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

Abstract

Protein kinase C epsilon (PKC ϵ) is one of major isoforms in novel PKC family. Although it has been extensively characterized in the past decade, the role of PKC ϵ in neuron is still not well understood. Advances in molecular biology have now removed significant barriers to the direct investigation of PKC ϵ functions in vivo, and PKC ϵ has been increasingly implicated in the neural biological functions and associated neurogenic diseases. Recent studies have provided important insights into the influence of PKC ϵ on cortical processing at both the single cell level and network level. These studies provide compelling evidence that PKC ϵ could regulate distinct aspects of neural signal transduction and suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of PKC ϵ signal pathway in the developing brain.

Keywords

protein kinase C ϵ / signal transduction / neurogenic disease

Introduction

Protein kinase C epsilon (PKC ϵ), one of the PKC family members, is a protein catalyzing a variety of Ser/Thr residues phosphorylated, which has been shown to be involved in many different cellular functions, such as cellular processes, proliferation, differentiation, neuronal plasticity, endocrine, exocrine, cardiovascular mechanism, inflammatory processes, gene expression, regulation of cell growth, ion channels activity and receptors desensitization [1–6]. In this review, we focus on the recent progress of the role of PKC ϵ in development of neurons and associated neural diseases.

Distribution of PKC ϵ

The distribution of PKC ϵ has been investigated and it is widely expressed throughout the body whereas it is present predominantly in brain [7,8]. Biochemistry analysis has disclosed that both membrane and cytosolic associated forms of PKC ϵ with different molecular weights are found in neuronal extracts. PKC ϵ expression is mainly found in the hippocampus, calleja’s islands, olfactory tubercle and in lower amounts in peripheral tissues with moderate expression in the cerebral cortex, teral septal nuclei, nucleus accumbens, frontal cortex and striatum and caudate putamen [9–12].

The structure of PKC ϵ

PKC ϵ was first discovered as a calcium-independent but phorbol ester/diacylglycerol sensitive protein kinase phosphorylating Ser/Thr residues [13,14]. PKC ϵ shares many structural features with other members of novel PKC family, like three conserved regions C₁, C₃ and C₄ and five variable regions V₁–V₅. C₁ zone may be the membrane binding site as it contains cysteine rich motifs that bind phorbol ester and diacylglycerols (DAG). C₁ is also known as regulatory regions area. C₃ and C₄ catalytic domains that contain a purine binding site for ATP, activation loop and C₄ area contains a substrate recognition site which is necessary for phosphorylated substrate recognition [15,16]. A unique feature of PKC ϵ is a six-amino-acid actin binding motif between the C₁a and C₁b subdomains [17]. It is demonstrated that the actin binding site between the C₁a and C₁b is important for morphological change of neurons [18].

Pharmacological functions of PKC ϵ

As a result of its diverse actions, PKC ϵ has received particular attention as promising targets for the treatment of several conditions such as pain, anxiety, inflammation, ischemia, addiction, and cancer [19–21]. Because it plays a multifaceted role in cellular responses, several therapeutic drugs targeting PKC ϵ have come up. Some drugs have been developed targeting against PKC ϵ. Those drugs ameliorate pathological conditions in acute myocardial infarction and reduce pain via specific modulation of membrane translocation of PKC ϵ. Yonezawa et al. have recently produced PKC ϵ abrogating peptides from the catalytic domain of PKC which specifically inhibit PKC ϵ and ameliorate pathological conditions in a rodent insulin resistance model [14]. Because PKC ϵ is found to be a critical component of TLR-4 signaling pathway and thereby, and play a key role in macrophage and dendritic cell (DC) activation in response to TLR agonists such as bacterial lipopolysaccharide, so controlling the activity of PKC ϵ might represent an efficient strategy to prevent or treat certain inflammatory disorders of microbial origin [19]. Whole-cell patch-clamp recording from sensory neurons showed that activin acutely sensitized capsaicin responses and depended on activin receptor kinase activity. Pharmacological studies revealed that the activin sensitization of capsaicin responses required PKC ϵ signaling and contributed to acute thermal hyperalgesia [22].

For drug development it is essential to elucidate the different steps in enzyme activation to indicate properties that are unique for PKC ϵ. These are not immediately involved in ATP binding but rather behave as selectivity filters for compounds competing with ATP [23]. The selective inhibition of PKC ϵ is disindolylmaleimide I. Pseudosubstrate sequence is a region that binds to the substrate binding pocket to keep the kinase in its inactive state. However, a recent study revealed that a PKC ϵ pseudosubstrate peptide also inhibits PKCα [24].

The role of PKC ϵ in signal transduction

PKC ϵ and LTP/LTD

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

Pharmacological and electrophysiological studies have shown that long-term potentiation (LTP) and long-term depression (LTD), specifically require PKC [26]. Long-term potentiation (LTP) is at least one component in the complex mechanism of learning and memory [8,27]. There are two types of LTP in the hippocampus: one is in SC-CA₁ and the other is in the MF-CA3 pathway [28]. The LTP in the SC-CA₁ is calcium dependent and PKC_g related NMDA receptor phosphorylation is involved in the postsynaptic neurons [26]. The LTP in the MF-CA₃ is believed to be mediated by presynaptic events. PKC ϵ is present at the terminals of neurons and is localized at the presynapses of the mossy fibers, consistent with a role for PKC ϵ in LTP at MF-CA₃ [29,30]. Presynaptic PKC ϵ also plays an essential role in synaptic maturation. Hama et al. reported that contacting between neurons and astrocytes makes an enhancement to the excitatory postsynaptic potential and induces excitatory synapses, and then inhibitors of PKC block the excitory synaptogenesis [31].

PKC ϵ modulates ion channels

In hippocampal neurons, muscarinic acetylcholine receptors can activate G-proteins, phospholipase C and PKC which phosphorylates brain Na⁺ channels and reduces peak Na⁺ currents due to acetylcholine. Overall, it is indicated that anchored PKC ϵ is the isozyme responsible for PKC-mediated reduction of peak Na⁺ currents in mouse hippocampal neurons [32]. The functional regulation of the sodium channel mRNA by PKC ϵ in the primary sensory neuron is important for the development of the peripheral pro-nociceptive state induced by repetitive inflammatory stimuli and for the maintenance of the behavioral persistent hypernociception [33].

On the basis of a combination of electrophysiological and biochemical approaches, it is reported the activation of PKC enhances Ca²⁺ channel activities and potentiates fast synaptic transmission as a result of direct phosphorylation of the Ca²⁺ channel’s α1 subunit. Several approaches have been done in our laboratory to show that forming PKCϵ-ENH-N-type Ca²⁺ channel macromolecular complex allows the rapid response of N-type Ca²⁺ channels to modulation by PKC [34–37]. That is a good example for the interaction of an adaptor protein, the specificity of PKC signaling is achieved not only for the substrate but also for the kinase itself. However, Gardezi SR et al. reported the PDLIM5 C-terminal region and LIM1-3 did not enhance PKC-dependent facilitation of CaV2.2 current. This finding prompted us to retest whether ENH is a component of a molecular complex with CaV2.2. It seems that the epitopes recognition disparation of ENH antibody led to the different observation [38]. These results indicated that ENH may have more refined regulation in forming this complex. And other approaches have shown PKC ϵ could upregulate voltage dependent calcium channels in cultured astrocytes [39]. The fact that mice lacking N-type voltage-dependent calcium channels display decreased pain responses and on top a decreased anxiety-like behavior suggest that the interaction between PKC ϵ and these channels could have behavioral implications [40].

And then, the hypothesis has been supported that the brain mitochondrial K-ATP (+) channel is an important target of ischemic preconditioning and the signal transduction pathways is initiated by PKC ϵ [41]. Recent results show propofol can inhibit I_K via the activation of PKC epsilon in rat cerebral parietal cortical neurons [42].

PKC ϵ and neuritis outgrowth

In neuroblastoma cells, overexpression of PKC ϵ, but not PKC α, βII, or δ leads to neurite outgrowth [43]. Localization of PKC ϵ to the plasma membrane and/or the cortical cytoskeleton is conceivably important for its effect on neurite outgrowth specifically involved in the neural cell adhesion molecule-stimulated neurite outgrowth [44], whereas the downregulation of PKC ϵ inhibits nerve growth factor-induced neurite outgrowth. The fact that increasing the levels of PKC ϵ is sufficient to induce neurites could imply that elevation of endogenous levels of PKC ϵ may be a mechanism through which neurite outgrowth is induced during neuronal differentiation. PKC ϵ is a common downstream mediator for several neuritogenic factors, a PMA incubation followed by nerve growth factor activates PKC ϵ leading to outgrowth of long neuritis [45].

