for the development of immunosupressant drugs (271). Overexpression of EFmDREAM
in the cerebellum of transgenic mice significantly reduces
Ca2⫹-REGULATED GENE EXPRESSION
tively localized at synapses. Following membrane depolarization in neurons there is an increase in NF-␬B DNA
binding that is inhibited by blockers of synaptic transmission, voltage-dependent Ca2⫹ channel inhibitors, or antagonists of glutamate receptors (207). In addition, in NF-␬B
p65⫺/⫺ mice, the study reveals a Ca2⫹-dependent role of
NF-␬B in learning and memory, which is not due to gross
differences in motivation, perceptual, or motor skills.
F. Novel Mechanisms Associated With
Ca2ⴙ-Dependent Gene Expression
Physiol Rev • VOL
nomena, and the cleaved fragments have been implicated in regulating channel activity by reducing Ca2⫹
influx (142). Recently, however, the COOH-terminal intracellular fragment of the Cav1.2 subunit of the L-type
VGCC, named, calcium channel-associated transcriptional regulator (CCAT), was shown to localize in the
nuclei of GABAergic inhibitory interneurons in the cortex
and hippocampus and to regulate transcription of selective target genes (106, 222).
Importantly, the nuclear pool of CCAT is rapidly
extruded in response to calcium entry following neuronal
membrane depolarization (106); CCAT-regulated gene expression is sensitive to calcium stimulation. Whether
CCAT is found in the nuclei of other cell types that
express L-type channels and regulates gene expression in
nonneuronal cells is not known.
Transcriptional regulation by CCAT does not seem to
involve direct interaction with DNA but rather involves
interaction with other nucleoproteins, such as p54(nrb)/
NonO (nuclear RNA- and DNA-binding protein of 54 kDa,
also known as Non-POU domain-containing octamerbinding protein) (264).
Since other Cav subunits have been reported to be
cleaved in neurons (126, 167, 322) and one of them, the
Cav 2.1 subunit, generates a COOH-terminal fragment that
has been localized to Purkinje cell nuclei (163), additional
effectors to be described may share with CCAT this novel
Ca2⫹-dependent mechanism to control gene expression.
IV. CALCIUM-DEPENDENT PROTEIN-PROTEIN
INTERACTIONS THAT MODULATE
GENE EXPRESSION
Like DREAM, other calcium sensors, mainly CaM but
also S-100 and calreticulin, are multifunctional proteins
able to interact with various nuclear targets after Ca2⫹
binding to regulate the activity of transcription factors or
enzymes that influence chromatin structure to eventually
change gene expression. From the viewpoint of control of
transcriptional networks by nuclear Ca2⫹, two types of
interactions will be discussed because of their significance: 1) the interaction between Ca2⫹-bound calcium
sensors and transcription factors of the bHLH (63) and
the nuclear receptors superfamilies (40, 74) and Sox proteins (14) and 2) the Ca2⫹-mediated changes in chromatin
structure.
A. Ca2ⴙ Sensors in the Nucleus
CaM, a small acidic protein, is the prototypic calcium
sensor (reviewed in Ref. 129a). CaM contains four EFhand Ca2⫹-binding motifs, distributed in pairs embedded
within two separate globular regions at the NH2 and
COOH termini. A flexible central helix completes the
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Search for new Ca2⫹-sensitive transcriptional effectors using a transactivator trap strategy led to the identification of CREST (for calcium responsive transactivator)
from a cerebral cortex cDNA library (4). Overexpression
of CREST as a Gal4 fusion protein drives expression of an
UAS reporter in nondifferentiated embryonic rat cortical
neurons in culture in response to potassium depolarization or bath application of glutamate, two well-characterized stimuli that increase intracellular calcium concentration and trigger a variety of cellular responses including
dendrite outgrowth and neuronal death (122).
CREST does not bind directly to DNA; therefore, it
must associate with other nucleoproteins to activate transcription. Indeed, CREST has been shown to interact with
CBP through its last nine COOH-terminal amino acids, a
mechanism that could explain CREST-mediated dendritic
growth, a process associated with CREB phosphorylation
after Ca2⫹/cAMP neuronal stimulation (reviewed in Ref.
