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University of Groningen Novel cyclic AMP signalling ... · 4. mAKAP in the mouse brain 5. AKAPs as...
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University of Groningen
Novel cyclic AMP signalling avenues in learning and memoryOstroveanu, A
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Publication date:2009
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Citation for published version (APA):Ostroveanu, A. (2009). Novel cyclic AMP signalling avenues in learning and memory. s.n.
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Chapter 7
General Discussion
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Chapter 7
Content
1. The role of A-kinase anchoring protein 150 in learning and memory
2. PKA anchoring to AKAPs in learning and memory
3. Tools to investigate the function of AKAP(s) signalosome
4. mAKAP in the mouse brain
5. AKAPs as new therapeutic targets
6. The role of Epac in learning and memory
7. Overall conclusion and future perspectives
8. Reference
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General discussion
1. The role of A-kinase anchoring protein 150 (AKAP150) in
learning and memory
Recently, A-kinase anchoring proteins (AKAP) emerged as prototypic coordinators of
cyclic adenosine monophosphate (cAMP) activated protein kinase (PKA) signaling
providing high specificity to PKA signaling. The most investigated member of this family
of proteins is AKAP79/150, a protein expressed in e.g. rodent (AKAP150) and human
(AKAP79) brain. We showed that AKAP150 is highly expressed in the mouse striatum,
cerebral cortex, and forebrain regions, while a relatively high expression was found in the
hippocampus and olfactory bulb of the mouse brain. Low/no expression was observed in
the cerebellum, hypothalamus, thalamus, and brain stem (Ostroveanu et al., 2007). When
the AKAP150 staining in the mouse brain is compared to the previously reported
AKAP150 immunoreactivity pattern in rats (Glantz et al., 1992, Lilly et al., 2005), it
becomes obvious that the AKAP150 distribution in rat brain is much more homogeneous
than in the mouse brain. For example, in mice the CA3 area of the hippocampus is very
densely stained compared to the remainder of the hippocampus (Ostroveanu et al., 2007),
while the rat hippocampus shows a homogenous staining. Overall, the expression patterns
of AKAP150 in the mouse and rat brain reveal an abundant presence in brain regions
involved in learning and memory such as the cortex and hippocampus. Although it is
difficult to speculate on the role of AKAP150 in the mouse brain on the basis of its
distribution, these data suggest that AKAP150 may well play a role in learning and
memory.
In a study focusing on the distribution of AKAP150 at rat CA1 pyramidal cell postsynaptic
densities (PSD), it was shown that AKAP150 interacts with components of the excitatory
PSD, whereas AKAP150 immunoreactivity (IR) was not associated with inhibitory
synapses (Lilly et al., 2005). In parallel to these findings, AKAP79/150 was identified as a
constituent of postsynaptic densities (PSD) of excitatory synapses in human cerebral cortex
(Carr et al., 1992). Moreover, AKAP79/150 is linked to the N- methyl D-aspartate receptor
(NMDAR) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)
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in the PSD through binding with postsynaptic density-95, discs large, zona occludens-1
(PDZ) domain, membrane-associated guanylate kinase (MAGUK), scaffold proteins
postsynaptic density-95 (PSD-95) and synapse-associated protein-97 (SAP97) (Colledge et
al., 2000). In addition to PKA, AKAP79/150 can also bind protein phosphatase 2B (PP2B)
and protein kinase C (PKC) (Carr et al., 1992b; Coghlan et al., 1995; Klauck et al., 1996;
Sik et al., 2000). It was found that this multi-enzyme signaling complex plays an important
role in coordinating changes in synaptic structure and receptor signaling functions
underlying synaptic plasticity (Dell'Acqua et al., 2006). For example, AKAP79/150 bound
PKA was found to be essential for the regulation of AMPA receptor surface expression and
synaptic plasticity (Rosenmund et al., 1994). Additional evidence that AKAP79/150 could
be implicated in synaptic transmission arises from the study of Genin and colleagues (2003)
who showed that AKAP150 mRNA is upregulated during the maintenance phase of long-
term potentiation (LTP), a mechanism of long-lasting enhancement in synaptic efficacy
(Genin et al., 2003). A very recent study by Lu et al. (2007) also suggested that AKAP150
can be involved in synaptic plasticity. In transgenic mice expressing a truncated form of
AKAP150 which cannot anchor PKA, hippocampal LTP was abolished in 7–12 but not 4-
week-old mice. From these data they concluded that PKA anchored to AKAP150 critically
contributes to LTP in the adult hippocampus (Lu et al, 2007). Changes in synaptic plasticity
are suggested to be the mechanism underlying learning and memory processes (Martin et
al., 2000; Micheau and Riedel 1999). The findings that AKAP79/150 plays an important
role in synaptic plasticity, thus, provide additional evidence for the hypothesis that
AKAP79/150 is important in learning and memory processes. However, knowledge on the
role of AKAP79/150 in learning and memory remained so far rather limited.
Initial evidence for a role of AKAPs and PKA anchoring in learning and memory came
from a study by Moita and colleagues. They blocked PKA anchoring in the lateral
amygdala of rats and subjected the animals to auditory fear conditioning (Moita et al.,
2002). Their data showed that inhibition of PKA binding to AKAPs in the rat lateral
amygdala impairs memory consolidation during auditory fear conditioning (Moita et al.,
2002). We provided the first direct evidence for a role of AKAP150 in learning and
memory processes by assessing the expression of AKAP150 in the mouse hippocampus
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General discussion
after a single training session in a contextual fear conditioning paradigm. We could show
for the first time that AKAP150 is upregulated in the mouse hippocampus 6 hours after
training in this fear conditioning test (Nijholt et al., 2007). The time point of 6 h correspond
to the late phase of memory consolidation and is critically regulated by cAMP signaling
pathways in fear motivated associative learning. Moreover, mice exposed to a novel context
also showed an AKAP150 upregulation in the mouse hippocampus (Nijholt et al., 2007).
Although we can only speculate on the possible role of the increased expression of
AKAP150, it might very well be that elevated AKAP150 levels result in a more efficient
propagation of signals carried by locally generated cAMP (Colledge et al., 2000; Feliciello,
et al., 1997), which in turn may contribute to processing the exposure to a novel context and
the consolidation of associative memory. Since AKAP150 levels were only measured 6 h
after training we cannot exclude that AKAP150 may also be important during other stages
of the memory process. In general, the upregulation of AKAP150 may be the result of de
novo protein synthesis or decreased protein degradation.
Recently several studies provided data on possible mechanism of how AKAP150 could
modulate learning and memory processes. It was shown that constitutive loss of AKAP150
in mice modifies excitatory synaptic transmission (Tunquist et al., 2008). This is achieved
by a deranged localization of PKA in AKAP150 null hippocampal neurons which in turn
modulates the postsynaptic AMPA receptors. These AKAP150 KO mice also exhibit
deficits in motor coordination and show memory retrieval impairment in the Morris water
maze (Tunquist et al., 2008). Hall and colleagues (2007) showed that AKAP150 copurifies
with L-type Ca2+ channels Cav1.2 in the rat forebrain. Cav1.2 constitutes 80% of the L-type
channels in the brain (Hell et al, 1993, Moosmang et al., 2005) and is concentrated at
postsynaptic sites (Hell et al., 1996). It has been shown that hippocampal pyramidal
neurons express predominantly the Cav1.2 channel (Hell et al., 1993, Davare et al., 2001,
Sinnegger-Brauns et al., 2004). Interestingly, conditional inactivation of the Cav1.2 gene in
the mouse hippocampus and neocortex leads to a selective loss of protein synthesis-
dependent NMDAR-independent Schaffer collateral/CA1 late-phase LTP and these mice
show a severe impairment in a water-maze spatial-discrimination task (Moosmang et al,
2005). Although it was shown that Cav1.2 binds several AKAPs in the brain (MAP2B
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(Davare et al., 1999, Hall et al., 2007), AKAP15 (Hall et al., 2007)), AKAP150 proved to
be critical for PKA-mediated regulation of this channel in the brain (Hall et al., 2007).
Overall, these data suggest that AKAP150 could be important in learning and memory via
the regulation of Ca2+ signaling through Cav1.2.
In addition, Chai et al. found evidence that AKAP150 co-immunoprecipitates with the acid-
sensing ion channels ASIC1a and ASIC2a (Chai et al., 2007). It has been shown that these
channels are critically regulated by AKAP150 and calcineurin/PP2B (Chai et al., 2007).