At the same time, members of the PKC family are enriched in growth cones and important for neurite outgrowth and growth cone turning [46,47]. It modulates nerve growth cone which guides neurites to predetermined targets by either turning toward or away from attractive or repulsive 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 can induce neurite outgrowth [8]. Interestingly, a peptide corresponding to the PKC ϵ actin binding site suppresses neurite outgrowth during neuronal differentiation and outgrowth. The morphological change of neurons is elicited by PKC ϵ through its functional domains C₁a and C₁b region between the actin cytoskeleton protein interactions and thus mediates the growth of nerve cell axons [18]. It is also reported that the PKC ϵ induced neurite outgrowth is blocked by activing Ras homolog gene family RhoA and led by inhibition of the RhoA effector (Rho-associated coiled-coil containing protein kinase, ROCK) [50]. Besides, activation of Cdc42 is implicated in PKC ϵ induced neurite outgrowth [8,51]. Shirai et al. investigated the possibility of the direct binding of PKC ϵ to phosphatidylinositol 4,5-bis phosphate (PIP₂) and its correlation with the neurite outgrowth. They found that the direct binding of PKCϵ to PIP₂ can induce neurite and may influence the function of actin binding proteins [52]. They believed that the open conformation of PKC ϵ could interact with RhoGAP and/or PIP2, and this could be regulated by the binding of PKC ϵ to actin [8]. These studies suggest a model for the involvement of PKC ϵ in neurite function. However, there are many other PKCϵ-associated proteins also reported in the neurite outgrowth. For example, Yamaguchi et al. reported that myristoylated alanine-rich C-kinase substrate (MARCKS) in lamellipodia formation was induced by IGF-I via the translocation of MARCKS, in association with PIP₂, and accumulation of β-actin in the membrane microdomains [53]. In addition, the neuronal growth-associated protein 43 (GAP43) is the major neuronal substrate of protein kinase C (PKC) and its phosphorylation status dictates its modulation of actin dynamics. GAP43 was able to protect against growth cone collapse mediated by PIP₂ inhibitors. The modification of GAP43 at its PKC phosphorylation site directs its distribution to different membrane microdomains that have distinct roles in the regulation of intrinsic and extrinsic behaviors in growing neurons [54]. These data suggest that the PKC ϵ may have more precise functions during the process of the neurite outgrowth.

PKC ϵ and associated neurogenic diseases

Ischemic preconditioning

PKC ϵ is sometimes related to ischemic preconditioning. Sometimes, mild ischemic insult, or ‘preconditioning,’ promotes tolerance against more severe subsequent ischemic insults in organs such as the heart and brain [55]. The signal transducers and activators of transcription were found to be essential for cardioprotection and preconditioning mediated by a signaling cascade that involves activation of PKC ϵ [56,57]. Neuroprotection against cerebral ischemia conferred by ischemic preconditioning requires translocation of PKC ϵ. In fact, the role of PKC ϵ in neural preconditioning has been investigated using hippocampal and primary cultured neurons. Distinguished with wild-type mice, preconditioning in PKC ϵ KO mice does not reduce infarct size caused by ischemia reperfusion and this implicates the involvement of PKC ϵ in preconditioning [41]. Myocardial protection can be achieved by brief ischemia-reperfusion of remote organs, a phenomenon described as remote preconditioning (RPC), since the intracellular mechanisms of RPC are not known, then it has been tested that RPC might activate myocardial PKC ϵ, an essential mediator of ischemic preconditioning. Isoflurane induces myocardial cells to release VEGF through activating PKC ϵ from the endochylema to the cytomembrane, suggesting a possible novel mechanism of isoflurane protecting myocardial cells [58].

Kim et al. demonstrated that inhibition of either PKC ϵ or ERK1/2 activation abolished COX-2 expression and neuroprotection due to ischemic preconditioning using two in vitro models [56]. PKC ϵ phosphorylates the mitochondrial K-ATP (+) channel during induction of ischemic preconditioning in the rat hippocampus [41,59]. This is a key mediator of neuroprotection which inhibits both Na⁺/K⁺-ATPase and voltage-gated sodium channels, primary mediators of the collapse of ion homeostasis during ischemia [60]. These results reflect a crucial role for the PKC ϵ pathway in the induction of neuroprotection via ischemic preconditioning.

Pain

PKC is able to phosphorylate several cellular components that serve as key regulatory components in signal transduction pathways of nociceptor excitation and sensitization [61].

PKC ϵ exerts a critical role in modulating the excitability of sensory neurons and is involved in the development of hypernociception which is increased sensitivity to noxious or innocuous stimuli in several animal models of acute and persistent inflammatory pain [62–64].

The neuropeptide substance P (SP) is expressed in unmyelinated primary sensory neurons and represents the best known “pain” neurotransmitter. It is generally believed that SP regulates pain transmission and sensitization by acting on neurokinin-1 receptor, which is expressed in postsynaptic dorsal horn neurons. PKC ϵ inhibitor completely blocked both SP-induced potentiation and heat hyperalgesia. SP also induces membrane translocation of PKC 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 nociceptors [66,67]. There are some studies that evaluated the contribution of PKC ϵ to the development of prostaglandin E-2-induced mechanical hypernociception [64,68]. In addition, some data reflected that the phosphorylation and agonists of protease activated receptor 2 mediated sensitization of the TRPV1 by PKC ϵ which plays an important role in the development of chronic pain [69,70]. It is essential for normal TRPV1 responses in vitro and in vivo, including ATP and bradykinin; enhance TRPV1 activity in a PKC-dependent manner [71]. Meanwhile, Patch-clamp techniques and Ca²⁺ imaging were used to examine the interaction between neurokinins and the capsaicin-evoked transient receptor potential TRPV1 responses in rat dorsal root ganglia neurons [72]. Indeed, PKC ϵ directly phosphorylates Ser502 and Ser800 of TRPV1 [73]. PKC ϵ is identified as important therapeutic targets may help to regulate inhibitory effects on TRPV1 and hence its desensitization [74]. These observations implicate PKC could make the signaling to sensitize the TRPV1 channel; and not only contributes to acute thermal hyperalgesia, but also suggests other pathways involved [75].