256). Interestingly, CREST⫺/⫺ mice show a reduction in
dendritic growth and branching that is specific for the
basal rather than apical dendrites in cortical pyramidal
neurons (4). Given the pleiotropic effects of the CREB/
CBP/TORC transcriptional network, future studies should
identify other CREST interactors in the nucleus responsible for this specific action on dentritic maturation. In
addition, CREST homodimerization has been proposed to
be necessary to block an inhibitory domain located next
to a nuclear localization signal in the COOH-terminal 150
amino acids of the protein (248).
A number of interesting questions about CREST can
be raised: 1) which are the final gene targets of CREST
that mediate the effect on dendrite growth; 2) 80% of
CREST⫺/⫺ mice die before adulthood within the second
or third week after birth, indicating that CREST may be
relevant for additional biological effects; and 3) how calcium signals actually activate CREST. This is an important issue, since no calcium binding motifs have been
observed in CREST and not even its interaction with CBP
has been shown to be induced upon neuronal depolarization (4).
Cleavage of the COOH-terminal end of voltagegated calcium channels (VGCCs) is a well-known phe-
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binding to DNA in a sequence-specific manner through
their HMG box and by interacting with specific partner
proteins (for a recent review, see Ref. 133). Interaction of
Ca2⫹-bound CaM with the HMG domain of Sox9, an early
embryonically expressed member of the family that regulates chondrogenesis, testis formation, and neural crest
development (133), blocks its nuclear import and consequent transcriptional activity (14). Missense mutations at
the Sox9 HMG box affect CaM interaction and result in
campomelic dysplasia/autosomal sex reversal (CD/SRA),
a severe bone malformation syndrome in which most XY
individuals show male-to-female sex reversal (14). Calcium regulation of Sox9 activity is thus crucial for its
biological effects. Since the HMG box is common to all
members of the Sox family, it can be predicted that calcium plays a major role during organ development by
selectively regulating the activity of specific Sox proteins.
B. Ca2ⴙ-Dependent Changes in
Chromatin Structure
Ca2⫹-dependent enzymes not only modify the activity
of specific transcriptional networks but also act on chromatin-associated proteins, histones (H) and high mobility
group (HMG) proteins, to evoke selective modifications in
the nucleosomal environment that encompass specific
genes to either expose or mask their regulatory sites to
transcriptional regulators. An example is the correlation
between c-fos induction and the increased sensitivity to
DNaseI of the c-fos gene (91), which is related to phosphorylation of histone H3 and HMG proteins (153).
Histones are essential components for the arrangement of the nucleosomes, and posttranslational modifications, including acetylation, phosphorylation, methylation, and ADP-ribosylation, have profound effects on
chromatin structure and on gene expression. The HMG
proteins are non-histone chromosomal proteins of low
molecular mass, fundamental for stabilizing the enhanceosome at promoter regions and mediating transcriptional elongation (80). Because of their critical role in
transcription, they are also called architectural transcription factors, although they do not make sequence-specific
contact with the DNA.
Of the posttranslational modifications, phosphorylation and acetylation/deacetylation are the best characterized in terms of their association with activity-dependent
changes in chromatin structure. Early work from Schulman’s laboratory (323) reported the specific phosphorylation of histone H3, but not other histones, and of HMG
protein-17 in isolated nuclei from untreated cells in response to an increase in external Ca2⫹ in vitro. The precise mechanism by which phosphorylation of these nucleosomal proteins facilitates transcription is not known;
however, it was elegantly demonstrated that phosphory-
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characteristic dumbbell-shaped structure (289). S-100
proteins are also EF-hand proteins able to interact in a
Ca2⫹-dependent manner with many targets, some of
which are common with CaM. Of particular importance
here is the property of both CaM and S-100 proteins to
establish electrostatic interactions with the basic DNAbinding domain of class I bHLH transcription factors (63,
231). Following interaction, binding to DNA is blocked,
and as a result, transcriptional activity is lost. In addition,
binding of Ca2⫹-loaded CaM or S100 proteins to bHLH
proteins may prevent posttranslational modifications, affecting their transactivation potential (22) or block their
interactions with components of the transcriptional machinery such as HATs, HDACs, or other nuclear proteins
including pRB, Notch, and Mos (177). Interaction of bHLH
proteins with the Ca2⫹/calcium sensor complex thus results in profound changes in their transcriptional activity
through a variety of mechanisms. bHLH proteins are a
family of numerous nucleoproteins, widely expressed in
various organs, where they are involved in the control of
cell growth and differentiation (203). The consequences
of bHLH protein regulation by calcium sensors are potentially very significant during neurogenesis, hematopoiesis,
and myogenesis. Studies so far are limited to in vitro
analysis or to the use of transfected cells. Genetically
modified murine models that demonstrate the physiological consequences of interactions between bHLH proteins
and calcium sensors for the control of gene expression
are, however, still missing. Although genetic ablation of
Neuro2D, a calcium-sensitive bHLH protein, results in
incorrect patterning and lack of synaptic maturation of
thalamocortical projections (144), knock-in mice expressing a Ca2⫹-insensitive mutant of Neuro2D should be required to directly relate the potential Ca2⫹ effect on the
thalamocortical development.
Calreticulin, a calcium-binding protein initially localized predominantly within the ER, interacts with the
DNA-binding domain of several nuclear receptors, including glucocorticoid, androgen, retinoic acid, and vitamin D
receptors. As a result of these interactions, calreticulin
inhibits nuclear receptor-mediated transcription (40, 74).
In addition, calreticulin mediates Ca2⫹-dependent nuclear
export of glucocorticoid receptors (131, 132). Calreticulin
thus reduces the accessibility of nuclear receptors to
regulate transcription through two mechanisms, blocking
the binding to DNA and reducing the presence of the
receptor in the nucleus. Deletion of the NH2-terminal
signal sequence of calreticulin appears to eliminate its
effects on glucocorticoid receptor transactivation (214),
but does not influence its function as a nuclear export
factor for the glucocorticoid receptor (75).
Finally, nuclear import of transcription factors can
also be regulated by CaM, as recently described for Sox
proteins. Sox (Sry-related HMG box) is a large family of
transcription factors that activate gene expression by
Ca2⫹-REGULATED GENE EXPRESSION
Physiol Rev • VOL
structure that permits the access of other proteins to the
DNA. The reverse effect is achieved after histone deacetylation. Activity-dependent changes in histone acetyltransferase activity have been presented earlier in this review.
Therefore, we now present recent studies focused on
activity-dependent mechanisms that modify the activity of
histone deacetylases. This includes protein-protein interactions, changes in the subcellular localization and posttranslational modifications, as well as regulation of their
availability either by controlling HDAC expression or proteolytic processing.
Mammalian HDACs are classified into three different
groups (I, II, and III) according to their sequence homology to yeast HDACs: reduced potassium dependency 3
(Rpd3), histone deacetylase 1 (Hda1), and silent information regulator 2 (Sir2), respectively. In general, HDACs do
not make direct contact with DNA and depend on other
nucleoproteins for recruitment to specific locations in the
genome. HDACs are normally bound to scaffold proteins
like Sin3 and are included in large multiprotein complexes (Sin3, NuRD/NRD/Mi2, and the CoREST complexes) that are multifunctional (for a review, see Ref.
280a). The main mechanism that regulates HDAC activity
is the protein-protein interaction within the multiprotein
complexes. An example of this is the increased enzymatic
activity of HDAC3 after the interaction with the silencer
complex SMRT/N-CoR (silencing mediator of retinoid and
thyroid receptor/nuclear receptor corepressor) (6, 125).
The activation mechanism involves the displacement of
an inhibitor protein called TCP-1 ring complex (TriC) that
is bound to and blocks HDAC3 enzymatic activity (115).
Another major mechanism for the regulation of HDAC
activity is through phosphorylation. For class I HDACs,
phosphorylation by casein kinase II and/or PKA results in
increased activity, except for HDAC8, for which it is
reduced after PKA phosphorylation (175, 245, 311). In the
case of class II HDACs, phosphorylation regulates their
subcellular localization and their ability to interact with
other proteins. Ca2⫹-dependent phosphorylation of
HDAC4 and -5 by CaMKIV thus results in unbinding from
MEF-2 proteins and in a multistep Ca2⫹-regulated process
that involves the interaction with 14-3-3 proteins, producing important changes in gene expression that result in
drastic phenotypic modifications (337, 338). It has been
demonstrated that spontaneous electrical activity is sufficient for nuclear export of HDAC4, while stimulation of
calcium flux through synaptic NMDA receptors or L-type
calcium channels induces the nuclear export of HDAC5.
Nuclear import of HDAC4 but not -5 is mediated by
sumoylation (158). These differences in the activation
thresholds for HDAC4 and HDAC5 nuclear export and the
distinct import processes could provide a mechanism for
input-specific gene expression (51). Dephosphorylation of
HDACs is also a Ca2⫹-sensitive process, since most class
I and II HDACs form complexes that include PP1 (44,
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lation follows the hyperacetylation and decreases methylation on the same NH2-terminal histone tails (58, 266).
On this basis, phosphorylation was proposed to stabilize
an open conformation, perhaps blocking access of transcriptional corepressors associated with HDACs and DNA
methyltransferases. An important issue has been to identify the kinase(s) responsible for histone phosphorylation
leading to transcriptional activation. Ca2⫹/CaM-dependent phosphorylation of histone H3 was reported first,
suggesting the involvement of a nuclear CaMK (317).
More recently, the mitogen- and stress-activated kinases,
MSK1 and MSK2, two effector kinases downstream of
ERK and p38, were demonstrated to be responsible for
the H3 and HMG protein 14 phosphorylation associated
with immediate early gene activation (283, 302) and cytokine gene expression during inflammation (266). Notably,
MSK kinases are also responsible for the direct activation
of NF-␬B p65 subunit and CREB (73, 314). Several Ca2⫹dependent kinases thus phosphorylate histone H3 and
specific transcription factors to coordinately activate
transcriptional networks that participate in the immediate
early or the inflammatory responses. The system is reset
by the calcineurin-dependent nuclear protein phosphatase 1, which has been implicated in H3 dephosphorylation (49).
Phosphorylation of histones and HMG proteins has
been studied mainly in vitro and in cultured cells. Nonetheless, two recent reports suggest a role in vivo, showing
that a light pulse during the subjective nighttime stimulates MSK1 phosphorylation of H3 (41, 67) in hypothalamic neurons of the suprachiasmatic nucleus, a major
central circadian clock. The effect of light is specific, and
the kinetics of H3 phosphorylation parallel the early induction of c-fos and mPer1 (the mouse ortholog of the
Drosophila gene period) in the same neuron (67). Moreover, systemic blockage of GABAB receptors with baclofen prevents light-induced H3 phosphorylation and
c-fos and mPer1 gene expression (67). These results correlate well with circadian variation in phosphoCREB in
suprachiasmatic neurons and light-induced upregulation
of CRE-dependent transcription during the subjective
nighttime (227). The architectural transcription factor
HMG-I(Y) regulates expression of the rhodopsin gene in
terminally differentiated retinal photoreceptors (50). The
mechanism involves the interaction of HMG-I(Y) with the
Crx homeoprotein, which participates in the circadian
regulation of rhodopsin gene expression (50). In addition,
phosphorylation of HMG-I(Y) by PKC also regulates its
activity as reported in tumoral cell lines (20).
Acetylation/deacetylation, linked predominantly to
activation and repression, respectively, are to date probably the most extensively studied posttranslational histone modifications. It is commonly accepted that acetylation partially neutralizes the positive charge of histones,
reducing their affinity for DNA, thereby creating an open
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V. EXEMPLIFYING THE COMPLEXITY OF
CALCIUM-DEPENDENT GENE EXPRESSION:
THE BRAIN-DERIVED NEUROTROPHIC
FACTOR COMPENDIUM
The mouse BDNF gene consists of five 5⬘ noncoding
exons and one 3⬘ exon that includes the entire ORF of the
biologically active protein (305). Each of the first five
Physiol Rev • VOL
exons has a 5⬘ flanking region that is transcribed and a
splice donor site at the 3⬘ end. Exon VI contains the only
splice acceptor site and two polyadenylation signals. By
alternative usage of the five promoters followed by splicing with exon VI and alternative usage of the two polyadenylation signals, transcription of the BDNF gene in
mice results in 10 different BDNF transcripts. In the rat,
the third exon is missing; thus exon III corresponds to
mouse exon IV, and so on. Nonetheless, the overall organization and regulation of the promoter regions associated with each exon is basically conserved (305).
Early induction of BDNF transcription in the rat
brain following neuronal activation occurs through the
differential usage of BDNF promoters I and III or IV (99,
213, 305), while in cultured rat cortical neurons, activation of voltage-sensitive calcium channels by increased
extracellular K⫹ concentrations results in the preferential
upregulation of BDNFIII transcripts (279, 300). Several
regulatory sites have been associated with the activitydependent expression of rat BDNF transcripts: binding
sites for CREB and USF on promoter I (297), RE-1/NRSE
sites recognized by members of the REST/NRSF family on
promoter II (306, 344, 345), C/EBP␣ and Sp1 sites that
regulate expression from promoter IV (298), and an estrogen-responsive element near exon V (282). In exon III,
the initial studies (279, 300) identified two main sites: 1) a
hemi-palindromic CRE site that binds CREB and is located between 40 and 30 bp upstream of the exon III
mRNA start site, and 2) a Ca2⫹-responsive sequence
(CRS-1) located between 72 and 47 bp upstream from the
start site. Because the nature of the nuclear factor(s)
binding to the CRS-1 site was unknown, activity-dependent regulation of BDNF was initially explained as a
kinase-dependent process with Ca2⫹-mediated CaMKIVdependent CREB phosphorylation. Several recent discoveries have modified this simplified notion.
Analysis of the rat CRS-1 by Greenberg’s laboratory
has identified three independent Ca2⫹-responsive regulatory sites: the CaRE1, CaRE2, and the CaRE3/CRE site
located 3⬘ from the CRS-1 site. While the CaRE3/CRE site
corresponds to the originally identified calcium responsive element and mediates transactivation of BDNF by the
activated CREB/CBP pathway, the other two sites interact
with proteins newly characterized as Ca2⫹-responsive
regulators of BDNF transcription. The CaRE1 sequence is
located at the 5⬘ end of the previously defined CRS-1 site
and binds a new protein termed CaRF, calcium responsive factor, identified using a one-hybrid approach in
yeast (301). Ability to bind to the CaRE1 sequence resides
in the NH2 terminal of CaRF, while the domain(s) responsible for its transactivating properties is located at the
COOH terminal. The CaRE2 sequence includes an E-box
(CANNTG) that binds to the upstream stimulatory factors
1 and 2 (USF1/2) (52). USF1 and USF2 are ubiquitously
expressed bHLH proteins that bind to E-boxes as homo-
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100), although other phosphatases such as PP4 might also
participate in the process (343). Finally, activity-dependent regulation of HDAC3 gene expression has been
shown in T cells after TCR stimulation by a mechanism
that involves repression by HDAC1 at the promoter level
(69, 169).
Naive T cells are those that have matured in the
thymus and emerged into the periphery but have not yet
encountered antigen. When these cells are first exposed
to antigen, they differentiate into effector T cell with the
ability to transcribe specific subsets of cytokine genes in
response to secondary stimulation. The process of Th1/
Th2 cell differentiation involves early antigen-induced
changes that are transient unless they are maintained by
the simultaneous stimulation with the specific cytokines.
Induction of Th1 or Th2 lineage-specific differentiation
involves the remodeling of the cytokine locus itself in a
process that is controlled by NFAT proteins (13, 17) acting on distal regulatory elements present in all cytokine
genes that have been examined, including IL-3, granulocyte-macrophage colony stimulating factor, IL-4, IL-10,
and IFN-␥ (2, 16, 59, 60, 86, 124). NFAT proteins act
together with STAT (signal transducer and activator of
transcription) factors to determine the Th1/Th2 lineage.
In Th1 cells, STAT1 and STAT4 act downstream of IL-12
and IFN-␥, respectively, while STAT6 acts downstream of
IL-4 in Th2 cells. The synergistic action of NFAT and
STAT elicits the lineage-specific expression of transcription factors T-bet and GATA3 for Th1 and Th2 differentiation, respectively. At the same time, NFAT cooperates
functionally with STAT proteins at cytokine regulatory
regions, initiating long-range changes in DNase I hypersensitivity and histone modification throughout the regulatory regions of the IFN-␥ and IL-4 genes (3, 13, 296). The
appearance of new DNase I-hypersensitive sites in the
IFN-␥ and IL-4 genes during Th1 and Th2 cell differentiation is blocked by CsA, demonstrating the Ca2⫹-dependent involvement of NFAT proteins in the remodeling of
cytokine genes (2). Although NFAT proteins bind to the
promoters of both IFN-␥ and IL-4 during the early stages
of naive T-cell activation, after initiation of Th1 cell differentiation, the locus of IL-4 is silenced resulting in the
specific binding of NFAT to the IFN-␥ promoter. Similarly,
during Th2 cell differentiation and after silencing of the
IFN-␥ locus, NFAT binds to the IL-4 promoter.
Ca2⫹-REGULATED GENE EXPRESSION
Physiol Rev • VOL
ton’s disease. In all three cases, a casual relationship with
BDNF has been shown in transgenic models that reproduce partial aspects of the disease, although a formal
demonstration of modified BDNF levels in the brains of
these patients has not yet been provided.
The Rett syndrome, an X-linked neurological disorder, is characterized by arrested neurological development and cognitive decline and is produced is most cases
by mutations in the MeCP2 protein (10, 276), the methyl
CpG binding protein that controls BDNFIII transcription
(54, 202). How these mutations relate to changes in BDNF
expression in Rett syndrome-derived neurons is not
known. The Rubinstein-Taybi syndrome is a rare congenital disorder characterized by severe mental retardation
as well as retarded and abnormal skeletal growth. The
disease is caused by heterozygous mutations of the CBP
gene that affect the COOH-terminal domain of the protein
(244). Interventions that increase CREB activity overcome memory deficits in CBP[HAT⫺/⫺] or heterozygous
CBP⫺/⫺ mice (5, 166), although changes in BDNF expression in these animal models have not been reported.
Huntington’s disease, a dominantly inherited neurodegenerative disorder, is characterized by chorea, cognitive abnormalities, and psychiatric disturbances and is
caused by a polyglutamine expansion in the huntingtin
protein (reviewed in Ref. 123a). Both gain- and loss-of-
FIG. 7. Multiple molecular mechanisms regulate the activity-dependent transcription of the rat BDNF promoter III. A: “inactive or closed”
conformation of the chromatin at the BDNF promoter III as a result of
DNA methylation (yellow dots) and the presence of nonacetylated histones (hatched ellipse). B: “active or open” chromatin conformation at
the BDNF promoter III region showing the different regulatory sites
and the nucleoproteins that interact with them. For details, see section
V in the text.
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or heterodimers to activate transcription of target genes
(272, 281). In addition, work in our laboratory characterized the binding of transcriptional repressor DREAM to
two DRE sites located within the CRS-1 sequence (209).
This indicates that DREAM may participate directly in the
basal as well as in the Ca2⫹-dependent regulation of
BDNFIII transcripts. Neither the nuclear translocation of
CaRF and USF nor their binding to the CaRE1/CaRE2
sequences, respectively, is affected by changes in the
Ca2⫹ concentration. This indicates that the stimulus-dependent transactivating response of CaRF or USF proteins may be mediated by so far unknown posttranscriptional modifications of these factors or by undisclosed
CaRF- and USF-interacting proteins that presumably are
responsible to sense and to respond to the Ca2⫹ signal
(55, 301). Taken together, these results indicate that a
CREB-independent, Ca2⫹-dependent regulation of BDNF
occurs but may require additional factors. Whether BDNF
is a bona fide target gene for CaRF, DREAM, and USF
proteins nonetheless remains to be firmly established
in vivo using appropriate genetically modified mouse
models.
Recent studies added a further degree of complexity
to the regulation of BDNF expression by showing that
DNA methylation and possibly chromatin remodeling
control activity-dependent expression of the BDNF gene.
Methylation of several CpG islands at the 5⬘ flanking
region of BDNF exon III is dramatically reduced following
depolarization of primary cultured cortical neurons (202).
This finding correlates with the activity-dependent reduction in the binding of methyl-CpG binding protein 2
(MeCP2) to BDNF exon III promoter and the increase in
BDNF expression in the brains of DNA methyltransferase
I⫺/⫺ (MnmI) and MeCP2⫺/⫺ mice (54, 202). Silencing of
BDNF upon MeCP2 binding involves HDAC1 recruitment
through the corepressor mSin3A and/or the histone methyltransferase SUV39H1 that dimethylates histone H3 on
K9, a hallmark of inactive chromatin structure (94, 202).
The mechanism controlling demethylation of CpG islands
after K⫹-induced depolarization is presently unknown,
although Ca2⫹-dependent phosphorylation of MeCP2 regulates its unbinding from methylated DNA (54). Whether
demethylation follows or precedes MeCP2 release from
BDNF CpG islands and the signal(s) responsible for resetting basal transcription activity at BDNF promoter III
after activity-dependent induction are not known.
BDNF is an important neurotrophic factor for neuronal connectivity and brain function (reviewed in Ref.
273a), and heterozygous BDNF deficient mice show important deficits in learning and memory (165). It is therefore not surprising that three devastating neurological
disorders have been associated with mutations in proteins that affect or participate in the activity-dependent
transactivation of the BDNF gene. These are the Rett
syndrome, the Rubinstein-Taybi syndrome, and Hunting-
439
440
MELLSTRÖM ET AL.
nuclear pool as well as mechanisms that control the passage of calcium ions through the nuclear pore should also
be provided. Whether the nuclear pools of phosphoinositides and calcium maintain a certain level of cross-talk to
affect chromatin remodeling and to influence transcriptional networks more directly are open questions looking
for an answer.
ACKNOWLEDGMENTS
We thank Dr. Lafarga and Dr. Berciano for immunocytochemistry in sensory neurons and C. Marks for critical reading
of the manuscript.
We apologize to those authors whose work we could not
include due to space limitations.
Address for reprint requests and other correspondence:
J. R. Naranjo, CNB, CSIC Campus de Cantoblanco, 28049 Madrid, Spain (e-mail: [email protected]).
GRANTS
B. Mellström is supported by a Ramon y Cajal Senior
Scientist Contract. M. Savignac and R. Gomez-Villafuertes are
supported by CEE-Marie Curie and J. De la Cierva Junior Scientist Contracts, respectively. The work in our laboratory is
supported by grants from the Human Frontiers Science Program
(RGP0156/2001), CEE (NoE/512032), Fundacion La Caixa, MEC,
FISS, and CAM.
VI. SUMMARY AND FUTURE DIRECTIONS
In addition to the well-known calcium-activated kinase- and phosphatase-dependent mechanisms that control gene expression, recent years have witnessed an
eruption of new calcium-sensitive proteins and calciumdependent pathways. This has added further complexity
to, and raised new questions about, the mechanisms that
impose spatial and temporal restrictions on the synchronically induced transcriptional activity at a given genomic
locus to control its expression profile. Also, it will be very
important to define the hierarchy of calcium-operated
pathways that simultaneously operate on the expression
of a given gene.
New experimental work has provided insights into
the nature and specificities of the calcium signal itself,
although it is still unclear how the different pools of free
intracellular calcium differentially activate or repress a
given transcriptional network. Many still unknown selfregulatory mechanisms probably participate in the finetuning of the transcriptional response in absolute terms,
as well as of the temporal characteristics of the response.
Finally, recent publications highlight the existence of
a nuclear pool of phosphoinositides and the emerging role
of nuclear inositol phosphates in gene expression (228,
277, 287). New evidence has argued in favor of a similarly
regulated nuclear calcium pool (88), although further
studies should establish indisputably that such a pool is
truly nuclear and independent from the ER pool. Mechanisms that might regulate the release of Ca2⫹ from such a
Physiol Rev • VOL
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