Interestingly, ASIC1a is abundantly expressed in the amygdala complex and other brain
regions known to be involved in fear memory, and has been implicated in LTP (Wemmie et
al., 2002, Chai et al., 2007). Moreover, ASIC1 null mice display deficits in cued and
contextual fear conditioning (Wemmie et al., 2003), whereas ASIC1a overexpression
enhances fear-related freezing behavior (Wemmie et al., 2004). Furthermore, inhibition of
PKA anchoring by Ht-31 induces a decrease in ASIC current amplitude in cultured mouse
cortical neurons and Chinese hamster ovary (CHO) cells (Chai et al., 2007). Altogether
these studies suggest that AKAP150 may be able to change memory performance via the
regulation of ASIC channels.
Recently, several other AKAPs were reported to be important contributors to learning and
memory processes. For example, it has been shown that AKAP Yu is involved in the
formation of long term memory in Pavlovian olfactory learning of Drosophila (Lu et al.,
2007) and WAVE-1 null-mice (the first AKAP null mouse model) are impaired in spatial
(Morris water maze) and non-spatial (novel object recognition) memory formation but not
in emotional learning and memory (passive avoidance) (Soderling et al., 2003).
In summary, these data provide evidence for an increasing number of AKAPs that are
involved in learning and memory in different species. Our data, together with future
findings will lead to the understanding of how AKAPs coordinate the action of signaling
networks in cognitive processes under physiological and pathological conditions.
Ultimately this knowledge on the coordination of signaling cascades may lead to the
development of novel, more fine-tuned, innovative therapeutic strategies to treat cognitive
dysfunction.
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2. PKA anchoring to AKAPs in learning and memory
Besides the role of particular AKAPs in learning and memory, it is at least as important to
have a good understanding of the role of enzyme binding to these AKAPs. We addressed
the question whether anchored PKA is critically involved in the different stages
(acquisition, consolidation, retrieval, and extinction) of contextual fear memory in mice.
Accordingly, we first injected mice intracerebroventricularly with St-Ht31 (a membrane
permeable peptide that competes for PKA anchoring) at different time points during the
memory process. Injecting mice before training with St-Ht31 to affect the acquisition phase
resulted in impaired associative fear memory 24 h after the training. Similarly, injection of
St-Ht31 immediately after training (consolidation phase) significantly attenuated
conditioned fear. The learning deficit observed when St-Ht31 was injected immediately
after training was similar to the effect of St-Ht31 injected before training. To discriminate
between acquisition and consolidation, we also performed the retention test 1 h after the
training with mice that were injected before the training. Interestingly, the performance of
St-Ht31 injected animals did not differ from the control groups when the retention test was
performed 1 h after training. The finding that mice which received St-Ht31 before training,
showed unimpaired freezing 1 h after training but attenuated freezing 24 h after training,
suggests that PKA anchoring onto AKAPs plays a specific role in the consolidation of
contextual fear memories but not in acquisition (Nijholt et al., 2008). Moreover, disrupting
PKA anchoring before the retention test had no effect on memory performance in
contextual fear conditioning (Nijholt et al., 2008).
Next, we tested the sub-region specific contribution of PKA anchoring in the hippocampus
to the consolidation phase of fear memory. Therefore we injected immediately after training
St-Ht31 locally in the CA1 area of the mouse hippocampus. During the retention test mice
showed reduced freezing behavior when compared to vehicle or non-injected animals,
which indicates that disrupting PKA anchoring locally in the CA1 is instrumental in the
consolidation of fear memory. Our finding that PKA anchoring is important in learning is
supported by the findings of Nie and colleagues (Nie et al., 2007). Genetically modified
mice conditionally expressing Ht31 in the forebrain regions show impairments in the spatial
version of the Morris water maze, a hippocampus-dependent memory task (Nie et al, 2007).
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Although these data showed that PKA anchoring is crucial for memory consolidation, they
did not provide information on whether type I and/or type II PKA is involved. However,
most of the AKAPs in the brain tether PKA type II. To date, no RI AKAP was described in
the brain and only a few dual RI/RII AKAPs were characterized (Huang et al, 1997). Since
we cannot completely rule out a role for RI anchoring, we injected stearated Super-AKAP-
IS, in the mouse CA1 area of hippocampus before training mice in contextual fear
conditioning. Super-AKAP-IS is a PKA anchoring inhibitory peptide that selectively binds
RIIβ subunits of PKA. This selective anchoring inhibitory peptide also impaired the
freezing behavior when injected immediately after training. Thus, RIIβ anchoring to
AKAPs in the CA1 of the mouse hippocampus is crucial and sufficient for the
consolidation of contextual fear memory.
Recently Isiegas and colleagues showed that neuronal PKA facilitates the extinction of
contextual fear (Isiegas et al., 2006). This was found in transgenic mice expressing from
birth a dominant-negative form of PKA and in mice in which the same PKA dominant-
negative form was temporarily regulated in brain regions thought to be involved in
extinction (Isiegas et al., 2006). In our lab, we assessed for the first time the role of PKA
anchoring in fear extinction. Mice were injected in the CA1 area of the hippocampus with
stearated Super-AKAP-IS immediately after each extinction trial of contextual fear
memory. We observed that inhibiting PKA anchoring in the hippocampus promotes the
extinction of contextual fear conditioning (Nijholt et al., 2008). We thus were the first to
show that disrupting RIIβ anchoring only in the hippocampus is sufficient to facilitate fear
extinction. Our data are supported by the finding that temporally transgenic inhibition of
PKA activity also promotes extinction (Isiegas et al., 2006). More evidence for a role of
PKA anchoring in memory formation was provided by studies in Drosophila where AKAP-
bound PKA is required for aversive memory during appetitive memory, a Pavlovian
olfactory learning task in which an electric shock is used as an aversive unconditioned
stimulus (Schwaerzel et al., 2007). Unfortunately, St-Ht31 and Super-AKAP-IS do not
specifically block PKA anchoring to a particular AKAP, and therefore it cannot be
concluded which AKAP(s) was involved in the impaired consolidation of contextual fear
memory. We thus determined the amount of PKA anchored to AKAP150 in the dorsal
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hippocampus after intrahippocampal injection of St-superAKAP-IS. St-superAKAP-IS was
shown to reduce the amount of PKA anchored to AKAP150 in the dorsal hippocampus
when compared to vehicle-injected mice.
It was reported that PKA bound to AKAP150 is crucial for the phosphorylation of GluR1
AMPA receptor subunit at Ser845 (Colledge et al., 2000, Tavalin et al, 2002). This
phosphorylation stimulates postsynaptic accumulation of GluR1-containing AMPARs
during LTP (Esteban et al, 2003; Oh et al, 2006). Previously, it has been shown that
treatment of hippocampal slices with membrane permeable Ht31 impairs PKA dependent
hippocampal late-phase LTP (L-LTP) (Huang et al., 2006). Recently, Nie and colleagues
showed in transgenic mice expressing Ht31 in the hippocampus that a disruption of PKA-
AKAP interactions does not alter PKA activity or basal synaptic transmission but that only
long lasting forms of hippocampal LTP are impaired (Nie et al, 2007). Interestingly,
disruption of PKA anchoring or inhibition of PKA activity in hippocampal neurons leads to
a PP2B dependent, long-term depression (LTD) -like downregulation of AMPAR currents
and loss of AMPAR surface expression that likely involves AKAP79/150 (Hoshi et al.,
2005; Rosenmund et al., 1994; Snyder et al., 2005; Tavalin et al., 2002). Overall, these data
suggest that AKAP79/150 regulates the balance between PKA and PP2B signaling to
control AMPAR phosphorylation underlying LTP and LTD in synaptic plasticity. However,
so far the dynamics of this process are poorly understood. NMDA treatments that induce
LTD at many synapses simultaneously (chem-LTD) in hippocampal neurons activate
PP2B/CaN signaling and disrupt the association of AKAP79/150 with PSD-95 and
cadherins. This leads to a loss of the AKAP from spines and coincides with the removal of
AMPA receptors from synapses (Gomez et al., 2002; Gorski et al., 2005). In hippocampal
slices, chem-LTD activation of PP2B/CaN is followed by a persistent redistribution of both
AKAP79/150 and PKA-RII from postsynaptic membranes to the cytoplasm, without
PP2B/CaN translocation (Smith et al., 2006). Furthermore, using fluorescence resonance
energy transfer microscopy in hippocampal neurons, Smith et al. showed that PKA
anchoring to AKAP79/150 is required for an NMDA receptor-dependent regulated
cytoplasmic translocation of PKA and AKAP79/150 (Smith et al., 2006).
In summary, PKA anchoring in the hippocampus is required for both long-lasting forms of
hippocampal synaptic plasticity, and learning and memory.
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3. Tools to investigate the function of AKAP(s) signalosome
Besides PKA, there are more AKAP binding partners that participate in learning and
memory processes. For example, protein phosphatases are already widely acknowledged as
key molecules in synaptic plasticity and learning and memory. However, the role of protein
phosphatase anchoring to AKAPs in learning and memory has not been investigated yet.
The most interesting way to explore the function of any AKAP signalosome is by
pharmacological studies and/or by genetic manipulation. Although the use of
pharmacological compounds that block PKA anchoring already yielded fundamental
insights into the role of AKAP signaling in various physiological systems, inhibitory
peptides for any other AKAP binding partners are still not available to date. This is most
likely due to the difficulty of designing such agents and of intracellular delivery, and to the
expected unspecific action of such peptides.
In future experiments the impact of the RI isoform-selective anchoring on learning and
memory processes could be assessed using the RI anchoring disruptor (RIAD) (Carlson et
al., 2006). To study in greater detail which specific AKAP is involved, it would be
necessary to develop inhibitors that disrupt the interaction of PKA with one particular
AKAP or to disrupt the interaction of PKA by introducing site-specific mutations in the
PKA binding domain of a specific AKAP. Recently, genetically modified mice were
generated in the AKAP field. It is not surprising that the first complete knockdown of an
AKAP was AKAP150 (Hall et al., 2007). In addition to the AKAP150 KO mouse, mice in
which the PKA binding site was removed from the AKAP150 gene were also generated
(Hall et al., 2007). However, these mice are still not perfect “tools” for investigating the
role of AKAP150 since the modification occurs also during development and compensatory
mechanisms cannot be overcome. To define a role for a specific AKAP in learning and
memory, precise control on the expression of the transgene in space and time is required.
Another advantage of this spatial inducible system, compared to constitutive deletion of a
gene or expression of a transgene, is a reduced chance of animal lethality. This is especially
relevant when the gene of interest plays a crucial role during development or encodes for a
toxic protein. Already, the tetracycline-dependent system is widely used as a tool for spatio-
temporal control of transgene expression. Using this system, Isiegas and coworkers
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generated genetically modified mice that conditionally express Ht31 in forebrain regions.
Behavioral studies with these Ht31 transgenic mice revealed impairments in spatial learning
and memory in the Morris water maze as well impairments in long-lasting forms of
hippocampal LTP (Isiegas et al., 2008).
In our lab we aimed to generate mice that inducibly express AKAP150 or AKAP150
mutants only in forebrain regions. In order to explore both the in vitro and in vivo relevance
of AKAP150 binding to PKA and PP2B, particularly in learning and memory, a strategy
was developed involving removal of the PKA and PP2B binding site from AKAP150.
Initially, using a polymerase chain reaction (PCR) based technique we were able to clone
the mouse AKAP150 protein. Later on, by comparing the mouse AKAP150 sequence with
the human AKAP79 and rat AKAP150 homologues we could identify the PKA and PP2B
binding site on mouse AKAP150 and generate several deletion mutants: the PKA binding
site deletion mutant, the PP2B binding site deletion mutant, and the PKA+PP2B binding
site deletion mutant (Fig. 1).
Fig. 1. Left panel. Schematic
diagram of the AKAP150
molecule. The PKA and PP2B
binding site are located near the C-
terminal end of the protein. The N-
terminal end of the protein
contains a binding site for PKC
and the membrane-targeting
domain. Right panel. Several mutants were generated: upper - binding site-deleting mutant for PKA, middle -
binding site-deleting mutant for PP2B, lower - binding site-deleting mutant for both PKA and PP2B
To generate mice with an AKAP150 overexpression or an AKAP150 mutant
overexpression we opted for the use of lentiviral vectors to transduce embryonic stem cells.
These stem cells can then be injected into a mouse blastocyst to create a chimerical
transgenic animal. Later on, by cross breeding of chimeric transgenic animals, a pure
transgenic animal can be obtained. These transgenic animals can then be used for
functional testing to determine the consequences of their altered genetic material (Fig. 2).
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Moreover, by using the lentiviral expression system, various cell lines could be infected in
addition to test the viability and function of AKAP150 and its mutants in vitro. We
managed to successfully infect embryonic stem cells with AKAP150 or AKAP150 binding
site deletion mutants (unpublished data). These results will allow us to move forward in
creating a transgenic animal expressing inducible AKAP150 binding site deletion mutants
in the near future. Unquestionably, these transgenic animals can be used in future
experiments for a better understanding of the role of AKAP150 and anchoring of PKA and
PP2B to AKAP150 in learning and memory.
GENE OF INTEREST
Virus producer cell line
Producing
viral particle
Lentiviral vector
+
Gene of interest Overexpress gene of interest
by infecting the cell line of interest
In vitro experiments
+
Infecting embryonic stem cells
Select for cells
expressing
desired gene
Inject transformed ES
cells into blastocyst
Transgenic animal
Behavioral
testing
Electrophysiology
Fig. 2. Flowchart of the lentiviral expression system. The genes of interested were cloned in lentiviral expression
vectors. Viral particles containing the transgene can be use to infect various cell lines. This will allow for in vitro
experiment to test the function of the wildtype and mutants. Viral particles can also be used to infect embryonic
stem cells that can be used to generate transgenic animals. The physiological relevance of mutant AKAP150 in
transgenic animals can be assessed by behavioral testing, in vitro experiments, and electrophysiology.
4. mAKAP in the mouse brain
In the last few years, the number of AKAPs that were identified and characterized increased
considerably. One of these, mAKAP (m of muscular), was found to be predominantly
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General discussion
expressed in cardiac and skeletal muscle, but also detected to some extent in the brain
(Kapiloff et al., 1999). Two alternatively spliced variants of mAKAP were subsequently
characterized: mAKAPα (preferentially expressed in the brain) and mAKAPβ (abundant in
cardiac myocytes and skeletal muscle). In addition to their tissue-specific expression,
mAKAPα and mAKAPβ considerably differ in size: the longer form mAKAPα contains an
additional 244 amino acid residue N-terminal extension (Michel et al., 2005). Detailed
knowledge on the localization of mAKAP in the brain remained so far limited. We showed
that mAKAP is abundantly expressed throughout the entire mouse brain (Ostroveanu et al.,
2009 submitted). Both immunohistochemistry and Western blotting revealed a high
expression of mAKAP in the cortex, cerebellum, thalamus, hypothalamus, and
hippocampus, while the lowest mAKAP expression was detected in the brain stem.
Moreover, at subcellular levels, mAKAP was abundantly expressed both in perikarya (e.g:
pyramidal neurons, Purkinje neurons), dendrites (e.g.: apical and basal dendrites of
hippocampus pyramidal neurons) and to some extent in fibers (e.g: amygdala, cortex). Our
results are in good agreement with the reported mRNA expression of AKAP100/mAKAP
in several human brain regions (Kapiloff et. al., 1999; McCartney et al., 1995).
The function of mAKAP in the brain still remains rather unexplored. Conversely, in the
heart the function of mAKAP was extensively studied. In the heart, mAKAP is targeted to
the nuclear envelope through the binding of three spectrin repeat domains, where it forms a
large macromolecular signaling complex containing several signal transduction molecules,
including PKA (Kapiloff et al, 1999, Kapiloff et al, 2001), the phosphodiesterase PDE4D3
(Dodge et al., 2001), the protein phosphatases PP2A and calcineurin (Kapiloff et al, 2001,
Pare et al., 2005), ryanodine receptors (RyR2) (Kapiloff et al, 2001, Marx et al., 2000,
Ruehr et al., 2003), the small GTPase Rap1, the guanine exchange factor Epac1 (Dodge-
Kafka et al., 2005), and the mitogen-activated protein kinases (MAPK) MEK5 and ERK5
(Dodge-Kafka et al., 2005). Both in the brain and heart, mAKAP can also bind 3’-
phosphoinositide-dependent kinase 1 (PDK1) and p90 ribosomal S6 kinase (RSK3) (Michel
et al., 2005). Although in the heart 12 mAKAPβ signalosome components were reported,
there are probably many more mAKAPβ binding partners.
The mAKAPα signalosome in the brain has not been characterized yet. It can be expected
that mAKAPα and mAKAPβ form more or less the same signalosome. Preliminary data
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from our laboratory show that mAKAPα co-immunoprecipitates with PDE4D3 and the
exchange protein directly activated by cAMP 2 (Epac2) from hippocampal lysates
(unpublished data). Whether Epac1 is also included in the mAKAPα macromolecular
complex, still needs to be determined. In addition, preliminary colocalization studies in
primary cortical neurons confirmed that mAKAP co-localizes with Epac2 and PKA-RIIβ
(Fig. 3; unpublished data).
mAKAP PKA-RIIβ Merge
mAKAP Epac2 Merge
Fig. 3. mAKAP colocalizes with Epac2 and PKA-RIIβ in primary cortical neurons. Primary cortical neurons from
E14 were probed with antibodies against mAKAP, Epac2 and PKA-RIIβ.
Since at the nuclear membrane of cardiomyocytes the mAKAP complex coordinates three
different cAMP effectors (PKA, PDE4D3 and Epac1), and also calcium and MAPK kinase
signalling pathways, it is likely that in the brain it has the same function. Since mAKAP
forms such a large signalosome, it is currently unclear whether there is a single, large
complex that contains all of the mAKAP binding partners or, alternatively, whether there
are different mAKAP signalosomes that contain varying combinations of the signaling
molecules. We detected the highest mAKAP expression presynaptically in brain regions
such as the central amygdaloid nucleus, supraoptic nucleus, paraventricular hypothalamic
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General discussion
nucleus, and suprachiasmatic nucleus (Ostroveanu et al., 2009 submitted). Our finding that
mAKAP is abundantly expressed, particularly presynaptically, suggests an important role
for mAKAP in coordinating signal transduction pathways involved in adequate brain
functioning. This presynaptic expression pattern overlaps remarkably well with the
expression pattern for corticotrophin releasing factor (CRF) (Pilcher & Joseph, 1984). The
paralleled distribution of mAKAP with the CRF system suggests that mAKAP may also be
involved in a variety of functions such as emotion and autonomic responses but also
memory processes. Furthermore, we found a dramatic decrease in mAKAP expression in
all brain regions of aged mice. It has been shown that the expression levels of many genes
related to neuronal signaling, plasticity, and structure are changed in the hypothalamus and
cortex of the aged mouse brain (Jiang et al., 2001). Several proteins are downregulated in
the aged brain. For example, the level of PKC β1 is significantly decreased in aged rats as
assessed by RT-PCR and Western blotting (Yao et al, 1998). Moreover, in brain tissue from
elderly patients diagnosed with mild cognitive impairments several synaptic proteins (e.g.
synaptophysin) in the frontal and temporal cortex were shown to be downregulated (Counts
et al., 2006). Although it is difficult to speculate on the role of mAKAP in the brain on the
basis of its distribution, it may very well be that mAKAP contributes to changes in brain
functioning in aged mice and that it plays a role in cognitive processes.
A growing body of work on the role of AKAPs in the brain and other tissues provides
evidence that these multifunctional scaffolding proteins facilitate the fidelity of cAMP
signaling. This tight control of cAMP signaling is clearly important in the maintenance of a
healthy state, whereas the loss of this regulation might initiate diseases. How mAKAP
mediates the crosstalk and the integration of different signaling pathways via its
multimolecular protein complexes and what function it serves in the brain remains,
however, to be determined.
5. AKAPs as new therapeutic targets
Several studies have implicated the AKAP signalosome in ion channel modulation, G-
protein-coupled receptor desensitization, vesicular secretion, actin cytoskeletal dynamics,
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cell division and gene transcription regulated by cAMP, Ca2+, and lipid second messengers
(Michel & Scott, 2002). Since many of these cellular processes are altered in human
disease, understanding the mechanisms of AKAP signaling pathways may aid in the
development of novel therapeutics. So far traditional treatment in cognitive disorders has
focused on the manipulation of cell surface protein function. However, pharmacological
manipulation of cAMP signaling cascades in space and time may ultimately give us more
control on where and when events occur within the cell. Through careful intervention in the
coordination of signaling cascades we can gently nudge a cell into a certain direction. By
targeting anchoring proteins, like AKAPs, we could achieve this subtle intervention.
6. The role of Epac in learning and memory
Fairly recently, a novel PKA-independent cAMP effector was discovered and named
exchange protein directly activated by cAMP (Epac). In independent studies, two variants
of the Epac protein, Epac1 (also called cAMP-GEF-I) and Epac2 (also called cAMP-GEF-
II), were characterized (de Rooij et al., 1998; Kawasaki et al., 1998). Both Epacs function
as guanine nucleotide-exchange factors (GEFs) that specifically activate Rap GTPases
(Rap1 and Rap2) upon binding to cAMP. Although Epac proteins have been found to
control key cellular processes, including cellular calcium handling, integrin-mediated cell
adhesion, gene expression, cardiac hypertrophy, inflammation, and exocytosis (Pereira et
al., 2007; Oestreich et al., 2007; Hucho et al., 2005; Rangarajan et al., 2003; Lotfi et al.,
2006; Kang et al., 2003; Morel et al., 2005), their role in the brain just started to be
investigated. Since cAMP signaling is established to be of critical importance in learning
and memory, a potential role for PKA-independent cAMP signaling through Epac proteins
in the process of learning and memory may be expected. Recently, Epac has been linked to
synaptic transmission and neuronal excitability (Zhong & Zucker, 2005), was shown to
modulate membrane potentials in cultured cerebellar neurons, thereby potentially regulating
cellular excitability (Ster et al., 2007), and to enhance neurotransmitter release at excitatory
synapses (Gekel & Neher, 2008). Very recently it has been shown that Epac is involved in
both LTP (Gelinas et al, 2008) and LTD (Ster et al., 2009) in the mouse hippocampus.
156
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General discussion
Since both changes in LTP and LTD that affect synaptic transmission in the hippocampus
are thought to be involved in memory formation, these data suggest furthermore the
involvement of Epac in learning and memory processes.
We showed that intrahippocampal delivery of 8-pCPT-2’O-Me-cAMP, a compound that
specifically activates Epac but not PKA, improves fear memory retrieval in contextual fear
conditioning whereas acquisition and consolidation were not affected (Ostroveanu et al.,
2009 submitted). The retrieval enhancing effect of the Epac activator was even more
prominent in the passive avoidance test, a behavioral paradigm based on associative
emotional learning similar to fear conditioning. Since the performance of the mice in the
retention tests may be influenced by the level of anxiety the animal experiences, we tested
the effect of 8-pCPT-2’O-Me-cAMP on anxiety behavior in an elevated plus maze.
Intrahippocampal 8-pCPT-2’O-Me-cAMP injection before the elevated plus maze had no
effect on anxiety. Therefore, the effect of Epac activation in the fear-motivated learning
tasks can be solely ascribed to enhanced memory retrieval of the association between the
electric footshock and the context (Ostroveanu et al., 2009 submitted). Ouyang and
colleagues also recently reported a role for Epac signaling in memory retrieval (Ouyang et
al., 2008). In their study, the memory retrieval impairment observed in dopamine-beta-
hydroxylase deficient mice could be rescued by intrahippocampal (i.h.) injection of a
selective PKA activator together with a selective Epac activator, whereas injection of one
of the activators alone did not overcome the retrieval deficit (Ouyang et al., 2008).
Interestingly, when cAMP agonists were infused into the dorsal hippocampus of wild-type
mice 30 min before testing retrieval, no significant effects on retrieval were observed when
the agonists were infused separately or in combination (Ouyang et al., 2008). The lack of
any effect on memory retrieval in the wild type mice is in contradiction with our findings
and may depend on the time of agonist delivery. Ouyang and colleagues performed the
injections 30 minutes before the retrieval, whereas in our experiments, Epac agonist was
injected into the CA1 are of the hippocampus 10 minutes before the memory test.
It has been shown that 8-pCPT-2’O-Me-cAMP activates both Epac1 and Epac2. Therefore,
the enhanced memory retrieval effect cannot be attributed to a particular Epac. We showed
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Chapter 7
that Epac2 is abundantly expressed throughout the whole mouse brain, whereas only low
levels of Epac1 were detected. Using semi-quantitative RT-PCR for Epac1 and Epac2 with
mRNA isolated from the hippocampus, Epac2 mRNA could be detected much earlier as
Epac1 mRNA, pointing towards much higher Epac2 than Epac1 mRNA levels in the
hippocampus (Ostroveanu et al., 2009 submitted). Our data are consistent with a previous
study from Kawasaki et al. who also reported a high expression of Epac2 in the rat brain
whereas Epac1 was barely detectable (Kawasaki et al., 1998). To date, no Epac-specific
inhibitors are available. Therefore, we established a protocol for in vivo lipid mediated
siRNA gene silencing in the mouse brain to investigate the role of Epac2 in learning and
memory. Local Epac2 silencing in the CA1 area of the hippocampus led to impaired
memory retrieval 3 days after conditioning whereas Epac2 silencing during the retention
test 17 days after conditioning had no effect on memory retrieval indicating a time-limited
function of Epac2 signaling after conditioning. The finding that Epac2 is abundantly
expressed in the mouse brain together with the finding that Epac2 silencing impairs
memory retrieval, suggests an important role for Epac2 in learning and memory. In our
experiments we could not completely exclude a role for Epac1 in these processes. Both
specific-Epac inhibitors and/or transgenic or knock-out mice will provide further evidence
on the role of Epac1 and Epac2 in cognitive processes.
Interestingly, expression levels of both Epac1 and Epac2 were reported to be altered in the
frontal cortex and hippocampal regions of brains showing Alzheimer’s pathology (McPhee
et al., 2005). Alzheimer disease (AD) is a neurodegenerative disease characterized by the
formation of β-amyloid plaques and neurofibrillary tangles. It has been shown that
amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic
plasticity and memory (Shankar et al., 2008). Moreover, in AD, neural degradation occurs
primarily in neurons involved in memory storage and retrieval (Arshavsky, 2006). So far
the relationship between changes in Epac expression and Alzheimer’s pathology remain
unclear, but it could very well be that Epac plays a role in the cognitive decline such as
observed in AD. This is also supported by the finding that the Epac2 levels are decreased in
AD. We have shown in our studies that activation of Epac in the mouse hippocampus
significantly and specifically improves the retrieval of fear memory. Considering both the
158
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General discussion
lack and the need of drugs proven to be effective in improving memory retrieval, the
specific facilitating effect of Epac activation on retrieval we observed, is of particular
interest and deserves further research into the role of Epac signaling in cognitive processes
under physiological and pathological conditions.
Recent findings in several physiological systems acknowledged Epac as coordinator of
specific cAMP signals independent of PKA. Interestingly, it appears that in part, signals
carried through Epac are spatially and temporally compartmentalized. For example, in the
heart mAKAP is able to target Epac1 (Dodge-Kafka et al., 2005), while in the brain
AKAP150 binds both Epac1 and Epac2 (Nijholt et al, 2008). Thus, the spatio-temporal
integration of cAMP pathways via Epac, PKA, AKAPs and PDEs dramatically increases
the complexity and, consequently, the possible readouts of cAMP signalling. Moreover,
since both Epac and PKA are ubiquitously expressed, an increase in cAMP levels will lead
to the activation of both effectors which in turn can execute independent responses or
develop a cross-talk effect. For example, it has been reported that PKA and Epac can exert
opposing effects on the regulation of the PKB/AKT pathway. While PKA suppresses PKB
phosphorylation and activity, activation of Epac leads to increased PKB phosphorylation
(Mei et al., 2002; Nijholt et al., 2008). Interestingly, we recently showed that PKA and
Epac-mediated PKB/Akt phosphorylation is coordinated in neurons by AKAP150 (Nijholt
et al., 2008). In addition to the opposing effects, PKA and Epac may also work
synergistically in other systems. For example both the stimulation of neurotensin (Li et al.,
2007) and the attenuation of cAMP signaling through phosphodiesterases depend on the
activation of Epac and PKA (Dodge-Kafka et al., 2005).
Future research will lead to a better understanding of the physiological roles of both Epac
isoforms. Eventually, this may lead to a more detailed knowledge of the distinct role that
individual Epacs play in shaping cAMP signalling in the mammalian brain. This in turn
could result in the development of new strategies for selective pharmacologic manipulation
of the different cAMP signaling systems in cognitive processes under physiological and
pathological conditions.
159
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Chapter 7
7. Overall conclusion and future perspectives
In the current thesis we aimed to investigate the role of two recently discovered, cAMP
signaling avenues, via A-kinase anchoring proteins (AKAPs) and via exchange protein
activated by cAMP (Epac), in memory processes. A large number of publications
established an instrumental role of cAMP signaling in learning and memory processes.
With the discovery of both AKAPs and Epac, cAMP research has undergone a revival and
there grew a general awareness that cAMP signaling is much more complex than was
initially believed. Accordingly, it has become apparent that AKAPs and Epac might
mediate a more fine-tuned level of organization for cAMP second messenger systems. Our
results yield important insights in the role of AKAPs, compartmentalized cAMP signaling
and Epac in the different stages of learning and memory.
It was previously believed that anchoring proteins in the brain were only scaffolds for the
signaling enzymes involved in cognitive processes. Nevertheless, recent data, including our
own, show a completely new role for AKAPs as dynamic and active contributors to the
molecular machinery of learning and memory. With the increased number of anchoring
proteins discovered in the brain, careful analysis on the individual role and contribution of
AKAPs in learning and memory will continue to be an important part of future research.
Unquestionably, further analysis of AKAP macromolecular complexes role in learning and
memory will be forthcoming from genetic approaches involving transgenic mice.
Genetically modified mice expressing truncated AKAP molecules that hinder tethering of
signaling enzymes, or mice lacking a particular AKAP, will permit a more precise
dissection of particular AKAP-PKA-signaling enzymes/complexes in vivo. These mice will
not only provide insight into the mechanisms of AKAP functions but may yield genetic
models of specific diseases.
In this thesis, we could also show that cAMP signals independent of PKA pathways are
essential events in learning and memory processes. Consequently, compelling evidence
points towards an important role for Epac in these processes. However, the mechanism by
160
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General discussion
which Epac activation affects learning and memory is still unknown. Understanding how
exactly cAMP signals are coordinated will bring light on the elusive process of learning and
memory and memory retrieval in particular.
cAMP signaling was shown to be crucial in cognitive deficits and may consequently be a
promising target for therapeutic agents. Clearly, the ultimate goal of research on learning
and memory is translating knowledge from the laboratory to clinical applications. Thus, in
addition to the fundamental significance of understanding cAMP signaling cascades, our
research opens up new routes for the development of new therapeutic strategies for
memory-associated disorders and pathologies.
8. Reference
Arshavsky, Y.I. (2006). Alzheimer's disease, brain immune privilege and memory: a hypothesis.
Journal of Neural Transmission 11, 1697-1707.
Carlson, C.R., Lygren, B., Berge, T., Hoshi, N., Wong, W., Taskén, K., & Scott, J.D. (2006).
Delineation of type I protein kinase A-selective signaling events using an RI anchoring disruptor.
Journal of Biological Chemistry 281, 21535-21545.
Carr, D. W., Hausken, Z. E., Fraser, I. D. C., Stofko-Hahn, R. E., & Scott, J. D. (1992). Association
of the Type I1 CAMP-dependent Protein Kinase with a Human Thyroid RII-anchoring Protein.
Cloning and characterization of the RII-binding domain. Journal of Biological Chemistry 267, 13376-
13382.
Carr, D.W., Stofko-Hahn, R.E., Fraser, I.D.C., Cone, R.D., & Scott, J.D. (1992). Localization of the
cAMP-dependent Protein Kinase to the Postsynaptic Densities by A-Kinase Anchoring Proteins.
Journal of Biological Chemistry 24, 16816-16823.
Chai, S., Li, M., Lan, J., Xiong, Z.G., Saugstad, J.A., & Simon, R.P. (2007). A kinase-anchoring
protein 150 and calcineurin are involved in regulation of acid-sensing ion channels ASIC1a and
ASIC2a. Journal of Biological Chemistry 31, 22668-22677.
161
http://www.ncbi.nlm.nih.gov/pubmed/16932992?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
-
Chapter 7
Coghlan, V.M., Perrino, B.A., Howard, M., Langeberg, L.K., Hicks, J.B., Gallatin, W.M., & Scott,
J.D. (1995). Association of protein kinase A and protein phosphatase 2B with a common anchoring
protein. Science 5194, 108-111.
Colledge, M., Dean, R.A., Scott, G.K., Langeberg, L.K., Huganir, R.L., & Scott, J.D. (2000).
Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex. Neuron 27, 107-119.
Counts, S.E., Nadeem, M., Lad, S.P., Wuu, J., & Mufson, E.J. (2006). Differential expression of
synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive
impairment. Journal of Neuropathology and Experimental Neurology 6, 592-601.
Davare, M.A., Dong, F., Rubin, C.S., & Hell, J.W. (1999). The A-kinase anchor protein MAP2B and
cAMP-dependent protein kinase are associated with class C L-type calcium channels in neurons.
Journal of Biological Chemistry 42, 30280-30287.
Davare, M.A., Avdonin, V., Hall, D.D., Peden, E.M., Burette, A., Weinberg, R.J., Horne, M.C.,
Hoshi, T., & Hell, J.W. (2001). A beta2 adrenergic receptor signaling complex assembled with the
Ca2+ channel Cav1.2. Science 5527, 98-101.
de Rooij, J., Zwartkruis, F.J., Verheijen, M.H., Cool, R.H., Nijman, S.M., Wittinghofer, A., & Bos,
J.L. (1998). Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP.
Nature 396, 474-477.
Dell'Acqua, M.L., Smith, K.E., Gorski, J.A., Horne, E.A., Gibson, E.S., & Gomez, L.L. (2006).
Regulation of neuronal PKA signaling through AKAP targeting dynamics. European Journal of Cell
Biology 85, 627-633.
Dodge, K. L., Khouangsathiene, S., Kapiloff, M. S., Mouton, R., Hill, E. V., Houslay, M. D.,
Langeberg, L. K., & Scott, J. D. (2001). mAKAP assembles a protein kinase A/PDE4
phosphodiesterase cAMP signaling module. EMBO Journal 20, 1921-1930.
Dodge-Kafka, K.L., Soughayer, J., Pare, G.C., Carlisle Michel, J.J., Langeberg, L.K., Kapiloff, M.S.,
& Scott, J.D. (2005). The protein kinase A anchoring protein mAKAP coordinates two integrated
cAMP effector pathways. Nature 437, 574-578.
Esteban, J.A., Shi, S.H., Wilson, C., Nuriya, M., Huganir, & R.L., Malinow, R. (2003). PKA
phosphorylation of AMPAR subunits controls synaptic trafficking underlying plasticity. Nature
162
http://www.ncbi.nlm.nih.gov/pubmed/7528941?ordinalpos=33&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/7528941?ordinalpos=33&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
-
General discussion
Neuroscience 6, 136-143.
Feliciello A., Li, Y., Avvedimento, E.V., Gottesman, M. E., &Rubin, C. S. (1997). A-kinase anchor
protein 75 increases the rate and magnitude of cAMP signaling to the nucleus. Current Biology, 7,
1011-1014.
Gekel, I., & Neher, E. (2008). Application of an Epac activator enhances neurotransmitter release at
excitatory central synapses. Journal of Neuroscience 28, 7991-8002.
Gelinas, J.N., Banko, J.L., Peters, M.M., Klann, E., Weeber, E.J., & Nguyen, P.V. (2008). Activation
of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the
hippocampus. Learning and Memory 15, 403-411.
Genin, A., French, P., Doyere, V., Davis, S., Errington, M. L., Maroun, M., Stean, T., Truchet, B.,
Webber, M., Wills, T., Richter-Levin, G., Sanger, G., Hunt, S. P., Mallet, J., Laroche, S., Bliss, T.V.,
& O'Connor, V. (2003). LTP but not seizure is associated with up-regulation of AKAP-150.
European Journal of Neuroscience, 17, 331-340.
Glantz, S.B., Amat, J.A., & Rubin, C.S., (1992). cAMP signaling in neurons: patterns of neuronal
expression and intracellular localization for a novel protein, AKAP150, that anchors the regulatory
subunit of cAMP-dependent protein kinase II beta. Molecular Biology of the Cell 3, 1215-1228.
Gomez, L.L., Alam, S., Smith, K.E., Horne, E., & Dell'Acqua, M.L. (2002). Regulation of A-kinase
anchoring protein 79/150-cAMP-dependent protein kinase postsynaptic targeting by NMDA receptor
activation of calcineurin and remodeling of dendritic actin. Journal of Neuroscience 16, 7027-7044.
Gorski, J.A., Gomez, L.L., Scott, J.D., & Dell'Acqua, M.L. (2005) Association of an A-kinase-
anchoring protein signaling scaffold with cadherin adhesion molecules in neurons and epithelial cells.
Molecular Biology of the Cell 8, 3574-3590.
Hall, D.D., Davare, M.A., Shi, M., Allen, M.L., Weisenhaus, M., McKnight, G.S., & Hell, J.W.
(2007). Critical role of cAMP-dependent protein kinase anchoring to the L-type calcium channel
Cav1.2 via A-kinase anchor protein 150 in neurons. Biochemistry 6, 1635-1646.
Hell, J.W., Westenbroek, R.E., Warner, C., Ahlijanian, M.K., Prystay, W., Gilbert, M.M., Snutch,
T.P., & Catterall, W.A. (1993). Identification and differential subcellular localization of the neuronal
class C and class D L-type calcium channel alpha 1 subunits. The Journal of Cell Biology 4, 949-962.
163
-
Chapter 7
Hell, J.W., Westenbroek, R.E., Breeze, L.J., Wang, K.K., Chavkin, C., & Catterall, W.A. (1996) N-
methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium
channels in hippocampal neurons. Proceedings of the National Academy of Sciences United States of
America 8, 3362-3367.
Hoshi, N., Langeberg, L.K., & Scott, J.D., (2005). Distinct enzyme combinations in AKAP signaling
complexes permit functional diversity. Nature Cell Biology 7, 1066-1073.
Huang, L.J., Durick, K., Weiner, J.A., Chun, J., & Taylor, S.S. (1997). Identification of a novel
protein kinase A anchoring protein that binds both type I and type II regulatory subunits. Journal of
Biological Chemistry 12, 8057-8064.
Huang, L.J., Durick, K., Weiner, J.A., Chun, J., & Taylor, S.S. (1997). D-AKAP2, a novel protein
kinase A anchoring protein with a putative RGS domain. Proceedings of the National Academy of
Sciences United States of America 21, 11184-11189. Huang, T., McDonough, C. B., & Abel T. (2006). Compartmentalized PKA signaling events are
required for synaptic tagging and capture during hippocampal late-phase long-term potentiation.
European Journal of Cell Biology, 85, 635-642.
Hucho, T.B., Dina, O.A., & Levine, J.D. (2005). Epac mediates a cAMP-to-PKC signaling in
inflammatory pain: an isolectin B4(+) neuron-specific mechanism. Journal of Neuroscience 25, 6119-
6126.
Isiegas, C., Park, A., Kandel, E.R., Abel, T., & Lattal, K.M. (2006). Transgenic inhibition of neuronal
protein kinase A activity facilitates fear extinction. Journal of Neuroscience 26, 12700-12707.
Isiegas, C., McDonough, C., Huang, T., Havekes, R., Fabian, S., Wu, L.J., Xu, H., Zhao, M.G., Kim,
J.I., Lee, Y.S., Lee, H.R., Ko, H.G., Lee, N., Choi, S.L., Lee, J.S., Son, H., Zhuo, M., Kaang, B.K., &
Abel, T. (2008). A novel conditional genetic system reveals that increasing neuronal cAMP enhances
memory and retrieval. Journal of Neuroscience 24, 6220-6230.
Jiang, C.H., Tsien, J.Z., Schultz, P.G.,& Hu, Y. (2001). The effects of aging on gene expression in the
hypothalamus and cortex of mice. Proceedings of the National Academy of Sciences United States of
America 4, 1930-1934.
Kang, G., Joseph, J.W., Chepurny, O.G., Monaco, M., Wheeler, M.B., Bos, J.L., Schwede, F.,
Genieser, H.G., & Holz, G.G. (2003). Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP as a
164
http://www.ncbi.nlm.nih.gov/pubmed/18550764?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/18550764?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/11172053?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/11172053?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kang%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Joseph%20JW%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Chepurny%20OG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Monaco%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Wheeler%20MB%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bos%20JL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Schwede%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Genieser%20HG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Holz%20GG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus
-
General discussion
stimulus for Ca2+-induced Ca2+ release and exocytosis in pancreatic beta-cells. Journal of Biological
Chemistry 10, 8279-8285.
Kapiloff, M.S., Schillace, R.V., Westphal, A.M., & Scott, J.D. (1999). mAKAP: an A-kinase
anchoring protein targeted to the nuclear membrane of differentiated myocytes. Journal of Cell
Science 112, 2725-2736.
Kapiloff, M.S., Jackson, N., & Airhart, N. (2001). mAKAP and the ryanodine receptor are part of a
multi-component signaling complex on the cardiomyocyte nuclear envelope. Journal of Cell Science
17, 3167-3176.
Kapiloff M.S., Schillace R.V., Westphal A.M., & Scott J.D. (1999). mAKAP: an A-kinase anchoring
protein targeted to the nuclear membrane of differentiated myocytes. Journal of Cell Science 114,
3167-3176.
Kawasaki, H., Springett, G.M., Mochizuki, N., Toki, S., Nakaya, M., Matsuda, M., Housman, D.E., &
Graybiel, A.M. (1998). A family of cAMP-binding proteins that directly activate Rap1. Science 282,
2275-2279.
Klauck, T.M., Faux, M.C., Labudda, K., Langeberg, L.K., Jaken, S., & Scott, J.D. (1996).
Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science 271,
1589-1592.
Li, J., O'Connor, K.L., Cheng, X., Mei, F.C., Uchida, T., Townsend, C.M. Jr., & Evers, B.M. (2007).
Cyclic adenosine 5'-monophosphate-stimulated neurotensin secretion is mediated through Rap1
downstream of both Epac and protein kinase A signaling pathways. Molecular Endocrinology 1, 159-
171.
Lilly, S.M., Alvarez, F.J., & Tietz, E.I., (2005). Synaptic and subcellular localization of A-kinase
anchoring protein 150 in rat hippocampal CA1 pyramidal cells: co-localization with excitatory
synaptic markers. Neuroscience 1, 155-163.
Lotfi, S., Li, Z., Sun, J., Zuo, Y., Lam, P.P., Kang, Y., Rahimi, M., Islam, D., Wang, P., Gaisano,
H.Y., & Jin, T. (2006). Role of the exchange protein directly activated by cyclic adenosine 5'-
monophosphate (Epac) pathway in regulating proglucagon gene expression in intestinal endocrine L
cells. Endocrinology 8, 3727-3736.
165
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Graybiel%20AM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/pubmed/16644915?ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16644915?ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16644915?ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
-
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Lu, Y., Allen, M., Halt, A.R., Weisenhaus, M., Dallapiazza, R.F., Hall, D.D., Usachev, Y.M.,
McKnight, G.S., & Hell, J.W. (2007) Age-dependent requirement of AKAP150-anchored PKA and
GluR2-lacking AMPA receptors in LTP. EMBO Journal 26, 4879-4890.
Martin, S.J., Grimwood, P.D., & Morris, R.G. (2000). Synaptic plasticity and memory: an evaluation
of the hypothesis. Annual Review of Neuroscience 2, 649-711.
Marx, S.O., Reiken, S., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., & Marks, A. R.
(2000). PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine
receptor): defective regulation in failing hearts. Cell 101, 365-376.
McCartney, S., Little, B.M., Langeberg, L.K., & Scott, J.D. (1995). Cloning and characterization of
A-kinase anchor protein 100 (AKAP100). A protein that targets A-kinase to the sarcoplasmic
reticulum. Journal of Biological Chemistry 270, 9327-9333.
McPhee, I., Gibson, L.C., Kewney, J., Darroch, C., Stevens, P.A., Spinks, D., Cooreman, A., &
MacKenzie, S.J. (2005) Cyclic nucleotide signaling: a molecular approach to drug discovery for
Alzheimer's disease. Biochemical Society Transactions 33, 1330-1332.
Mei, F.C., Qiao, J., Tsygankova, O.M., Meinkoth, J.L., Quilliam, L.A., & Cheng, X. (2002).
Differential signaling of cyclic AMP: opposing effects of exchange protein directly activated by
cyclic AMP and cAMP-dependent protein kinase on protein kinase B activation. Journal of
Biological Chemistry 13, 11497-11504.
Micheau, J., & Riedel, G. (1999). Protein kinases: which one is the memory molecule? Cellular and
Molecular Life Sciences 4, 534-548.
Michel J., Townley, I.K., Dodge-Kafka, K.L., Zhang, F., Kapiloff, M.S., & Scott, J.D. (2005). Spatial
restriction of PDK1 activation cascades by anchoring to mAKAPα. Molecular Cell 20, 661-672.
Michel, J.J., & Scott, J.D. (2002). AKAP mediated signal transduction. Annual Review of
Pharmacology and Toxicology 42, 235-257.
Moita, M.A., Lamprecht, R., Nader, K., & LeDoux, J.E., (2002). A-kinase anchoring proteins in
amygdala are involved in auditory fear memory. Nature Neuroscience 5, 837-838.
Moosmang, S., Haider, N., Klugbauer, N., Adelsberger, H., Langwieser, N., Müller, J., Stiess, M.,
Marais, E., Schulla, V., Lacinova, L., Goebbels, S., Nave, K.A., Storm, D.R., Hofmann, F., &
166
http://www.ncbi.nlm.nih.gov/pubmed/10845078?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/10845078?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mei%20FC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Qiao%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Tsygankova%20OM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Meinkoth%20JL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Quilliam%20LA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Cheng%20X%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/pubmed/11807172?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
-
General discussion
Kleppisch, T.(2005). Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent
synaptic plasticity and spatial memory. Journal of Neuroscience 43, 9883-9892.
Nie, T., McDonough, C.B., Huang, T., Nguyen, P.V., & Abel, T. (2007). Genetic disruption of
protein kinase A anchoring reveals a role for compartmentalized kinase signaling in theta-burst long-
term potentiation and spatial memory. Journal of Neuroscience 27, 10278-10288.
Nijholt, I.M., Ostroveanu, A., de Bruyn, M., Luiten, P.G., Eisel, U.L., & Van der Zee E.A. (2007).
Both exposure to a novel context and associative learning induce an upregulation of AKAP150
protein in mouse hippocampus. Neurobiology of Learning and Memory, 87, 693-696.
Nijholt I., Ostroveanu A., Scheper W., Penke B., Luiten P., Van der Zee E., & Eisel U. (2008).
Inhibition of PKA anchoring to A-kinase anchoring proteins impairs consolidation and facilitates
extinction of contextual fear memories. Neurobiology of Learning and Memory 87, 693-696.
Nijholt I.M., Dolga A.M., Ostroveanu A., Luiten P.G., Schmidt M., & Eisel U.L. (2008). Neuronal
AKAP150 coordinates PKA and Epac mediated PKB/AKT phosphorylation. Cellular Signaling 10,
1715-1724.
Oestreich, E.A., Wang, H., Malik, S., Kaproth-Joslin, K.A., Blaxall, B.C., Kelley, G.G., Dirksen,
R.T., & Smrcka, A.V. (2007). Epac-mediated activation of phospholipase C(epsilon) plays a critical
role in beta-adrenergic receptor-dependent enhancement of Ca2+ mobilization in cardiac myocytes.
Journal of Biological Chemistry 8, 5488-5495.
Oh, M.C., Derkach, V.A., Guire, E.S., & Soderling, T.R. (2006). Extrasynaptic membrane trafficking
regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation.
Journal of Biological Chemistry 2, 752-758.
Ostroveanu, A., Van der Zee, E.A., Dolga, A.M., Luiten, P.G., Eisel, U.L. & Nijholt, I.M. (2007). A-
kinase anchoring protein 150 in the mouse brain is concentrated in areas involved in learning and
memory. Brain Research 1145, 97-107.
Ostroveanu, A., Van der Zee, E.A., Eisel, U.L. & Nijholt, I.M. (2009). Detailed analysis of mAKAP
expression in the brain of young and old mice. Submitted
Ostroveanu, A., Van der Zee, E.A., Eisel, U.L., Schmidt, M., & Nijholt, I.M. (2009). Exchange
protein activated by cyclic AMP 2 (Epac2) plays a specific and time-limited role in memory retrieval.
Submitted
167
-
Chapter 7
Ouyang, M., Zhang, L., Zhu, J.J., Schwede, F., & Thomas, S.A. (2008). Epac signaling is required for
hippocampus-dependent memory retrieval. Proceedings of the National Academy of Sciences United
States of America 105, 11993-11997.
Pare, G.C., Bauman, A.L., McHenry, M., Michel, J.J., Dodge-Kafka, K.L., & Kapiloff, M.S. (2005).
The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic
receptor signaling. Journal of Cell Science 118, 5637-5646.
Pereira, L., Métrich, M., Fernández-Velasco, M., Lucas, A., Leroy, J., Perrier, R., Morel, E.,
Fischmeister, R., Richard, S., Bénitah, J.P., Lezoualc'h, F., & Gómez, A.M. (2007). The cAMP
binding protein Epac modulates Ca2+ sparks by a Ca2+/calmodulin kinase signalling pathway in rat
cardiac myocytes. The Journal of Physiology 2, 685-694.
Pilcher, W.H., & Joseph, S.A. (1984). Co-localization of CRF-ir perikarya and ACTH-ir fibers in rat
brain. Brain Research 299, 91-102.
Rangarajan, S., Enserink, J.M., Kuiperij, H.B., de Rooij, J., Price, L.S., Schwede, F., & Bos, J.L.
(2003). Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon
stimulation of the beta 2-adrenergic receptor. The Journal of Cell Biology 4, 487-493.
Rosenmund, C., Carr, D.W., Bergeson, S.E., Nilaver, G., Scott, J.D., & Westbrook, G.L., (1994).
Anchoring of protein kinase A is required for modulation of AMPA/kainate receptors on hippocampal
neurons. Nature 368, 853-856.
Ruehr, M.L., Russell, M.A., Ferguson, D.G., Bhat, M., Ma, J., Damron, D.S., Scott, J.D., & Bond, M.
(2003). Targeting of protein kinase A by muscle A kinase-anchoring protein (mAKAP) regulates
phosphorylation and function of the skeletal muscle ryanodine receptor. Journal of Biological
Chemistry 278, 24831-24836.
Schwaerzel, M., Jaeckel, A., & Mueller, U. (2007). Signaling at A-kinase anchoring proteins
organizes anesthesia-sensitive memory in Drosophila. Journal of Neuroscience, 27, 1229-1233.
Shankar, G.M., Li, S., Mehta, T.H., Garcia-Munoz, A., Shepardson, N.E., Smith, I., Brett, F.M.,
Farrell, M.A., Rowan, M.J., Lemere, C.A., Regan, C.M., Walsh, D.M., Sabatini, B.L., & Selkoe, D.J.
(2008). Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic
plasticity and memory. Nature Medicine 8, 837-842.
168
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pereira%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fern%C3%A1ndez-Velasco%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lucas%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Leroy%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Morel%20E%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fischmeister%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Richard%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22B%C3%A9nitah%20JP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lezoualc'h%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22G%C3%B3mez%20AM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/pubmed/12578910?ordinalpos=28&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/12578910?ordinalpos=28&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Shankar%20GM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Li%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mehta%20TH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Garcia-Munoz%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Shepardson%20NE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Smith%20I%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Brett%20FM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Farrell%20MA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lemere%20CA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Regan%20CM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Walsh%20DM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sabatini%20BL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Selkoe%20DJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus
-
General discussion
Sik, A., Gulacsi, A., Lai, Y., Doyle, W.K., Pacia, S., Mody, I., & Freund, T.F., (2000). Localization
of the A kinase anchoring protein AKAP79 in the human hippocampus. European Journal of
Neuroscience 12, 1155-64.
Sinnegger-Brauns, M., Hetzenauer, A., Huber, I., Renström, E., Wietzorrek, G., Berjukov ,S., Cavalli,
M., Walter, D., Koschak, A., Waldschütz, R., Hering, S., Bova, S., Rorsman, P., Pongs, O.,
Singewald, N., & Striessnig, J. (2004). Isoform-specific regulation of mood behavior and pancreatic
βcell and cardiovascular function by L-type Ca 2+ channels. Journal of Clinical Investigation 10,
1430-1439.
Smith, K.E., Gibson, E.S., & Dell'Acqua, M.L. (2006). cAMP-dependent protein kinase postsynaptic
localization regulated by NMDA receptor activation through translocation of an A-kinase anchoring
protein scaffold protein. The Journal of Neuroscience 9, 2391-2402.
Snyder, E.M., Colledge, M., Crozier, R.A., Chen, W.S., Scott, J.D., & Bear, M.F. (2005). Role for A
kinase-anchoring proteins (AKAPS) in glutamate receptor trafficking and long term synaptic
depression. Journal of Biological Chemistry 280, 16962-16968.
Soderling, S.H., Langeberg, L.K., Soderling, J.A., Davee, S.M., Simerly, R., Raber, J., & Scott, J.D.
(2003). Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice.
Proceedings of the National Academy of Sciences United States of America 100, 1723-1728.
Ster, J., De Bock, F., Guérineau, N.C., Janossy, A., Barrère-Lemaire, S., Bos, J.L., Bockaert, J., &
Fagni, L.(2007). Exchange protein activated by cAMP (Epac) mediates cAMP activation of p38
MAPK and modulation of Ca2+-dependent K+ channels in cerebellar neurons. Proceedings of the
National Academy of Sciences United States of America 104, 2519-2524.
Ster, J., de Bock, F., Bertaso, F., Abitbol, K., Daniel, H., Bockaert, J., & Fagni, L. (2009). Epac
mediates PACAP-dependent LTD in the hippocampus. The Journal of Physiology 1, 101-113.
Tavalin, S.J., Colledge, M., Hell, J.W., Langeberg, L.K., Huganir, R.L., & Scott, J.D., (2002).
Regulation of GluR1 by the A-kinase anchoring protein 79 (AKAP79) signaling complex shares
properties with long-term depression. Journal of Neuroscience 22, 3044-3051
Tunquist, B.J., Hoshi, N., Guire, E.S., Zhang, F., Mullendorff, K., Langeberg, L.K., Raber, J., &
Scott, J.D. (2008). Loss of AKAP150 perturbs distinct neuronal processes in mice. Proceedings of the
National Academy of Sciences United States of America 34, 12557-1262.
169
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Smith%20KE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gibson%20ES%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/pubmed/18711127?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
-
Chapter 7
Wemmie, J.A., Chen, J., Askwith, C.C., Hruska-Hageman, A.M., Price, M.P., Nolan, B.C., Yoder,
P.G., Lamani, E., Hoshi, T., Freeman, J.H. Jr, & Welsh, M.J. (2002).The acid-activated ion channel
ASIC contributes to synaptic plasticity, learning, and memory. Neuron 3, 463-477.
Wemmie, J.A., Askwith, C.C., Lamani, E., Cassell, M.D., Freeman, J.H. Jr, & Welsh, M.J. (2003).
Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to
fear conditioning. Journal of Neuroscience 13, 5496-5502.
Wemmie, J.A., Coryell, M.W., Askwith, C.C., Lamani, E., Leonard, A.S., Sigmund, C.D., & Welsh,
M.J. (2004). Overexpression of acid-sensing ion channel 1a in transgenic mice increases acquired
fear-related behavior. Proceedings of the National Academy of Sciences United States of America 10,
3621-3626.
Yao, J.-J., Huang, Z.-H., Masten, S.J., Mizutani, T., Nakashima, S., & Nozawa, Y. (1998). Changes in
the expression of protein kinase C (PKC), phospholipases C (PLC) and D (PLD) isoforms in spleen,
brain and kidney of the aged rat: RT-PCR and Western blot analysis Mechanisms of Ageing and
Development 1, 151-172.
Zhong, N., & Zucker, R.S. (2005). cAMP acts on exchange protein activated by cAMP/cAMP-
regulated guanine nucleotide exchange protein to regulate transmitter release at the crayfish
neuromuscular junction. Journal of Neuroscience 25, 208-214.
170