Alcohol addiction

Zoological studies with null mutant mice show that PKC ϵ regulates alcohol self-administration [76]. Mice lacking the PKC ϵ self-administer 75% less ethanol and exhibit supersensitivity to acute ethanol and allosteric positive modulators of GABA receptors when compared with wild-type controls [77,78]. PKC ϵ knockout mice behave reduced ethanol consumption, sensitivity, reward and anxiety-like behavior compared with wild-type animals; even enhanced GABA receptor activity [79]. Correlation with the increased GABA transmission in the animals was confirmed by the increased sensitivity to ethanol and the higher chloridion uptake upon stimulation [80]. Expression of the PKC ϵ in the brain controls ethanol-drinking behavior and it has an alcohol binding site in its second cysteine-rich regulatory domain [76,81]. In the studies of examining the role of PKC ϵ in this action of ethanol on ventral segmental area neurons, people find the results that the activation of PKC ϵ isoenzyme contributes to ethanol induced potentiation of functions [82], so drugs targeting PKC ϵ may be useful to curb excessive drinking and be a possible therapeutic target for development of anxiolytics [79].

There is another result indicating CRF mediates anxiety associated with stress and drug dependence and regulates ethanol intake. In the central amygdale, ethanol acts to enhance GABA release and PKC ϵ might lie downstream of CRF₁ receptors [77]. Lesscher et al. reported amygdala PKC ϵ is important for ethanol consumption in mice. Local knockdown of PKC ϵ in the amygdala reduced ethanol consumption and preference in a limited-access paradigm. Further, mice that are heterozygous for the PKC ϵ allele consume less ethanol compared with wild-type mice in this paradigm. These mice have a>50% reduction in the abundance of PKC ϵ in the amygdala compared with wild-type mice [83]. These data identify a different PKC ϵ signaling pathway in the CeA that is activated by CRF₁ receptor stimulation, mediates GABA release at nerve terminals, and regulates anxiety and alcohol consumption [77]. However, the precise function and mechanism of this action are not yet to be fully understood and still remain a debate [79,80]. It seems that different methods lead to different results gained respectively from mutant mice and CeA neurons. Whether these divers systems on organic and cellular levels have some kinds of net-effective factors or not is still unknown. How PKC ϵ regulates ethanol consumption need further confirmed. But PKC ϵ which plays a key function in the induction of alcohol self-administration is definite.

Perspectives

Functional studies demonstrate that activation of PKC ϵ is consistent with its role in several diseases and neurons. The fact that PKC ϵ at the molecular level behaves as a sensitizer in a number of distinct pathways, some of which are involved in pain, suggests that it could be another mechanism in which emotional and physical pain are linked. Further elucidation of its signaling cascades in these brain regions will manifest the importance of PKC ϵ as a sensitizing kinase in the central neron system (CNS) as well as the development of novel therapies against pain and anxiety disorders. Future developments in bioinformatics tools should greatly aid in the search for phosphorylation sites on substrates of PKC ϵ. However, a chemical inhibitor of PKC ϵ is necessary because the inhibitors used so far are peptides that cannot be employed effectively in in vivo neural studies. More specific inhibitors and activators which could cross the blood–brain barrier would be useful to define the precise functions of PKC ϵ in diseases and neurons.

References

[1] Battaini F. Protein kinase C isoforms as therapeutic targets in nervous system disease states. Pharmacol Res, 2001, 44(5): 353-361

[2] Chen G, Masana M I, Manji H K. Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo. Bipolar Disord, 2000, 2(3 Pt 2): 217-236

[3] Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J, 1995, 9(7): 484-496

[4] Van Kolen K, Pullan S, Neefs J M, Dautzenberg F M. Nociceptive and behavioural sensitisation by protein kinase Cepsilon signalling in the CNS. J Neurochem, 2008, 104(1): 1-13

[5] Bruch R C, Kang J S, Moore M L Jr, Medler K F. Protein kinase C and receptor kinase gene expression in olfactory receptor neurons. J Neurobiol, 1997, 33(4): 387-394

[6] Zeidman R, Löfgren B, Pâhlman S, Larsson C. PKCepsilon, via its regulatory domain and independently of its catalytic domain, induces neurite-like processes in neuroblastoma cells. J Cell Biol, 1999, 145(4): 713-726

[7] Patten S A, Sihra R K, Dhami K S, Coutts C A, Ali D W. Differential expression of PKC isoforms in developing zebrafish. Int J Dev Neurosci, 2007, 25(3): 155-164

[8] Shirai Y, Adachi N, Saito N. Protein kinase Cepsilon: function in neurons. FEBS J, 2008, 275(16): 3988-3994

[9] Minami H, Owada Y, Suzuki R, Handa Y, Kondo H. Localization of mRNAs for novel, atypical as well as conventional protein kinase C (PKC) isoforms in the brain of developing and mature rats. J Mol Neurosci, 2000, 15(2): 121-135

[10] Saito N, Itouji A, Totani Y, Osawa I, Koide H, Fujisawa N, Ogita K, Tanaka C. Cellular and intracellular localization of epsilon-subspecies of protein kinase C in the rat brain; presynaptic localization of the epsilon-subspecies. Brain Res, 1993, 607(1-2): 241-248

[11] Uhlén M, Björling E, Agaton C, Szigyarto C A, Amini B, Andersen E, Andersson A C, Angelidou P, Asplund A, Asplund C, Berglund L, Bergström K, Brumer H, Cerjan D, Ekström M, Elobeid A, Eriksson C, Fagerberg L, Falk R, Fall J, Forsberg M, Björklund M G, Gumbel K, Halimi A, Hallin I, Hamsten C, Hansson M, Hedhammar M, Hercules G, Kampf C, Larsson K, Lindskog M, Lodewyckx W, Lund J, Lundeberg J, Magnusson K, Malm E, Nilsson P, Odling J, Oksvold P, Olsson I, Oster E, Ottosson J, Paavilainen L, Persson A, Rimini R, Rockberg J, Runeson M, Sivertsson A, Sköllermo A, Steen J, Stenvall M, Sterky F, Strömberg S, Sundberg M, Tegel H, Tourle S, Wahlund E, Waldén A, Wan J, Wernérus H, Westberg J, Wester K, Wrethagen U, Xu L L, Hober S, Pontén F. A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics, 2005, 4(12): 1920-1932

[12] Uhlen M, Ponten F. Antibody-based proteomics for human tissue profiling. Mol Cell Proteomics, 2005, 4(4): 384-393

[13] Akita Y. Protein kinase C-epsilon (PKC-epsilon): its unique structure and function. J Biochem, 2002, 132(6): 847-852

[14] Yonezawa T, Kurata R, Kimura M, Inoko H. PKC delta and epsilon in drug targeting and therapeutics. Recent Pat DNA Gene Seq, 2009, 3(2): 96-101

[15] Newton P M, Messing R O. The substrates and binding partners of protein kinase Cepsilon. Biochem J, 2010, 427(2): 189-196

[16] Newton P M, Ron D. Protein kinase C and alcohol addiction. Pharmacol Res, 2007, 55(6): 570-577

[17] Prekeris R, Mayhew M W, Cooper J B, Terrian D M. Identification and localization of an actin-binding motif that is unique to the epsilon isoform of protein kinase C and participates in the regulation of synaptic function. J Cell Biol, 1996, 132(1-2): 77-90

[18] Zeidman R, Trollér U, Raghunath A, Påhlman S, Larsson C. Protein kinase Cepsilon actin-binding site is important for neurite outgrowth during neuronal differentiation. Mol Biol Cell, 2002, 13(1): 12-24

[19] Aksoy E, Goldman M, Willems F. Protein kinase C epsilon: a new target to control inflammation and immune-mediated disorders. Int J Biochem Cell Biol, 2004, 36(2): 183-188

[20] Basu A, Sivaprasad U. Protein kinase Cepsilon makes the life and death decision. Cell Signal, 2007, 19(8): 1633-1642

[21] Gorin M A, Pan Q. Protein kinase C epsilon: an oncogene and emerging tumor biomarker. Mol Cancer, 2009, 8(1): 9

[22] Zhu W G, Xu P, Cuascut F X, Hall A K, Oxford G S. Activin acutely sensitizes dorsal root ganglion neurons and induces hyperalgesia via PKC-mediated potentiation of transient receptor potential vanilloid I. J Neurosci, 2007, 27(50): 13770-13780

[23] Keri G O L, Eros D. Signal transduction therapy with rationally designed kinase inhibitors. Curr Signal Transduct Ther, 2006, 1(1): 67-95

[24] Johnson J A. Differential inhibition by alpha and epsilon PKC pseudosubstrate sequences: a putative mechanism for preferential PKC activation in neonatal cardiac myocytes. Life Sci, 2004, 74(25): 3153-3172

[25] Hernandez A I, Blace N, Crary J F, Serrano P A, Leitges M, Libien J M, Weinstein G, Tcherapanov A, Sacktor T C. Protein kinase M zeta synthesis from a brain mRNA encoding an independent protein kinase C zeta catalytic domain. Implications for the molecular mechanism of memory. J Biol Chem, 2003, 278(41): 40305-40316

[26] Saito N, Shirai Y. Protein kinase C gamma (PKC gamma): function of neuron specific isotype. J Biochem, 2002, 132(5): 683-687

[27] Osten P, Hrabetova S, Sacktor T C. Differential downregulation of protein kinase C isoforms in spreading depression. Neurosci Lett, 1996, 221(1): 37-40

[28] Hussain R J, Carpenter D O. A comparison of the roles of protein kinase C in long-term potentiation in rat hippocampal areas CA1 and CA3. Cell Mol Neurobiol, 2005, 25(3-4): 649-661

[29] Hussain R J, Carpenter D O. Development of synaptic responses and plasticity at the SC-CA1 and MF-CA3 synapses in rat hippocampus. Cell Mol Neurobiol, 2001, 21(4): 357-368

[30] Tao W Q, Xiao P, Xu S T, Hu X J, Ou Y Q. Changes of synaptic transmission efficiency in the MF-CA3 and PP-CA3 pathways of rat hippocampus during discrimination learning. Sheng Li Xue Bao, 1996, 48(5): 431-436

[31] Hama H, Hara C, Yamaguchi K, Miyawaki A. PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes. Neuron, 2004, 41(3): 405-415

[32] Chen Y, Cantrell A R, Messing R O, Scheuer T, Catterall W A. Specific modulation of Na+ channels in hippocampal neurons by protein kinase C epsilon. J Neurosci, 2005, 25(2): 507-513

[33] Villarreal C F, Sachs D, Funez M I, Parada C A, de Queiroz Cunha F, Ferreira S H. The peripheral pro-nociceptive state induced by repetitive inflammatory stimuli involves continuous activation of protein kinase A and protein kinase C epsilon and its Na(V)1.8 sodium channel functional regulation in the primary sensory neuron. Biochem Pharmacol, 2009, 77(5): 867-877

[34] Squassina A, Congiu D, Manconi F, Manchia M, Chillotti C, Lampus S, Severino G, Zompo M D. The PDLIM5 gene and lithium prophylaxis: an association and gene expression analysis in Sardinian patients with bipolar disorder. Pharmacol Res, 2008, 57(5): 369-373

[35] Chen Y, Lai M Z, Maeno-Hikichi Y, Zhang J F. Essential role of the LIM domain in the formation of the PKC epsilon-ENH-N-type Ca²⁺ channel complex. Cell Signal, 2006, 18(2): 215-224

[36] Zhang J, Chen Y, Lai M, and Maeno-Hikichi Y. A phosphatase is part of a PKC-n-type calcium channel signaling complex in neurons. Society for Neuroscience Abstract Viewer and Itinerary Planner, 2002, No. 115.7.

[37] Maeno-Hikichi Y, Chang S, Matsummura K, Lai M, Lin H, Nakagawa N, Kuroda S, Zhang J F. A PKC epsilon-ENH-channel complex spedifically modulates N-type Ca²⁺ channels. Nat Neurosci, 2003, 6(5): 468-475

[38] Gardezi S R, Weber A M, Li Q, Wong F K, Stanley E F. PDLIM5 is not a neuronal CaV2.2 adaptor protein. Nat Neurosci, 2009, 12(8): 957-958, author reply 958

[39] Burgos M, Pastor M D, González J C, Martinez-Galan J R, Vaquero C F, Fradejas N, Benavides A, Hernández-Guijo J M, Tranque P, Calvo S. PKC epsilon upregulates voltage-dependent calcium channels in cultured astrocytes. Glia, 2007, 55(14): 1437-1448

[40] Saegusa H, Kurihara T, Zong S, Kazuno A, Matsuda Y, Nonaka T, Han W, Toriyama H, Tanabe T. Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca²⁺ channel. EMBO J, 2001, 20(10): 2349-2356

[41] Raval A P, Dave K R, DeFazio R A, Perez-Pinzon M A. epsilonPKC phosphorylates the mitochondrial K(+) (ATP) channel during induction of ischemic preconditioning in the rat hippocampus. Brain Res, 2007, 1184: 345-353

[42] Song C Y, Xi H J, Yang L, Qu L H, Zi Y, Zhou J, Cui X G, Gao W, Wang N, Pan Z W, and Li W Z. Propofol inhibited the delayed rectifier potassium current (I(k)) via activation of protein kinase C epsilon in rat parietal cortical neurons. Eur J Pharmacol, 2011, 653(1–3): 16–20

[43] Zeidman R, Pettersson L, Sailaja P R, Truedsson E, Fagerström S, Påhlman S, Larsson C. Novel and classical protein kinase C isoforms have different functions in proliferation, survival and differentiation of neuroblastoma cells. Int J Cancer, 1999, 81(3): 494-501

[44] Kolkova K, Stensman H, Berezin V, Bock E, Larsson C. Distinct roles of PKC isoforms in NCAM-mediated neurite outgrowth. J Neurochem, 2005, 92(4): 886-894

[45] Burry R W. PKC activators (phorbol ester or bryostatin) stimulate outgrowth of NGF-dependent neurites in a subline of PC12 cells. J Neurosci Res, 1998, 53(2): 214-222

[46] Mikule K, Sunpaweravong S, Gatlin J C, Pfenninger K H. Eicosanoid activation of protein kinase C epsilon: involvement in growth cone repellent signaling. J Biol Chem, 2003, 278(23): 21168-21177

[47] Théodore L, Derossi D, Chassaing G, Llirbat B, Kubes M, Jordan P, Chneiweiss H, Godement P, Prochiantz A. Intraneuronal delivery of protein kinase C pseudosubstrate leads to growth cone collapse. J Neurosci, 1995, 15(11): 7158-7167

[48] Isbister C M, O’Connor T P. Mechanisms of growth cone guidance and motility in the developing grasshopper embryo. J Neurobiol, 2000, 44(2): 271-280

[49] Tessier-Lavigne M, Goodman C S. The molecular biology of axon guidance. Science, 1996, 274(5290): 1123-1133

[50] Ling M, Trollér U, Zeidman R, Lundberg C, Larsson C. Induction of neurites by the regulatory domains of PKC delta and epsilon is counteracted by PKC catalytic activity and by the RhoA pathway. Exp Cell Res, 2004, 292(1): 135-150

[51] Trollér U, Larsson C. Cdc42 is involved in PKCepsilon- and delta-induced neurite outgrowth and stress fibre dismantling. Biochem Biophys Res Commun, 2006, 349(1): 91-98

[52] Shirai Y, Murakami T, Kuramasu M, Iijima L, Saito N. A novel PIP2 binding of epsilon PKC and its contribution to the neurite induction ability. J Neurochem, 2007, 102(5): 1635-1644

[53] Yamaguchi H, Shiraishi M, Fukami K, Tanabe A, Ikeda-Matsuo Y, Naito Y, Sasaki Y. MARCKS regulates lamellipodia formation induced by IGF-I via association with PIP2 and beta-actin at membrane microdomains. J Cell Physiol, 2009, 220(3): 748-755

[54] Nguyen L, He Q, Meiri K F. Regulation of GAP-43 at serine 41 acts as a switch to modulate both intrinsic and extrinsic behaviors of growing neurons, via altered membrane distribution. Mol Cell Neurosci, 2009, 41(1): 62-73

[55] Tauskela J S, chakravarthy B R, Murray C L, Wang Y Z, Comas T, Hogan M, Hakim A, Morley P. Evidence from cultured rat cortical neurons of differences in the mechanism of ischemic preconditioning of brain and heart. Brain Res, 1999, 827(1-2): 143-151

[56] Kim E J, Raval A P, Perez-Pinzon M A. Preconditioning mediated by sublethal oxygen-glucose deprivation-induced cyclooxygenase-2 expression via the signal transducers and activators of transcription 3 phosphorylation. J Cereb Blood Flow Metab, 2008, 28(7): 1329-1340

[57] Wolfrum S, Schneider K, Heidbreder M, Nienstedt J, Dominiak P, Dendorfer A. Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform. Cardiovasc Res, 2002, 55(3): 583-589

[58] Liu Z G, Xia Z Y, Chen X D, Luo T. Isoflurane induces expression of vascular endothelial growth factor through activating protein kinase C in myocardial cells. Chin J Traumatol, 2010, 13(5): 284-288

[59] Budas G R, Mochly-Rosen D. Mitochondrial protein kinase Cepsilon (PKCepsilon): emerging role in cardiac protection from ischaemic damage. Biochem Soc Trans, 2007, 35(Pt 5): 1052-1054

[60] Dave K R, Anthony Defazio R, Raval A P, Dashkin O, Saul I, Iceman K E, Perez-Pinzon M A, Drew K L. Protein kinase C epsilon activation delays neuronal depolarization during cardiac arrest in the euthermic arctic ground squirrel. J Neurochem, 2009, 110(4): 1170-1179

[61] Ferreira J, Trichês K M, Medeiros R, Calixto J B. Mechanisms involved in the nociception produced by peripheral protein kinase c activation in mice. Pain, 2005, 117(1-2): 171-181

[62] Davis J B, Gray J, Gunthorpe M J, Hatcher J P, Davey P T, Overend P, Harries M H, Latcham J, Clapham C, Atkinson K, Hughes S A, Rance K, Grau E, Harper A J, Pugh P L, Rogers D C, Bingham S, Randall A, Sheardown S A. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature, 2000, 405(6783): 183-187

[63] Hucho T B, Dina O A, Kuhn J, Levine J D. Estrogen controls PKCepsilon-dependent mechanical hyperalgesia through direct action on nociceptive neurons. Eur J Neurosci, 2006, 24(2): 527-534

[64] Sachs D, Villarreal C F, Cunha F Q, Parada C A, Ferreira Sh. The role of PKA and PKCepsilon pathways in prostaglandin E2-mediated hypernociception. Br J Pharmacol, 2009, 156(5): 826-834

[65] Zhang H, Cang C L, Kawasaki Y, Liang L L, Zhang Y Q, Ji R R, Zhao Z Q. Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCepsilon: a novel pathway for heat hyperalgesia. J Neurosci, 2007, 27(44): 12067-12077

[66] Khasar S G, Lin Y H, Martin A, Dadgar J, McMahon T, Wang D, Hundle B, Aley K O, Isenberg W, McCarter G, Green P G, Hodge C W, Levine J D, Messing R O. A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice. Neuron, 1999, 24(1): 253-260

[67] Khasar S G, McCarter G, Levine J D. Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors. J Neurophysiol, 1999, 81(3): 1104-1112

[68] Ferrari L F, Bogen O, Levine J D. Nociceptor subpopulations involved in hyperalgesic priming. Neuroscience, 2010, 165(3): 896-901

[69] Amadesi S, Cottrell G S, Divino L, Chapman K, Grady E F, Bautista F, Karanjia R, Barajas-Lopez C, Vanner S, Vergnolle N, Bunnett N W. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase C epsilon- and A-dependent mechanisms in rats and mice. J Physiol, 2006, 575(2): 555-571

[70] Bautista F, Amadesi S, Karanjia R, Barajas-Lopez C, Burnett N, Vanner S. Protease activated receptor 2 (PAR2) Sensitization of TRPV1 currents is mediated by protein kinase CE and protein kinase A. Gastroenterology, 2006, 130(4): A336-A336

[71] Srinivasan R, Wolfe D, Goss J, Watkins S, de Groat W C, Sculptoreanu A, Glorioso J C. Protein kinase C epsilon contributes to basal and sensitizing responses of TRPV1 to capsaicin in rat dorsal root ganglion neurons. Eur J Neurosci, 2008, 28(7): 1241-1254

[72] Sculptoreanu A, Aura Kullmann F, de Groat W C. Neurokinin 2 receptor-mediated activation of protein kinase C modulates capsaicin responses in DRG neurons from adult rats. Eur J Neurosci, 2008, 27(12): 3171-3181

[73] Numazaki M, Tominaga T, Toyooka H, Tominaga M. Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. J Biol Chem, 2002, 277(16): 13375-13378

[74] Mandadi S, Tominaga T, Numazaki M, Murayama N, Saito N, Armati P J, Roufogalis B D, Tominaga M. Tominaga, Numazaki M, Murayama N, Saito N, Armati P J, Roufogalis B D, and Tominaga M. Increased sensitivity of desensitized TRPV1 by PMA occurs through PKC epsilon-mediated phosphorylation at S800. Pain, 2006, 123(1-2): 106-116

[75] Honan S A, McNaughton P A. Sensitisation of TRPV1 in rat sensory neurones by activation of SNSRs. Neurosci Lett, 2007, 422(1): 1-6

[76] Choi D S, Wang D, Chang W, McMahon T, Taylor S, Messing R O. Expression of the PKC epsilon in the brain controls ethanol-drinking behavior. Society for Neuroscience Abstracts, 2001, 27(1): 1495

[77] Bajo M, Cruz M T, Siggins G R, Messing R, Roberto M. Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala. Proc Natl Acad Sci USA, 2008, 105(24): 8410-8415

[78] Besheer J, Lepoutre V, Mole B, Hodge C W. GABAA receptor regulation of voluntary ethanol drinking requires PKCepsilon. Synapse, 2006, 60(6): 411-419

[79] Hodge C W, Raber J, McMahon T, Walter H, Sanchez-Perez A M, Olive M F, Mehmert K, Morrow A L, Messing R O. Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cepsilon. J Clin Invest, 2002, 110(7): 1003-1010

[80] Hodge C W, Mehmert K K, Kelley S P, McMahon T, Haywood A, Olive M F, Wang D, Sanchez-Perez A M, Messing R O. Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKCepsilon. Nat Neurosci, 1999, 2(11): 997-1002

[81] Das J, Pany S, Rahman G M, Slater S J. PKC epsilon has an alcohol-binding site in its second cysteine-rich regulatory domain. Biochem J, 2009, 421(3): 405-413

[82] Jiang Z L, Ye J H. Protein kinase C epsilon is involved in ethanol potentiation of glycine-gated Cl(-) current in rat neurons of ventral tegmental area. Neuropharmacology, 2003, 44(4): 493-502

[83] Lesscher H M, Wallace M J, Zeng L, Wang V, Deitchman J K, McMahon T, Messing R O, Newton P M. Amygdala protein kinase C epsilon controls alcohol consumption. Genes Brain Behav, 2009, 8(5): 493-499

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg