Current Drug Targets - CNS & Neurological Disorders, 2005, 4, 541-552 541

Protein Kinase C Isozymes: Memory Therapeutic Potential

Miao-Kun Sun*,1 and Daniel L. Alkon1,2

1
Blanchette Rockefeller Neurosciences Institute, West Virginia University and 2Johns Hopkins University, Rockville, MD.
USA

Abstract: PKC plays an important role in many types of learning and memory. Evidence has been provided that PKC
activation and translocation are induced in associative learning tasks. PKC inhibition, on the other hand, impairs
learning and memory, consistent with the observations that transgenic animal models with a particular PKC isoform
deficit exhibit impaired capacity in cognition. The dramatic impact of PKC pharmacology on learning and memory is
further emphasized by a regulatory role of PKC isozymes in amyloid production and accumulation. Recent study reveals
that PKC activation greatly reduces neurotoxic amyloid production and accumulation. PKC activators, therefore, may
have important therapeutic values in the treatment of dementia, especially when fine-tuning of selective isoform
activity can be effectively achieved pharmacologically, with further development of isozymes-specific agents. The
success of antidementia therapy with agents that act on PKC signaling cascades depends on whether such agents at their
effective doses would significantly disrupt or interfere with other vital functions that rely on a narrow range of PKC
activities.

Protein kinase C (PKC), ubiquitous in the central nervous
system and activated by Ca2+, phospholipids and
diacylglycerol, or phorbol-ester [1], has been found to mediate
various extracellular signals into the cell and intracellular
signal events [2]. The PKC signaling pathway plays an
important and regulatory role in a wide range of vital
biological functions and processes [3-5], including
proliferation, altered gene expression, synaptic plasticity,
neuronal injury, differentiation, cell growth and apoptosis, and
oncogenesis, depending on cell identity and states.
The importance of a normal functional control through
PKC signaling cascades for brain health and functions is well
established. The brain has, in fact, the highest concentration of
PKC than any organ in the body [6], especially in vital neural
structures that are involved in cognition and mood regulation.
In the nervous system, activation of PKC leads to changes in
such vital responses as enhancing calcium action potentials,
increasing neurotransmitter release, and decreasing voltage-
+ +
gated Na currents [7-9] and voltage-dependent K currents [10,
11] as well as calcium-activated potassium current in
hippocampus, all relevant to information processing in
cognition. Particularly, PKC activation in the hippocampus
and related neural structures produces potentiation of synaptic
responses, mimicking those seen in long-term potentiation
(LTP) of the glutamatergic post-synaptic responses [12] and
enhanced summation of excitatory post-synaptic potentials
with rabbit eye blink conditioning [13]. The hippocampus in
mammals is involved in many types of cognitive performances
as well as mood regulation [14-17] and plays a critical role in
episodic, declarative, and spatial learning and memory [18]. It
is a highly plastic and vulnerable brain structure that may be
damaged in major depression and by a variety of injuries that
change PKC signaling cascades. Dysfunction of PKC is
*Address correspondence to the author at the Blanchette Rockefeller
Neurosciences Institute, 9601 Medical Center Drive, Academic and
Research Bldg., Room 319, Rockville, MD. USA; E-mail: mksun@brni-
jhu.org
associated with the development of Alzheimer’s disease (AD)
and other neurodegenerative disorders. Changes in synaptic
transmission and signal processing in this structure are bound
to have dramatic consequences on cognition and behavior.
Expression of a PKC inhibitor in Purkinje cells using the
promoter of the Purkinjie cell-specific gene pcp-2(L7) in mice
has also been reported to block cerebellar long-term depression
(LTD) and adaptation of the vestibulo-ocular reflex [19]. These
and other evidence (see below) point to an important role of
various isoforms of PKC in the formation of memory traces
and thus potential opportunities in the development of
cognition therapeutic agents that modify PKC activity and
signal cascade(s). On the other hand, PKC is sensitive to a
variety of neurotoxic/injurious events and may mediate some
pathological responses of the nervous system to injury. In this
short review article, we intend to summarize the roles of PKC
in learning and memory and neural injury, and to indicate
potential of developing cognition therapeutic agents that act on
the PKC system.
PROTEIN KINASE C ISOFORMS AND MOLECULAR
TARGETS
PKC activity, with the active site usually located at the C-
terminus to phosphorylate serine and threonine residues, is
mediated by a family of at least twelve PKC isoforms [20-22]
(Fig. 1). Each isoform of the twelve identified PKC isozymes
is encoded by a separate gene, with the exception of the
I and

II isoforms, which are splice variants.
The structural features of PKC include two main regulatory
2+
domains (the activator-binding C1 and the Ca -binding C2
domains) at the NH2-terminal that mediate membrane
association and activation, a C-terminal active site that
functions as a serine/threonine kinase, and a pseudosubstrate
sequence adjacent to the C1 domain (Fig. 1). The C2 domain
also contains binding sites for lipids and proteins. The
catalytic domain of PKC isozymes has the C3 and C4
domains. The former possesses the binding site for ATP, the
phosphate donor for phosphotransferase activity. The latter has

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542 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5
Fig. (1). Structures of the PKC isozymes. PS: pseudosubstrate.
the binding site for substrates. The C1 domains represent zinc
2+
finger structures that bind diacylglycerol and other non-Ca
PKC activators. For instance, the regulatory domains of novel
PKC (nPKC) contain two C1 sub-domains (C1A and C1B),
each of which interact with sn-1,2-diacylglycerol and phorbol
esters [23-25]. The C1A and C1B domains are, however, not
equivalent, with their relative affinities depending on the
isozymes. The C1A domain of PKC, for example, has high
affinity for diacylglycerol and is critical for the diacylglycerol-
induced membrane binding and PKC activation, while the
C1B domain exhibits high affinity for phorbol esters [26].
These differences indicate potential for developing isozyme-
selective PKC activators. The activator-binding sites within the
C1 domain of PKC are also able to bind alcohols and
anesthetics [27]. In the inactive conformation, a
pseudosubstrate sequence interacts with the substrate-binding
region, keeping the enzyme in the inactive state.
The twelve PKC isoforms can be further divided into three
subgroups, cPKC, nPKC, and aPKC, based on their molecular
structures and thus co-factor requirements. The cPKC, or
classical PKCs, contains the activator-binding C1 domain and
2+
the C2 region corresponding to the Ca binding site [28]. The
2+
cPKC requires Ca as a co-factor for activation and consists of

,  I, II, and  isoforms. The nPKC, including ,
,
’, , , an essential involvement of PKC in synaptic plasticity and
and
isoforms, on the other hand, is calcium-independent
2+
[28]. These isoforms do not have the Ca binding C2 region
[28-30] and do not require Ca2+ as a co-factor for activation.
They contain a C2-like structure, which may be involved in
interaction with proteins and phospholipids. A common feature
of these two subgroup PKCs is that they contain both C1A
and C1B sub-domains and can all be activated by
diacylglycerol, phorbol esters, and bryostatins. The third
group, aPKC, atypical PKC isozymes, includes  and /
isoforms. The aPKC contains a single C1 domain and does not
bind diacylglycerol, phorbol esters, or bryostatins. It does not
2+
contain the Ca binding C2 region and one of the repeated
cysteine-rich zinc finger binding motifs within the C1 domain
[31, 32]. It is not clear how aPKC activity is regulated in vivo.
Many of the isoforms are expressed in the same cells. The
biological significance of the heterogeneity of the PKC family
has not been really established. For instance, we do not know
Sun and Alkon
in most cases which particular PKC isozyme(s) may mediate
the observed effects. Obviously, signal cascades that are not
triggered by calcium waves are better relayed by the calcium-
independent pathways. aPKC appears to have higher structural
restriction for activators than the other subgroups, although the
biological meaning of such difference remains to be studied.
Nevertheless, evidence has been provided that atypical PKC
whose expression levels are correlated with nucleotide excision
repair activity and protein levels, probably regulates the
expression of nucleotide repair proteins [33]. Unfortunately, the
PKC pharmacology has been limited by the availability of
water soluble, specific inhibitors of PKC isozymes for an in
vivo administration. The pharmacological antagonism and
isozyme involvement therefore remain to be studied in detail
in the future.
PKC is activated by synaptic inputs and intracellular
signals that are involved in information processing in
cognition, including glutamatergic inputs [34], cholinergic
inputs [9], serotonergic inputs [7, 8], dopaminergic inputs
[35], intracellular calcium and diacylglycerol elevations, and
other hormones [36]. It is gradually recognized that structural
plasticity may also play an important role in signal processing
in cognition and involves PKC activity. Thus, in addition to
transmission, PKC activity signals growth. Growth and other
stimuli cause a transient increase in levels of cellular
diacylglycerol, which activates PKC as well as produces some
other effects that appear to be PKC-independent [37]. PKC
signaling triggered by local cell-cell contact appears to be a
mechanism through which astrocytes regulate neuronal
development. The mechanism involved can be briefly described
as that local contact with astrocytes via integrin receptors
elicits PKC activation and excitatory synaptogenesis in
neurons, through the arachidonic acid cascade [38]. The cascade
represents an underlying mechanism for global neuronal
maturation following local astrocyte adhesion, probably
including neurogenesis in adults such as that matured
hippocampal astrocytes regulate neurogenesis by instructing
stem cells to adopt a neuronal fate [39, 40]. It is not clear,
however, whether the integrin-PKC-cascade plays an essential
role in the formation of memory traces in the brain in adults.
Protein Kinase C Isozymes: Memory Therapeutic Potential Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 543
PKCs interact with a large diverse family of PKC-
interacting proteins [4, 41, 42], including the receptors for
activated C-kinase (RACKs). These phosphoproteins are the
PKC substrates, through which PKC regulates cellular
functions. One of the phosphoproteins that are heavily
phosphorylated by PKC is localized to the presynaptic
terminal. It was first identified by Gispen and his colleagues in
the Netherlands and was named as B50 by them for the brain
protein with an approximate molecular weight of 50 kDa (for
review, see [43]. It was then named as F1 [44] and GAP-43 for
a growth-associated protein with an approximate molecular
weight of 43 kDa [45]. GAP-43 is found exclusively in the
brain [43], is localized to the membranes of axonal processes,
and is not found in membranes of dendritic processes ([46-48],
except in the olfactory system [49]). Its expression is up-
regulated during spatial learning and memory [50]. Transgenic
mice overexpressing GAP-43 have been found to exhibit an
enhanced memory in a maze task [44], while heterozygous
GAP-43 knockout mice have impaired hippocampus-dependent
memory [51].
The separate localization of PKC and its membrane-
associated substrates, such as GAP-43, in the cells dictates an
essential step in the PKC activation and translocation. PKC
translocation to membrane component thus becomes a marker
indicating PKC activation and is commonly studied. Early
studies defined an important involvement of PKC activation in
associative learning [10]. Such activation is indeed associated
with a characterized PKC translocation from cytosol to
membrane component [52, 53], an essential step leading to
substrate activation. The PKC translocation from the
cytoplasm to the membrane component of the cells is
associated with phosphorylation of GAP-43 and with the
induction of LTP [54]. The phenomenon of PKC translocation
occurs presynaptically, as in the case of phosphorylation of
GAP-43 [54] and LTP [55], as well as postsynaptically, as in
the case of associative learning [52].
PROTEIN KINASE C AND CELLULAR SIGNALING
In memory formation, it is generally believed that the
frequency and intensity of calcium spikes/waves represent
important signal of the experienced events.
PKC can ‘detect’ the calcium spike frequency and intensity,
thus the pattern and frequency of synaptic inputs, in a unique
pattern and cycle of calcium-induced translocation and
diacylglycerol-mediated kinase activation [56]. For instance,
receptor stimuli that trigger repetitive calcium spikes induce
PKC in a way in which PKC responds to persistent
diacylglycerol increases combined with high- but not low-
frequency calcium spikes [57]. This is because calcium acts
rapidly. The calcium spike can translocate PKC and minimally
activate cPKC. Diacylglycerol binding to PKC is initially
prevented by a pseudosubstrate clamp, keeping the
diacylglycerol-binding site inaccessible and delaying calcium-
and diacylglycerol-mediated kinase activation. After
termination of calcium signals, bound diacylglycerol prolongs
kinase activity. Once diacylglycerol concentration is high, low-
frequency calcium spikes lead to a small and oscillating cPKC
activity with an activity that is reversed after each spike.
Diacylglycerol alone is not sufficient to retain PKC at the
plasma membrane. A drop in calcium concentration will result
in the dissociation of the kinase. Such dissociation, however,
is effectively prevented in the presence of high-frequency
calcium spikes and persistent calcium increases. Only high-
frequency calcium spikes and persistent calcium increases can
lead to an integration of cPKC activity, inducing a much
higher amplitude of and lasting kinase activity.
While cPKC is not activated when calcium spikes are
absent, other PKC isoforms are well positioned to respond to
signal events without associated calcium spikes. Protein kinase
C regulates the nuclear localization of diacylglycerol kinase-
[58], which terminates signaling from diacylglycerol by
converting it to phosphatidic acid. The nuclear-localization
signal of diacylglycerol kinase- is localized in a region that is
homologous to the phosphorylation-site domain of the
MARCKS protein, a major target for PKC. Reducing nuclear
diacylglycerol levels by diacylglycerol kinase- attenuates cell
growth.
PROTEIN KINASE C AND MEMBRANE
RECEPTOR/CHANNEL ACTIVITY
Receptor/channel states and activity have dramatic
consequence on signal transfer through the neural network and
synaptic plasticity that underlie learning and memory. These
include the potassium channels, glutamatergic cationic
channels, voltage-gated Na+ channels, and -aminobutyric acid
(GABA)A receptor channels, all sensitive to changes in PKC
activity. The calcium- and phospholipid-dependent PKCs
control membrane electrical properties [59, 60] and modulate
neurotransmitter receptor function [61-63]. For instance,
activation of PKC by phorbol esters and synthetic
diacylglyceroles has been shown to attenuate voltage-gated
potassium currents in a number of cell types, including the
CA1 pyramidal cells, the “place” cells, in the hippocampus
[10, 11, 19, 64-67]. PKC phosphorylates the voltage-gated
+
Na channels in hippocampal neurons and is responsible for
+
PKC-mediated reduction of Na currents in the neurons [9]. A
reduction in the voltage-gated Na+ currents is expected to
increase spike threshold and reduce spike train duration, as
shown in prefrontal cortex neurons [7, 8]. Reduction in
potassium channel conductance, on the other hand, represents
an important change that is associated with potentiated
synaptic transmission and many types of learning and memory.
PKC modulates the glutamate system, including the
ionotropic receptors and metabotropic receptors. PKC
activation, for example, with 12- O-tetradecanoylphorbol
modifies both
-amino-3-hydroxy-5-methyl-4-
isoxazoleproprionate receptor (AMPAR) and N-methyl-D-
aspartate receptors (NMDAR) mobility, increasing their
extrasynaptic and synaptic diffusion [68]. In addition, PKC
activation has been found to result in phosphorylation of
glutamate receptor (GluR) 2/3 (at serine 880) in the Purkinje
cells. PKC activation in the hippocampal CA1 pyramidal cells
has also been reported to produce an inhibition of the slow
after-hyperpolarization, thus, resulting in an enhanced
excitability. Evidence has also been provided that metabotropic
GluR (mGluR)6-containing kainate receptors are probably the
trigger for PKC-mediated inhibition of slow after-
hyperpolarization in the hippocampal CA1 pyramidal neurons
[69]. Glutamate also desensitizes mGluR5a and mGluR5b,
544 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5
through PKC-mediated phosphorylation of mGluR5 at
multiple sites [70].
In the brain at large and in the hippocampus particularly,
the GABA system plays an important role in controlling
neuronal activity and information transfer through the neural
network related to cognition. PKC also appears to mediate
brain-derived neurotrophic factor (BDNF)-induced modulation
of GABAA receptor phosphorylation and activity [71]. The
impact of BDNF-PKC-GABA transmission cascade in the
hippocampus and related brain structures on cognition and
mood remains to be evaluated in the future.
PROTEIN KINASE C AND NEUROTRANSMISSION
It is well-established that synaptic transmission through
neurotransmitter release is fundamental to signal processing
between neurons and through neural networks. PKC appears to
play an important role in the regulation of synaptic
transmission in the nervous system.
First, the synthesis of many neurotransmitters is under
PKC regulation. For instance, cholinergic neurons play an
important role in learning and memory and their damaged
function in fact characterizes the early brain injury and memory
deficits in AD patients. Choline acetyltransferase synthesizes
acetylcholine in the cholinergic neurons. The enzyme is
differentially phosphorylated by PKC isoforms on four serines
(Ser-440, -346, -347, -476) and one threonine (Thr-255),
regulating its catalytic activity [72]. PKC activity plays an
important regulatory role in GABAergic synaptic transmission
[73]. In the glutamate system, phorbol esters have been shown
to increase the size of the readily releasable pool and the rate at
which the pool refills at glutamatergic hippocampal synapses.
This effect is produced by a PKC-dependent mechanism [74].
The PKC pathway may therefore regulate synaptic strength by
modulating the readily releasable pool of the glutamatergic
vesicles. The calcium- and phospholipid-dependent PKCs also
regulate neurotransmitter release [74-76] and regulate gene
expression in mature neurons [77]. However, others report that
phorbol ester- and diacylglycerol-induced augmentation of
transmitter release is mediated by Munc13s, a presynaptic
protein that contains diacylglycerol/phorbol ester binding C1
domain, but not by PKCs [78].
PROTEIN KINASE C AND SYNAPTIC PLASTICITY
It is generally believed that learned experience depends on
the expression of modified synaptic transmission in the
relevant synapses. The involvement of PKC isozymes in
synaptic plasticity and learning and memory has been the focus
of many investigations. Activation of PKC leads to the
phosphorylation of numerous proteins, including glutamate
receptor 2/3 (at serine 880) in Purkinje cells. The glutamate
receptor 2/3 phosphorylation appears to be the critical step for
parallel fiber LTD [79]. In the neural networks, PKC activation
generally facilitates synaptic plasticity, including such
responses as an enhancement of calcium influx, an increase in
neurotransmitter release, a decrease in a calcium-activated
current in the hippocampus, actions that produce a potentiation
of synaptic responses [10-13, 56, 80, 81]. These functional
changes are likely associated with morphological changes that
are also induced by PKC activation. In cultured hippocampal
Sun and Alkon
neurons, for example, activation of PKC induces rapid
morphological plasticity in dendrites and spines [82].
The involvement of PKC activity in synaptic plasticity has
been investigated intensively. Early studies have revealed that
by using inhibitors for both kinases (PKC and CaMKII), LTP
of the glutamatergic synapses is sustained by persistent protein
kinase activity but is not due to a substrate that remains stably
phosphorylated [83]. LTP is not due to a long-lived kinase
activator, since the persistently active kinase exists in the
absence of an activator. However, the same study suggests that
the process of autophosphorylation, while potentially
contributing to the persistent kinase activity, does not
completely account for the sustained kinase activation. When
more selective antagonists became available, the antagonists to
either PKC or CaMKII were postsynaptically injected into
hippocampal pyramidal cells, resulting in a blockade of
induction of LTP of the glutamatergic synapses [84, 85]. Thus,
both PKC and calcium-calmodulin-dependent protein kinase II
are involved in the induction of LTP. These investigators also
found that once LTP was established, intracellular injection of
the non-selective kinase inhibitor H-7 had no effect.
Antagonists that block the autophosphorylation of CaMKII
were also shown to block the induction of LTP (for review, see
[86]. These are exclusively postsynaptic. However, Malinow et
al. [83] showed that potentially there is presynaptic
involvement. When H-7 was applied extracellularly instead of
injecting it intracellularly, LTP remains sensitive to
extracellular kinase inhibition. Thus, while intracellular
postsynaptic events are insensitive to kinase inhibition, once
LTP is established, events occurring outside of the intracellular
postsynaptic realm remain sensitive to kinase inhibition.
Location exposed to extracellularly applied H-7 includes the
presynaptic terminal as well as pre- and postsynaptic events
occurring within the domain of the synaptic cleft. Of course,
the contribution and maintenance of LTP differ depending on
the fiber tract and cell group that is being examined [87].
However, the PKC effects on LTP of the glutamatergic
synapses may not necessarily mean corresponding effects on
cognition. Dissociation of memory performance from LTP has
been observed and reported frequently. For instance, mice
deficit in PKC
have been found to show normal brain
anatomy and normal hippocampal synaptic transmission,
normal paired facilitation, and normal LTP of the
glutamatergic synaptic responses, but a loss of learning and
memory in both cued and contextual fear conditioning [88].
The involvement of PKC activity in LTD of glutamatergic
synapses has also been suggested. LTD in the hippocampal
CA1 field is associated with a transient decrease in pre- and/or
postsynaptic PKC substrate phosphorylation [89, 90]. But, the
exact impact of such an involvement on learning and memory
remains to be studied.
Not only does synaptic facilitation and synaptogenesis
involve PKC activation, synaptic activity-induced synapse
elimination may also involve PKC. One possibility is that
different isoforms may be involved. PKC in both presynaptic
and postsynaptic elements has been proposed to play an
important role in activity-dependentsynaptic elimination at the
neuromuscular synapse [91]. PKC-deficient neurons that
innervate normal muscle exhibited a marked deficit in activity-
related synapse reduction.
Protein Kinase C Isozymes: Memory Therapeutic Potential Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 545
PROTEIN KINASE C AND MEMORY
The central question in memory pharmaceutics based on
PKC activity modulation is the importance of PKC activity in
learning and memory, and in memory disorders. The evidence
available indicates an essential role of PKC in learning and
memory. PKCs have been implicated in many types of
cognitive tasks, including learning and memory of eye blink
conditioning [80, 81, 92-94], spatial learning and memory [52,
95-99], olfactory discrimination learning [100], conditioned
taste aversion [101], contextual fear memory [102, 103], and
conditioned avoidance [104].
The involvement of PKC in brain functions and disorders,
including cognition, mood regulation, and neurodegeneration,
is implicated by several factors. Brain, especially the
hippocampus and related structures that play critical roles in
cognition, express the highest levels of PKC in the body. In
addition, neural events and activated inputs that occur in
learning and memory activate PKC. Associative learning
produces translocation of PKC activity from the cytosolic to
the membrane compartment of the CA1 region of the
hippocampus [52]. Glutamate activates PKC in the
hippocampus [34]. PKC may also mediate, at least partly,
arginine vasopressin-induced facilitation of memory retention
in a step-through passive avoidance task in mice [36].
PKC is activated in many cognitive tasks with enhanced
phosphorylation of its substrate proteins. GAP-43, for
example, has been found to be phosphorylated in association
with LTP (for review, see [43]) and the phosphorylation of this
presynaptic protein lasts for several days. Bryostatin-1, a PKC
activator, enhances spatial memory in rats [105]. Furthermore,
reduced PKC activity is associated with AD dementia [106,
107] and suicide victims [108], suggesting an involvement in
cognition and mood regulation. Age-related spatial memory
impairment is associated with altered subcellular concentrations
of PKC and may be indicative of deficient signal transduction
and neuronal plasticity in the hippocampal formation. The
connection between PKC and memory and dementia is
illustrated by a decreased PKC and  levels and activities in
the temporal cortex [109, 110] without changes in PKC
mRNA [111] and in crude extracts from the hippocampus,
temporal and frontal cortex [112]. Activity of PKC enzyme
extract purified from endogenous modulators is not modified
in all brain areas of AD patients [113]. These observations
suggest either changed isoform degradation or increased
endogenous inhibitors of PKC activity in AD brain. Another
important change is RACKs, the substrate for activated PKCs.
RACKs are important regulators of PKC function [114].
Deficit in RACK1 levels has been reported in both soluble and
particulate fractions from AD brain frontal cortex [115].
PKC inhibition has been consistently found to significantly
impair performance of cognitive tasks. Intracerebroventricular
injection of PKC inhibitors, for example, has been found to
cause marked memory impairment in passive avoidance task
and water maze task [116]. Relationships between spatial
learning (water maze) in rats and hippocampal concentrations
of calcium-dependent PKC are isoform-specific and mainly of
PKC isoform [98]. Studies with transgenic animals further
support the critical role of PKC in learning and memory.
PKC, for instance, was found to predominantlyexpress in the
neocortex, in area CA1 of the hippocampus, and in the
basolateral nucleus of the amygdala in mice [88]. Mice
deficient in PKC have been found to exhibit a loss of learning
in both cued and contextual fear conditioning [88] although
their brain anatomy, hippocampal synaptic transmission,
responses to paired facilitation, and LTP of the hippocampal
glutamatergic synapses all appear normal.
One important anti dementia action of PKC activation
could be to facilitate PKC translocation and has been observed
to occur in a variety of associative memory tasks [105]. A
second potentially important action of PKC in anti-dementia
is its role in regulation and modulation of amyloid production.
Activation of PKC
and  is known to enhance sAPP

production [117, 118] and to reduce A production [119].
Evidence has been provided that the administration of
bryostatin-1 reduced A40 in the brains of AD transgenic mice
and both brain A40 and A42 in AD double-transgenic mice
[120]. The action has an obvious therapeutic value for
bryostatin-1 to be an anti-dementic agent, as long as neurotoxic
amyloid defines much of the pathogenesis of AD. Some of this
apparent therapeutic benefit of bryostatin-1 may be produced
through its persistent activation of PKC in the absence of
down-regulation of the isoform [121].
Furthermore, some of the AD neuropathology and
functional impairment in cognition may be mediated by an A-
induced PKC inhibition. As mentioned above, all of the PKC
isozymes, except PKC
(human) and its murine homolog,
PKD, contain a pseudosubstrate motif in the regulatory region.
The motif is an autoinhibitory domain of PKCs, maintaining
their inactive state. It turns out that As contain a putative
PKC pseudosubstrate domain (A 28-30). A is found in the
cerebrospinal fluid and blood of normal human subjects.
Evidence has been presented that A (1
M) directly inhibits
PKC
and  activation by phorbol-12,13-dibutyrate [122]. The
action may play a physiological role and/or a
pathophysiological one. Through its binding to PKC, A can
induce PKC degradation [107], reduce PKC-mediated
phosphorylation [123, 124], and decrease PKC membrane
translocation [125]. In cultured brain endothelial cells, A1-40
induced translocation of PKC from membrane fraction to
cytosol [125]. The interaction between PKC and A suggests
that restoration of the inhibited PKC activity may have direct
therapeutic effects to cognition. Furthermore, recent evidence
indicates that PKC activation inhibits glycogen synthase 3
kinase [126, 127] and thereby reduces tau phosphorylation
[128]. This last event is considered important for the
production of another pathological hallmark of AD:
neurofibrillary tangles.
PKC ACTIVATORS
The main focus of agents that act on PKC isoforms and
cascades as potential memory therapeutics is PKC activators,
since PKC activators facilitate synaptic plasticity, enhance
learning and memory, reduce neurotoxic amyloid production
and accumulation, and inhibit tau phosphorylation.
PKC activators, such as diacylglycerol, arachidonic acid
(Fig. 2), phorbol esters, bryostatins, aplysiatoxins, and
teleocidins, bind to a hydrophilic cleft in a largely hydrophobic
surface of the C1 domains, resulting in an enhanced
hydrophobicity of the surface and promoting the interaction
between the C1 domain and the phospholipid bilayer of the
546 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 Sun and Alkon

O
H
R O COOH
O R

O
OH
Arachidonic acid
(S)-1,2-Diacyl-sn-glycerol
O O
O O
O O
O O

H
H H
H H
H
OH
OH
OH
OH OH
OH O
O
Phorbol 12,13-dibutyrate Phorbol 12-myristate 13-acetate

OH
O OAc
B A
O O O

3 O
OH H OH
O O
C
26
O OH
O
O
O

Bryostatin-1

Fig. (2). Chemical structures of some PKC activators. R and R’ are either saturated or unsaturated hydrocarbon chains.

cell membranes and driving removal of the pseudosubstrate
region from the catalytic site of the enzyme.
Diacylglycerol is an endogenous PKC activator, which
binds to the C1 domain of cPKC and nPKC, with binding
3 regulation of PKC
in several cancer cell lines [136, 137] and
affinity at
M levels (for displacing bound [20- H]phorbol
12,13-dibutyrate from; [129]. The hydrocarbon chains are to
facilitate partitioning into the lipid-rich membrane
environment.
Phorbol esters, such as phorbol 12.13-dibutyrate and
phorbol 12-myristate 13-acetate (Fig. 2), also bind to the C1
domain of cPKC and nPKC, with binding affinities over 2
orders of magnitude greater than those of diacylglycerol. Their
higher potencies are derived from a conformationally rigid
orientation of hydrophilic pharmacophores. There are reports,
however, that some observed effects that are produced with
phorbol esters and viewed as PKC-mediated may be mediated
by other signaling molecules, and not by PKCs [78].
Bryostatin-1 [130, 131], a macrocyclic lactone (Fig. 2), is
an antineoplastic agent that potently activates PKC with
chemical structure unrelated to phorbol esters. It is isolated
from the marine Bugula neritina [131]. Bryostatin-1, acting as
a partial agonist, can selectively modulate PKC isozymes, such
as PKC
, PKC and PKC [132-135], at very low
concentrations (at nM or sub-nM concentrations), but prevents
tumor cell growth, probably through a selective down-
preventing certain PKC from undergoing down-regulation
[138]. These profiles make it an especially attractive lead for
the design of new PKC probes. The binding of bryostatin-1 to
PKC results in PKC activation, autophosphorylation, and
translocation to the cell membrane. Bryostatin-1-bound PKC
is then down-regulated by ubiquitination and degradation in
proteasomes. Short exposures to bryostatin-1 activate PKC,
while prolonged exposures are followed by down-regulation of
PKC. Down-regulation is most significant when PKC is
exposed to high and/or prolonged high concentrations of
bryostatin-1 [132, 133, 139, 140]. Studies of structure-activity
relations of brayostatin-1 for PKC isoforms [141, 142] indicate
that the intact 20-membered macrolactone ring is needed for
good PKC binding activity, while the A-ring and the B-ring
exocyclic olefin can be deleted from the 20-membered structure
without inducing much change in PKC-binding affinity. The
C(26) free hydroxyl is essential for a good interaction with
Protein Kinase C Isozymes: Memory Therapeutic Potential Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 547
PKC isozymes, while C(3)-hydroxyl with (R)-stereochemistry
is important for a high affinity.
OTHER CONCERNS
An involvement of PKC activity in the synaptic plasticity
and cognition indicates a possibility that agents acting on the
PKC signal cascade(s) may have therapeutic values in
cognition and dementia. As briefly mentioned above, PKC
regulates and modulates a variety of other biological functions,
raising valid concerns of specificities and other side and
adverse effects that may be produced by agents that change
PKC activity and signal cascade(s). In addition to an
involvement of PKCs in the development of morphine
tolerance [143], the main concerns for the development of PKC
agents in the treatment of dementia and cognition enhancers are
their potential adverse effects.
1. Cardiovascular System
One major concern is the impact of modulation of PKC
activity on cardiovascular functions. PKC is involved in
regulating cardiovascular functions [144, 145]. The effects of
PKC activity on the health of cardiovascular system are
complicated by the fact that PKC activity may be both
essential and damaging to a normal cardiovascular function,
emphasizing the importance of defining isoform specificity in
functional involvements and controlling the levels of PKC
isoform-specific activation.
PKC activators are known to stimulate cardiomyocyte
hypertrophy [146], with an elevated risk for the development
of heart failure. The particular isoforms involved include
PKC
[147], PKC [148], PKC, and PKC [149].
Activation of PKC and mitochondrial translocation occur at
the onset of heart reperfusion after cardiac ischemia and
mediates apoptosis by facilitating the accumulation and
dephosphorylation of the pro-apoptotic BAD (Bcl-2 associated
death promoter), dephosphorylation of Akt, cytochrome c
release, PARP cleavage, and DNA laddering [150]. Evidence
has also been provided that inhibition of PKC is able to
provide the protection of the heart from ischemia and
reperfusion-induced damage [151, 152]. In addition, enhanced
activation of PKC is correlated with the vascular complications
of diabetes mellitus. LY333531, a specific PKC inhibitor,
has been shown to antagonize retinal, cardiac and renal vascular
dysfunction in diabetic rats [153] and patients [154]. These
cardiac responses to PKC activation represent adverse effects
that have to be addressed in cognition therapy especially when
the same PKC isoforms are the pharmacological targets in the
cognition therapies.
However, PKC and  isoforms are not only involved in
heart failure and myocardial hypertrophy and ischemic injury
to the cardiomyocytes, but also in ischemic preconditioning.
PKC may represent one of the pathways converged to inhibit
glycogen synthase kinase-3 and the mitochondrial
permeability transition pore [155]. PKC is also involved in
maintaining normal cardiomyocyte cytoskeletal integrity.
Cardiac ischemia in mice triggers PKC translocation, which
was inhibited by transgenic expression of PKC-specific
translocation inhibitor protein fragment (V1) [156]. Thus,
levels of V1 expression confer striking resistance to
postischemic dysfunction without inducing structural and
genetic changes. At high levels, however, V1 expression
depresses cardiac contractile function and disrupts cytoskeletal
structures to form aggregates, in addition to increased
expression of fetal cardiac genes [156]. PKC and  isoforms
may also mediate isoflurane-induced improvement of
functional and metabolic recovery in isolated ischemic rat
hearts [157]. Some of the cardiac effects may involve PKC-
mediated desensitization of 1- and 2-adrenergic receptors
[158]. In cases of PKC involvement in ischemic
preconditioning, a small degree of PKC activation would be
expected to provide a period of protection of the ischemia-
sensitive neurons from stroke/ischemic injury.
2. Sensation of Thermal and Inflammatory Pain
PKC is involved in mediating the sensation of thermal and
inflammatory pain, including bradykinin- and anandamide-
induced nociception [159]. In the nociceptive dorsal root
ganglion neurons, PKC enhances the activity of the slowly
+
inactivating Na channels [160]. There is therefore a possibility
that PKC activators may facilitate thermal and inflammatory
nociception, especially in those sensitive patients.
3. Hypoxic and Ischemic Injury
The second major concern in developing agents acting on
PKC cascade(s) as cognition therapeutics is potential impact of
such agents on neural responses to stroke and ischemic injury.
Hypoxia/ischemia triggers glutamate release and accumulation
in the extracellular space and activates several PKC isoforms in
neurons. It is well-established that hypoxia/ischemia produces
2+
NMDA-, Ca -, and PKC-dependent LTP [161] and increases
calcium influx through ionotropic glutamate receptors of the
cortical neurons, via PKC-mediated phosphorylationof NMDA
receptors [162]. In cultured rat hippocampal neurons,
application of 0.5 mM glutamate for 5 min (neurotoxicity)
increases PKC phosphotransferase activity by 3.7-fold and
protein levels by 5.5-fold in the membrane fraction, without
changing PKC activity in the cytosol [34]. Such PKC
activation would be expected to mediate or enhance neuronal
stroke/ischemic injury, rather than to provide preconditioning-
like neural protection.
Hypoxia/ischemia is known to induce changes in gene
expression, some of which are actually mediated by PKC.
Regulation of EPO mRNA by cellular O2 tension is known to
represent a homeostatic mechanism for maintaining tissue
oxygenation [163]. In RIF (radiation-induced fibrosarcoma)
tumor cells, PKC
, , and  isoforms are expressed, but only
PKC is specifically translocated to the membrane and
involved in the transcriptional activation of heat shock
transcription factor (HSF) and hypoxia-inducible factor- (HIF
[164]) 1 by hypoxia [165]. A bioflavonoid quercetin (QCT;
100
M), a well-known inhibitor of hsp gene expression, was
found to significantly inhibit the transcriptional activation of
HSF and HIF-1, by abrogating completely the PKC
translocation [165]. QCT, however, is known to inhibit several
protein kinases, including tyrosine kinase, casein kinase II, and
phosphorylase kinase. EPO rRNA accumulation was also
observed as early as 1 h after hypoxia and lasted for 8 h, and
the accumulation was blocked by QCT [165]. In addition,
inhibiting PKC activation, either pharmacologically with
phorbol 12-myristate 13-acetate (400 nM) or with
548 Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5
bisindolymaleimide II (50 nM) or genetically by transient
transfection of a dominant negative PKC, significantly
inhibited the transcriptional activation of HSF and HIF-1 by
hypoxia [165]. The membrane translocation of PKC depends
on the activation of phosphoinositol 3-kinase (PI3K).
Treatment with PI3K inhibitor, wortmannin (50 nM) or
LY294002 (5
M), abrogated not only PKC translocation but
also the subsequent transcriptional activation of HSF and HIF-
1 by hypoxia [165].
PI3K activation generates D3-phosphorylated
phosphoinositide (D3PPI), which has been shown to act on the
phosphoinositides-dependent kinase-1 (PDK-1) [166, 167] and
atypical PKCs [167]. In other systems, Akt was suggested to
be a likely target of the D3PPI rather than PDK-1 [168, 169].
Hippocampal CA1 pyramidal cells and network are
particularly sensitive to hypoxic/ischemic damage [170-174].
In the hippocampus, anoxic LTP, a pathophysiological
response to acute hypoxia and ischemia in CA1 pyramidal cells
was reported to be blocked, not by the specific cAMP-
dependent protein kinase (PKA) inhibitor Rp-cyclic adenosine
3’,5’-monophospnate (25
M), but by PKC inhibitors NPC-
15437 (
M), H-7 (20
M), or intracellular application of PKC
inhibitor (PKCI) 19-36 (50
M) into the recorded neurons
[175], indicating that induction of anoxic LTP requires
activation of postsynaptic PKC. The involvement of
2+
intracellular release of Ca is indicated by the effectiveness of
2+
intracellular Ca chelator BAPTA into the postsynaptic CA1
neurons in preventing the anoxic LTP [175].
PKCs are indicated in mediating ischemic and reperfusion
damage. A selective PKC peptide inhibitor, for example, has
been found to reduce cellular injury in a rat hippocampal slice
model of cerebral ischemia, when present both during the
ischemic episode and for the first 3 hours of reperfusion. The
inhibitor decreased infarct size in vivo in rats with transient
middle cerebral artery occlusion when administered at the
onset, at 1 hr, or at 6 hr of reperfusion [176]. Global ischemia
increases PKC mRNA and protein levels in the cortex and
hippocampus and these levels are also increased in the
compromised peri-infarct region after local cerebral ischemia
[177, 178]. The increased PKC expression in the penumbral
area may be responsible for the delayed neuronal damage [179].
4. Stress
Stress, on the other hand, is also known to induce high
levels of PKC activity in the prefrontal cortex. The enhanced
PKC over-activity can disrupt prefrontal cortical regulation of
behavior and thought, and impair working memory [180].
PKC mediates modulation of the serotonergic regulation of
GABA transmission by the stress-related neuropeptide
corticotropin-releasing factor [181]. PKC activators may
potentiate stress-mediated psychiatric disorders. Such an
interaction between corticotropin-releasingfactor and 5-HT may
play an important role in psychiatric disorders.
5. Oxidants
Part of the signal factors in neurodegenerativedisorders and
aging is oxidants. All the PKC isoforms are sensitive to
oxidants [182, 183]. Hydrogen peroxide, for instance, can
Sun and Alkon
tyrosine-phosphorylate PKCs with a modification in catalytic
activity, including an activation of PKC [184]. PKC is also
sensitive to oxidative stress, with its activation leading to
neuronal death [185]. The effects of oxidants on PKC can be
attenuated or eliminated by lipid-soluble antioxidants, such as
vitamin E, which also exhibits a PKC-dependent and
antioxidant-independent inhibition of platelet aggregation
[186]. In rabbit hippocampus, immunocytochemical analysis
reveals a significant aging-related increase in PKC1, 2, and
 immunoreactivity in the cell bodies and dendrites of the
principal cells and interneurons in the hilar region and a
decreased number of PKC
and -positive interneurons in the
stratum oriens [187], although it has not been evaluated
whether such increase is related to aging-related oxidant
accumulation. The enhanced PKC immunoreactivity may be
related to reduced protein-protein interactions of PKC with its
anchoring protein RACK1.
6. Amyloid and Dementia
Although the majority of studies report that PKC activation
results in an increased sAPP
production [117, 118] and a
decreased neurotoxic A production [119, 120], there is a
concern that PKC may mediate some A neurotoxicity. In
primary neuronal cultures, treatment with A1-40 for 48 h
2+
caused a significant increase in the content and activity of Ca -
dependent (
, II) and -independent (, ) PKC isoforms,
followed by down-regulation of 72 h, probably resulting from
over-activation [188]. The A1-40-induced biphasic PKC
activation and down-regulation was exacerbated by hypoxia
[188], indicating increased vulnerability in AD patients with
vascular complications.
Some of the pathophysiological actions of PKCs appear to
be involved in dementia. Riluzole, the only drug used to
control amyotrophic lateral sclerosis, directly inhibits PKC
[189], in addition to an antiglutamatergic action. PKC may
2+
also mediate Pb -induced inhibition of nicotinic cholinergic
modulation of synaptic transmission in the hippocampus
[190]. A recent study reveals that GAP-43 is consistently
elevated in a subfield of the hippocampus in AD brain,
associated with elevated growth protein and neural sprouting,
and that increased expression GAP-43 may lead to a mis-
wiring of circuits critical for memory function [191].
7. Neuronal Survival
PKC is both pro-growth and apoptotic. Different PKC
isoforms may exhibit differential effects on growth and
apoptosis, depending on cell types and states. Some PKC
activators may act as tumor promoters and others, as anti-
tumor agents. nPKCs are involved in tumor promotion [192-
194]. Only careful evaluation will reveal whether they possess
tumor-promoting capabilities, since we have very little
knowledge of isoform involvement and underlying
mechanisms. PKC, for instance, has been found to activate
caspases and be a proapoptotic intermediate in several types of
cells [195-200], including neurons [201, 2002]. Experimental
brain injury is associated with PKC activation, such as the

and  isoforms, in regions undergoing neuronal degeneration
[203].
Protein Kinase C Isozymes: Memory Therapeutic Potential Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 5 549

CONCLUDING REMARKS mediated by PKC-independent pathways [32]. All these can

only be answered by further intensive studies. It appears that
There is no doubt that PKCs play an important role in the ligand-binding sites of the PKC isozymes possess some
learning and memory and that agents acting on the PKC signal different profiles so that highly potent isozyme-selective PKC
cascade(s) have promising therapeutic values in anti-dementia activators may be developed in the near future [215, 216] and
therapy. Activation of PKC represents a potential therapeutic that PKC activators have powerful anti-dementia/memory-
strategy in improving memory and mood. PKC may be enhancing and antidepressive activities in animal models (105,
involved in regulation of 5-HT receptor activity [204]. The 217-219). With a full understanding of the intracellular targets
phorbol esters have been reported to be potent PKC of individual PKC isozymes in different cell types (220), the
stimulators. However, their potential as therapeutic drugs is use of pharmacological or molecular therapeutic approaches
limited by their action as tumor promoters [205]. Bryostatin-1 based on modulation of PKC activity/cascades might be
is distinct from the phorbol esters in several properties. For justified clinically in the future.
instance, unlike the phorbol esters, it lacks tumor-promoting
capabilities and actually counteracts tumor promotion induced
by phorbol esters [206]. In clinical trials as an anti-tumor LIST OF ABBREVIATIONS
agent, bryostatin-1 is reasonably well-tolerated, having a
-2 -1
maximum tolerated dose of 25
g m week [207]. Its main A = Amyloid- peptide
dose-limiting toxicity is myalgia. AD = Alzheimer’s disease
Several issues, however, need to be addressed before AMPA =
-Amino-3-hydroxy-5-methyl-isoxazole-propio-
bryostatin-1 and its analogues might be developed as nic acid
therapeutic drugs. PKC is involved in a variety of functions
and neurological disorders. It remains to be demonstrated AMPAR = AMPA receptor
whether a relatively non-selective activator of this pathway aPKC = Atypical PKC
would be clinically useful in the treatment of the psychiatric
illness. Defining the underlying isozyme(s) and developing BDNF = Brain-derived neurotropic factor
isozyme-specific agents are thus essential. For instance, the cPKC = Classical PKC
PKC and PKC are implicated in heart failure and myocardial
hypertrophy. Inhibition of PKC and activation of PKC D3PPI = D3-phosphorylated phsophoinositide
appear to protect against myocardial ischemia, but a low level GABA = -Aminobutyric acid
of PKC activation is essential to maintain normal
GAP = Growth-associated protein
cardiomyocyte cytoskeletal integrity [156]. PKC isozyme
activation plays an important pathological role in anoxic LTP GluR = Glutamate receptor
of the glutamatergic synaptic responses in the CA1 pyramidal HIF = Hypoxia-inducible factor
cells of the hippocampus [208], glutamate excitotoxicity in
cultured rat hippocampal neurons [34], tau phosphorylation HSF = Heat shock transcription factor
[209], caspases-mediated apoptosis [210], and amyloid LTD = Long-term depression
neurotoxicity [188]. On the other hand, bryostatin-1 activates

-secretase and thus reduces the production and accumulation LTP = Long-term potentiation
of neurotoxic amyloid [119, 120]. PKC is also capable of mGluR = Metabotropic glutamate receptor
activating the extracellular signal-regulated kinase signaling
pathway through Ras-dependent and –independent cascades, NMDA = N-methyl-D-aspartate
regulating cell proliferation and enhancing cell survival [32], NMDAR = NMDA receptor
opposite to its pro-apoptotic action. Potential toxic side effects
of PKC activation in the periphery might be addressed with co- nPKC = Novel PKC
administration of CNS-impermeant PKC inhibitors/ PKC PDK-1 = Phosphoinositides-dependent kinase-1
cascade inhibitors and/or dosing schedules that only
PKC = Protein kinase C
periodically activate PKC in the brain.
PKCI = PKCI
These concerns, including impact on cardiovascular
function, stroke/ischemia, may be addressed when more studies RACK = Receptor for activated C kinase
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