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

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

Acknowledgments

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

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg