REVIEW

The role of protein kinase C epsilon in neural signaltransduction and neurogenic diseases

Yuan CHEN (✉), MD, PhD, Qi TIAN, BS

Neurobiology Research Center, Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510080, China

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Abstract Protein kinase C epsilon (PKC ε) is one ofmajor isoforms in novel PKC family. Although it has beenextensively characterized in the past decade, the role ofPKC ε in neuron is still not well understood. Advances inmolecular biology have now removed significant barriersto the direct investigation of PKC ε functions in vivo, andPKC ε has been increasingly implicated in the neuralbiological functions and associated neurogenic diseases.Recent studies have provided important insights into theinfluence of PKC ε on cortical processing at both the singlecell level and network level. These studies providecompelling evidence that PKC ε could regulate distinctaspects of neural signal transduction and suggest that thecoordinated actions of a number of molecular signalscontribute to the specification and differentiation of PKC εsignal pathway in the developing brain.

Keywords protein kinase C ε; signal transduction;neurogenic disease

1 Introduction

Protein kinase C epsilon (PKC ε), one of the PKC familymembers, is a protein catalyzing a variety of Ser/Thrresidues phosphorylated, which has been shown to beinvolved in many different cellular functions, such ascellular processes, proliferation, differentiation, neuronalplasticity, endocrine, exocrine, cardiovascular mechanism,inflammatory processes, gene expression, regulation of cellgrowth, ion channels activity and receptors desensitization[1–6]. In this review, we focus on the recent progress of therole of PKC ε in development of neurons and associatedneural diseases.

2 Distribution of PKC ε

The distribution of PKC ε has been investigated and it iswidely expressed throughout the body whereas it is presentpredominantly in brain [7,8]. Biochemistry analysis hasdisclosed that both membrane and cytosolic associatedforms of PKC ε with different molecular weights are foundin neuronal extracts. PKC ε expression is mainly found inthe hippocampus, calleja’s islands, olfactory tubercle andin lower amounts in peripheral tissues with moderateexpression in the cerebral cortex, teral septal nuclei,nucleus accumbens, frontal cortex and striatum andcaudate putamen [9–12].

3 The structure of PKC ε

PKC ε was first discovered as a calcium-independent butphorbol ester/diacylglycerol sensitive protein kinase phos-phorylating Ser/Thr residues [13,14]. PKC ε shares manystructural features with other members of novel PKCfamily, like three conserved regions C1, C3 and C4 and fivevariable regions V1–V5. C1 zone may be the membranebinding site as it contains cysteine rich motifs that bindphorbol ester and diacylglycerols (DAG). C1 is also knownas regulatory regions area. C3 and C4 catalytic domains thatcontain a purine binding site for ATP, activation loop andC4 area contains a substrate recognition site which isnecessary for phosphorylated substrate recognition[15,16]. A unique feature of PKC ε is a six-amino-acidactin binding motif between the C1a and C1b subdomains[17]. It is demonstrated that the actin binding site betweenthe C1a and C1b is important for morphological change ofneurons [18].

4 Pharmacological functions of PKC ε

As a result of its diverse actions, PKC ε has received

Received November 15, 2010; accepted January 11, 2011

E-mail: cheny33@mail.sysu.edu.cn

Front. Med. 2011, 5(1): 70–76DOI 10.1007/s11684-011-0119-9

particular attention as promising targets for the treatment ofseveral conditions such as pain, anxiety, inflammation,ischemia, addiction, and cancer [19–21]. Because it plays amultifaceted role in cellular responses, several therapeuticdrugs targeting PKC ε have come up. Some drugs havebeen developed targeting against PKC ε. Those drugsameliorate pathological conditions in acute myocardialinfarction and reduce pain via specific modulation ofmembrane translocation of PKC ε. Yonezawa et al. haverecently produced PKC ε abrogating peptides from thecatalytic domain of PKC which specifically inhibit PKC εand ameliorate pathological conditions in a rodent insulinresistance model [14]. Because PKC ε is found to be acritical component of TLR-4 signaling pathway andthereby, and play a key role in macrophage and dendriticcell (DC) activation in response to TLR agonists such asbacterial lipopolysaccharide, so controlling the activity ofPKC ε might represent an efficient strategy to prevent ortreat certain inflammatory disorders of microbial origin[19]. Whole-cell patch-clamp recording from sensoryneurons showed that activin acutely sensitized capsaicinresponses and depended on activin receptor kinase activity.Pharmacological studies revealed that the activin sensitiza-tion of capsaicin responses required PKC ε signaling andcontributed to acute thermal hyperalgesia [22].For drug development it is essential to elucidate the

different steps in enzyme activation to indicate propertiesthat are unique for PKC ε. These are not immediatelyinvolved in ATP binding but rather behave as selectivityfilters for compounds competing with ATP [23]. Theselective inhibition of PKC ε is disindolylmaleimide I.Pseudosubstrate sequence is a region that binds to thesubstrate binding pocket to keep the kinase in its inactivestate. However, a recent study revealed that a PKC εpseudosubstrate peptide also inhibits PKCα [24].

5 The role of PKC ε in signal transduction

5.1 PKC ε and LTP/LTD

As a protein kinase, PKC ε can accurately and reversiblymodify protein functions to influence cellular events.Although the predominant isozymes of PKC family inbrain have been reported to be α, β, γ, δ, ε, and ζ subtypes[3,25], the roles of PKC isozymes in neurons have not beenfully characterized but PKC ε is thought to be one ofessential factors of signal transduction pathway in neuron.Pharmacological and electrophysiological studies have

shown that long-term potentiation (LTP) and long-termdepression (LTD), specifically require PKC [26]. Long-term potentiation (LTP) is at least one component in thecomplex mechanism of learning and memory [8,27]. Thereare two types of LTP in the hippocampus: one is inSC-CA1 and the other is in the MF-CA3 pathway [28]. TheLTP in the SC-CA1 is calcium dependent and PKCg related

NMDA receptor phosphorylation is involved in thepostsynaptic neurons [26]. The LTP in the MF-CA3 isbelieved to be mediated by presynaptic events. PKC ε ispresent at the terminals of neurons and is localized at thepresynapses of the mossy fibers, consistent with a role forPKC ε in LTP at MF-CA3 [29,30]. Presynaptic PKC ε alsoplays an essential role in synaptic maturation. Hama et al.reported that contacting between neurons and astrocytesmakes an enhancement to the excitatory postsynapticpotential and induces excitatory synapses, and theninhibitors of PKC block the excitory synaptogenesis [31].

5.2 PKC ε modulates ion channels

In hippocampal neurons, muscarinic acetylcholine recep-tors can activate G-proteins, phospholipase C and PKCwhich phosphorylates brain Na+ channels and reducespeak Na+ currents due to acetylcholine. Overall, it isindicated that anchored PKC ε is the isozyme responsiblefor PKC-mediated reduction of peak Na+ currents inmouse hippocampal neurons [32]. The functional regula-tion of the sodium channel mRNA by PKC ε in the primarysensory neuron is important for the development of theperipheral pro-nociceptive state induced by repetitiveinflammatory stimuli and for the maintenance of thebehavioral persistent hypernociception [33].On the basis of a combination of electrophysiological

and biochemical approaches, it is reported the activation ofPKC enhances Ca2+ channel activities and potentiates fastsynaptic transmission as a result of direct phosphorylationof the Ca2+ channel’s α1 subunit. Several approaches havebeen done in our laboratory to show that forming PKCε-ENH-N-type Ca2+ channel macromolecular complexallows the rapid response of N-type Ca2+ channels tomodulation by PKC [34–37]. That is a good example forthe interaction of an adaptor protein, the specificity of PKCsignaling is achieved not only for the substrate but also forthe kinase itself. However, Gardezi SR et al. reported thePDLIM5 C-terminal region and LIM1-3 did not enhancePKC-dependent facilitation of CaV2.2 current. Thisfinding prompted us to retest whether ENH is a componentof a molecular complex with CaV2.2. It seems that theepitopes recognition disparation of ENH antibody led tothe different observation [38]. These results indicated thatENH may have more refined regulation in forming thiscomplex. And other approaches have shown PKC ε couldupregulate voltage dependent calcium channels in culturedastrocytes [39]. The fact that mice lacking N-type voltage-dependent calcium channels display decreased painresponses and on top a decreased anxiety-like behaviorsuggest that the interaction between PKC ε and thesechannels could have behavioral implications [40].And then, the hypothesis has been supported that the

brain mitochondrial K-ATP (+) channel is an importanttarget of ischemic preconditioning and the signal transduc-tion pathways is initiated by PKC ε [41]. Recent results

Yuan CHEN and Qi TIAN. The role of PKC ε signaling in neuron 71

show propofol can inhibit IK via the activation of PKCepsilon in rat cerebral parietal cortical neurons [42].

5.3 PKC ε and neuritis outgrowth

In neuroblastoma cells, overexpression of PKC ε, but notPKC α, βII, or δ leads to neurite outgrowth [43].Localization of PKC ε to the plasma membrane and/orthe cortical cytoskeleton is conceivably important for itseffect on neurite outgrowth specifically involved in theneural cell adhesion molecule-stimulated neurite out-growth [44], whereas the downregulation of PKC εinhibits nerve growth factor-induced neurite outgrowth.The fact that increasing the levels of PKC ε is sufficient toinduce neurites could imply that elevation of endogenouslevels of PKC ε may be a mechanism through whichneurite outgrowth is induced during neuronal differentia-tion. PKC ε is a common downstream mediator for severalneuritogenic factors, a PMA incubation followed by nervegrowth factor activates PKC ε leading to outgrowth of longneuritis [45].At the same time, members of the PKC family are

enriched in growth cones and important for neuriteoutgrowth and growth cone turning [46,47]. It modulatesnerve growth cone which guides neurites to predeterminedtargets by either turning toward or away from attractive orrepulsive pathfinding cues [48,49].PKC ε usually induces neurite outgrowth via its

regulatory domain and independently of its kinase activity,because expression of the regulatory domain alone caninduce neurite outgrowth [8]. Interestingly, a peptidecorresponding to the PKC ε actin binding site suppressesneurite outgrowth during neuronal differentiation andoutgrowth. The morphological change of neurons iselicited by PKC ε through its functional domains C1aand C1b region between the actin cytoskeleton proteininteractions and thus mediates the growth of nerve cellaxons [18]. It is also reported that the PKC ε inducedneurite outgrowth is blocked by activing Ras homologgene family RhoA and led by inhibition of the RhoAeffector (Rho-associated coiled-coil containing proteinkinase, ROCK) [50]. Besides, activation of Cdc42 isimplicated in PKC ε induced neurite outgrowth [8,51].Shirai et al. investigated the possibility of the directbinding of PKC ε to phosphatidylinositol 4,5-bis phos-phate (PIP2) and its correlation with the neurite outgrowth.They found that the direct binding of PKCε to PIP2 caninduce neurite and may influence the function of actinbinding proteins [52]. They believed that the openconformation of PKC ε could interact with RhoGAPand/or PIP2, and this could be regulated by the binding ofPKC ε to actin [8]. These studies suggest a model for theinvolvement of PKC ε in neurite function. However, thereare many other PKCε-associated proteins also reported inthe neurite outgrowth. For example, Yamaguchi et al.reported that myristoylated alanine-rich C-kinase substrate

(MARCKS) in lamellipodia formation was induced byIGF-I via the translocation of MARCKS, in associationwith PIP2, and accumulation of β-actin in the membranemicrodomains [53]. In addition, the neuronal growth-associated protein 43 (GAP43) is the major neuronalsubstrate of protein kinase C (PKC) and its phosphoryla-tion status dictates its modulation of actin dynamics.GAP43 was able to protect against growth cone collapsemediated by PIP2 inhibitors. The modification of GAP43 atits PKC phosphorylation site directs its distribution todifferent membrane microdomains that have distinct rolesin the regulation of intrinsic and extrinsic behaviors ingrowing neurons [54]. These data suggest that the PKC εmay have more precise functions during the process of theneurite outgrowth.

6 PKC ε and associated neurogenicdiseases

6.1 Ischemic preconditioning

PKC ε is sometimes related to ischemic preconditioning.Sometimes, mild ischemic insult, or ‘preconditioning,’promotes tolerance against more severe subsequentischemic insults in organs such as the heart and brain[55]. The signal transducers and activators of transcriptionwere found to be essential for cardioprotection andpreconditioning mediated by a signaling cascade thatinvolves activation of PKC ε [56,57]. Neuroprotectionagainst cerebral ischemia conferred by ischemic precondi-tioning requires translocation of PKC ε. In fact, the role ofPKC ε in neural preconditioning has been investigatedusing hippocampal and primary cultured neurons. Distin-guished with wild-type mice, preconditioning in PKC εKO mice does not reduce infarct size caused by ischemiareperfusion and this implicates the involvement of PKC εin preconditioning [41]. Myocardial protection can beachieved by brief ischemia-reperfusion of remote organs, aphenomenon described as remote preconditioning (RPC),since the intracellular mechanisms of RPC are not known,then it has been tested that RPC might activate myocardialPKC ε, an essential mediator of ischemic preconditioning.Isoflurane induces myocardial cells to release VEGFthrough activating PKC ε from the endochylema to thecytomembrane, suggesting a possible novel mechanism ofisoflurane protecting myocardial cells [58].Kim et al. demonstrated that inhibition of either PKC ε

or ERK1/2 activation abolished COX-2 expression andneuroprotection due to ischemic preconditioning using twoin vitro models [56]. PKC ε phosphorylates the mitochon-drial K-ATP (+) channel during induction of ischemicpreconditioning in the rat hippocampus [41,59]. This is akey mediator of neuroprotection which inhibits both Na+/K+-ATPase and voltage-gated sodium channels, primarymediators of the collapse of ion homeostasis during

72 Front. Med. 2011, 5(1): 70–76

ischemia [60]. These results reflect a crucial role for thePKC ε pathway in the induction of neuroprotection viaischemic preconditioning.

6.2 Pain

PKC is able to phosphorylate several cellular componentsthat serve as key regulatory components in signaltransduction pathways of nociceptor excitation andsensitization [61].PKC ε exerts a critical role in modulating the excitability

of sensory neurons and is involved in the development ofhypernociception which is increased sensitivity to noxiousor innocuous stimuli in several animal models of acute andpersistent inflammatory pain [62–64].The neuropeptide substance P (SP) is expressed in

unmyelinated primary sensory neurons and represents thebest known “pain” neurotransmitter. It is generallybelieved that SP regulates pain transmission and sensitiza-tion by acting on neurokinin-1 receptor, which is expressedin postsynaptic dorsal horn neurons. PKC ε inhibitorcompletely blocked both SP-induced potentiation and heathyperalgesia. SP also induces membrane translocation ofPKC ε in a portion of small dorsal root ganglion (DRG)neurons [65].PKC ε contributes greatly to the development of

inflammatory hypernociception and sensitization of noci-ceptors [66,67]. There are some studies that evaluated thecontribution of PKC ε to the development of prostaglandinE-2-induced mechanical hypernociception [64,68]. Inaddition, some data reflected that the phosphorylationand agonists of protease activated receptor 2 mediatedsensitization of the TRPV1 by PKC ε which plays animportant role in the development of chronic pain [69,70].It is essential for normal TRPV1 responses in vitro and invivo, including ATP and bradykinin; enhance TRPV1activity in a PKC-dependent manner [71]. Meanwhile,Patch-clamp techniques and Ca2+ imaging were used toexamine the interaction between neurokinins and thecapsaicin-evoked transient receptor potential TRPV1responses in rat dorsal root ganglia neurons [72]. Indeed,PKC ε directly phosphorylates Ser502 and Ser800 ofTRPV1 [73]. PKC ε is identified as important therapeutictargets may help to regulate inhibitory effects on TRPV1and hence its desensitization [74]. These observationsimplicate PKC could make the signaling to sensitize theTRPV1 channel; and not only contributes to acute thermalhyperalgesia, but also suggests other pathways involved[75].

6.3 Alcohol addiction

Zoological studies with null mutant mice show that PKC εregulates alcohol self-administration [76]. Mice lackingthe PKC ε self-administer 75% less ethanol and exhibitsupersensitivity to acute ethanol and allosteric positive

modulators of GABA receptors when compared withwild-type controls [77,78]. PKC ε knockout mice behavereduced ethanol consumption, sensitivity, reward andanxiety-like behavior compared with wild-type animals;even enhanced GABA receptor activity [79]. Correlationwith the increased GABA transmission in the animals wasconfirmed by the increased sensitivity to ethanol and thehigher chloridion uptake upon stimulation [80]. Expres-sion of the PKC ε in the brain controls ethanol-drinkingbehavior and it has an alcohol binding site in its secondcysteine-rich regulatory domain [76,81]. In the studies ofexamining the role of PKC ε in this action of ethanol onventral segmental area neurons, people find the results thatthe activation of PKC ε isoenzyme contributes to ethanolinduced potentiation of functions [82], so drugs targetingPKC ε may be useful to curb excessive drinking and be apossible therapeutic target for development of anxiolytics[79].There is another result indicating CRF mediates anxiety

associated with stress and drug dependence and regulatesethanol intake. In the central amygdale, ethanol acts toenhance GABA release and PKC ε might lie downstreamof CRF1 receptors [77]. Lesscher et al. reported amygdalaPKC ε is important for ethanol consumption in mice. Localknockdown of PKC ε in the amygdala reduced ethanolconsumption and preference in a limited-access paradigm.Further, mice that are heterozygous for the PKC ε alleleconsume less ethanol compared with wild-type mice in thisparadigm. These mice have a> 50% reduction in theabundance of PKC ε in the amygdala compared with wild-type mice [83]. These data identify a different PKC εsignaling pathway in the CeA that is activated by CRF1receptor stimulation, mediates GABA release at nerveterminals, and regulates anxiety and alcohol consumption[77]. However, the precise function and mechanism of thisaction are not yet to be fully understood and still remain adebate [79,80]. It seems that different methods lead todifferent results gained respectively from mutant mice andCeA neurons. Whether these divers systems on organicand cellular levels have some kinds of net-effective factorsor not is still unknown. How PKC ε regulates ethanolconsumption need further confirmed. But PKC ε whichplays a key function in the induction of alcohol self-administration is definite.

7 Perspectives

Functional studies demonstrate that activation of PKC ε isconsistent with its role in several diseases and neurons. Thefact that PKC ε at the molecular level behaves as asensitizer in a number of distinct pathways, some of whichare involved in pain, suggests that it could be anothermechanism in which emotional and physical pain arelinked. Further elucidation of its signaling cascades inthese brain regions will manifest the importance of PKC ε

Yuan CHEN and Qi TIAN. The role of PKC ε signaling in neuron 73

as a sensitizing kinase in the central neron system (CNS) aswell as the development of novel therapies against painand anxiety disorders. Future developments in bioinfor-matics tools should greatly aid in the search forphosphorylation sites on substrates of PKC ε. However,a chemical inhibitor of PKC ε is necessary because theinhibitors used so far are peptides that cannot be employedeffectively in in vivo neural studies. More specificinhibitors and activators which could cross the blood–brain barrier would be useful to define the precise functionsof PKC ε in diseases and neurons.

Acknowledgements This work was supported by the National NaturalScience Foundation of China (Grant No 30870785).

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