PKCα，βⅡ，δ在大鼠视网膜发育过程中的差异表达
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摘要
目的:研究蛋白激酶C三种同工酶PKCα,βⅡ,δ在正常大鼠出生后视网膜发育过程中的差异表达情况。
方法:采用实时荧光定量逆转录-聚合酶链反应(real time RT-PCR)方法检测正常大鼠视网膜发育过程中PKCα,βⅡ,δmRNA水平的表达差异;通过免疫组织化学的方法检测PKCα,βⅡ,δ蛋白水平的表达情况。
结果:Real time RT-PCR结果显示,大鼠出生后14d(P14)之前,视网膜组织中PKCα,βⅡmRNA表达逐渐升高, P14之后有所下降;PKCδ在生后早期高表达;成年后3种同工酶mRNA表达稳定。视网膜切片免疫组织化学染色光密度测定结果与mRNA表达相符。染色阳性产物定位显示,出生后当天(P0)PKCα,βⅡ阳性产物染色不明显,PKCδ阳性产物在原始神经母细胞层和原始节细胞层均有表达。随着视网膜的发育,生后7d(P7)PKCα染色阳性产物在外丛状层和内核层染色明显;PKCβⅡ的阳性产物主要在内核层、内丛状层、外丛状层和神经节细胞层染色明显;PKCδ的阳性产物主要分布在外界膜和视锥、视杆层。随着视网膜的发育,到了出生后14d(P14)PKCα可以在外丛状层看到轮廓清晰的强染色细胞,βⅡ染色阳性产物在神经节细胞层染色加深,内核层、内丛状层、外丛状层染色变浅;PKCδ在外界膜染色加深;视网膜发育成熟后,3种同工酶的阳性染色部位不变。
结论:PKCα,βⅡ,δ在大鼠出生后视网膜发育过程中均有表达,并有一定的发育规律性,提示这3种同工酶与大鼠生后视网膜的发育过程密切相关;PKCα,βⅡ,δ表达的差异性提示:每种同工酶在参与视网膜发育方面可能具有不同的功能。PKCα可能对视杆-双极细胞发育有重要意义;PKCβⅡ可能对视网膜神经节细胞的发育过程有重要作用。PKCδ可能与视网膜生后早期原始神经母细胞和原始神经节细胞的分化及细胞凋亡过程有关。
Objective:To investigate the exprepression and distribution of protein kinase Cα,βⅡ,δin the retinal during the development of poatnatal hamster.
Methods: Real time RT-PCR method was used to detect the expression of mRNA;Immunocytochemical menthod was used to detect peotein.
Results : The rusult of Real time RT-PCR showed that PKCα,βⅡmRNA was continual rise before 14th day of poatnatal development and then reduced till the lowest point in the adulthood. PKCδwas highly express in the early period of poatnatal development.The result of of spectrodensitometry was match to the result of Real time RT-PCR . In the first day(P0), the expression of PKCα,βⅡwas poor , the expression of PKCδwas found in neuroblastic layer and ganglion cell layer.With the development, at the seventh day, PKCαwas pronoounced in the external plexiform layer and inner nuclear layer; PKCβⅡwas pronoounced in the inner nuclear layer,inner plexiform layer, external plexiform layer and ganglion cell layer; PKCδwas pronoounced in the external limiting membrane and cone and rod layer.At the 14th day, isozymes were more localized than before. With mature the three isoenyme distribute invariably.
Conclution: Protein kinase Cα,βⅡ,δwere expressed regularly in the whole process of rat retina development. It is suggest that the three isoenzyme is closely related to the early development of ratina in the postnatal hamster;The changed expression of PKCα,βⅡ,δis suggested as: each isoenzyme may have different roles in processing of rat ratinal development. PKCαmay be important to retinal rod-bipolar cells development; PKCβⅡmay be important to ratinal ganglion cells; PKCδmay participate the process of differentiation and Apoptosis of Primitive neuroblastic cells and Primitive ganglion cells in the early period .
方法:采用实时荧光定量逆转录-聚合酶链反应(real time RT-PCR)方法检测正常大鼠视网膜发育过程中PKCα,βⅡ,δmRNA水平的表达差异;通过免疫组织化学的方法检测PKCα,βⅡ,δ蛋白水平的表达情况。
结果:Real time RT-PCR结果显示,大鼠出生后14d(P14)之前,视网膜组织中PKCα,βⅡmRNA表达逐渐升高, P14之后有所下降;PKCδ在生后早期高表达;成年后3种同工酶mRNA表达稳定。视网膜切片免疫组织化学染色光密度测定结果与mRNA表达相符。染色阳性产物定位显示,出生后当天(P0)PKCα,βⅡ阳性产物染色不明显,PKCδ阳性产物在原始神经母细胞层和原始节细胞层均有表达。随着视网膜的发育,生后7d(P7)PKCα染色阳性产物在外丛状层和内核层染色明显;PKCβⅡ的阳性产物主要在内核层、内丛状层、外丛状层和神经节细胞层染色明显;PKCδ的阳性产物主要分布在外界膜和视锥、视杆层。随着视网膜的发育,到了出生后14d(P14)PKCα可以在外丛状层看到轮廓清晰的强染色细胞,βⅡ染色阳性产物在神经节细胞层染色加深,内核层、内丛状层、外丛状层染色变浅;PKCδ在外界膜染色加深;视网膜发育成熟后,3种同工酶的阳性染色部位不变。
结论:PKCα,βⅡ,δ在大鼠出生后视网膜发育过程中均有表达,并有一定的发育规律性,提示这3种同工酶与大鼠生后视网膜的发育过程密切相关;PKCα,βⅡ,δ表达的差异性提示:每种同工酶在参与视网膜发育方面可能具有不同的功能。PKCα可能对视杆-双极细胞发育有重要意义;PKCβⅡ可能对视网膜神经节细胞的发育过程有重要作用。PKCδ可能与视网膜生后早期原始神经母细胞和原始神经节细胞的分化及细胞凋亡过程有关。
Objective:To investigate the exprepression and distribution of protein kinase Cα,βⅡ,δin the retinal during the development of poatnatal hamster.
Methods: Real time RT-PCR method was used to detect the expression of mRNA;Immunocytochemical menthod was used to detect peotein.
Results : The rusult of Real time RT-PCR showed that PKCα,βⅡmRNA was continual rise before 14th day of poatnatal development and then reduced till the lowest point in the adulthood. PKCδwas highly express in the early period of poatnatal development.The result of of spectrodensitometry was match to the result of Real time RT-PCR . In the first day(P0), the expression of PKCα,βⅡwas poor , the expression of PKCδwas found in neuroblastic layer and ganglion cell layer.With the development, at the seventh day, PKCαwas pronoounced in the external plexiform layer and inner nuclear layer; PKCβⅡwas pronoounced in the inner nuclear layer,inner plexiform layer, external plexiform layer and ganglion cell layer; PKCδwas pronoounced in the external limiting membrane and cone and rod layer.At the 14th day, isozymes were more localized than before. With mature the three isoenyme distribute invariably.
Conclution: Protein kinase Cα,βⅡ,δwere expressed regularly in the whole process of rat retina development. It is suggest that the three isoenzyme is closely related to the early development of ratina in the postnatal hamster;The changed expression of PKCα,βⅡ,δis suggested as: each isoenzyme may have different roles in processing of rat ratinal development. PKCαmay be important to retinal rod-bipolar cells development; PKCβⅡmay be important to ratinal ganglion cells; PKCδmay participate the process of differentiation and Apoptosis of Primitive neuroblastic cells and Primitive ganglion cells in the early period .
引文
1. Young RW.Cell diferentiation in the retina of the mouse[J].Anat Rec,1985,212(2):199—205.
2. C,epko CL,Austin CP,Yang x,et e1.Cell fate determination in the vertebrate retina[J].ProcNatlAcadSci USA,1996,93(2):589—595.
3. John P.M.Wood,Roobert J.Mccord,Osboene.N. Retinal protein kinase C Neurochem.Int.1997,Vol.30:119-136.
4.Caminos E,Velasco A. A comparative study of protein kinase C-like immunoreactive cells in the retina.Brain Behav Evol ,2000,56:330-339.
5.Zhang DR,Yeh HH.Protein kinase C-like immunoreactivity in rod bipolar cells of the rat retina: a developmental study.Vis neurosci,1991,6(5):429-437.
6. Larry IB,Aryeh R,GAP43:an intrinsic determinant of neuronal development and planticty.TINS,1997;20(2):84
7. He Q, Dent E W, Meiri KF.Modulation of actin Filament behavior by GAP-43(Neuromodulin)is dependent on the phosphorylation status of serine 41,the protein kinase C site[J]. J Neurosci,1997,17(10):3515-351
8. Yoshida K,Miki Y,Kufe D.Activation of SAPK/JNK signaling by PKCδ in response to DNA damage[J].J Biol Chem,2002.277(50):48372-48378.
9.Eitel K,Staiger H,Rieger J,et al.Protein kinase C Delta activation and translocation to the nucleus are required for fatty acid--induced apoptosis ofinsulin-secreting cells[J].Diabetes,2003,52(4):991—997.
10. Mellor H.Parker PJ.The extended Protein Kinase C superfamily. Biochem J.1998;332:281- 292.
11 Patrick Moriarty,Alan J.Dickson J,Erichsen Mike Boulton.Protein kinase C isoenzyme expression in retinal cells.Ophthalmic Res ,2000,32:57-60.
12. Jun kosaka,Akira Sezuki et al.Differential licalization and expression of αandβisoenzymes of protein kinase C in the rat retina.Journal of Neuroscience Research.1998;54:655-663
13. Kjell Johansson,1 Anitha Bruun, et al.Immunohistochemical Analysis of theDeveloping Inner Plexiform Layer in Postnatal Rat Retina.Investigative Ophthalmology & Visual Science, January 2000, Vol. 41, No. 1
14.Da-Yu Wu,Marisa A.Mcdonald et al.PKC isozymes in the enhanced regrowth of retinal neurites after optic nerve injury[J].Invest Ophthalmol VisSci,2003;44:2783-2790
15.Kateryna kolkova,Helena Stensman et al.Distinct roles of PKC isoforms in NCAM-mediated neurite out growth[J].Journal of Neurochemistry,2005,92:886-894
16. Franco W. and Pico Caroni.Phosphorylation-site mutagenesis of the growth-assciated protein GAP43 modulates its effects on cell spreading and morphology.Journal of cell Biology,Volume 120,1993.
17. John T,Schmidt,et al.Presynaptic Protein kinase C controls maturation and branch dynamics of developing retinotectal arbors:possible role in activity-driven sharpening.[J] J Neurobiol 2003;58:328-340
18. Helen C. Gallagher, Keith J. Murphy, Andrew G.Protein kinase C delta regulates neural cell adhesion molecule polysialylation state in the rat brain。J. Neurochem. (2001) 77, 425-434.
19. Zhang DR,Yeh HH.Protein kinase C-like immunoreactivity in rod bipolar cells of the rat retina: a developmental study[J].Vis neurosci,1991,6(5):429-437
20. Jun kosaka,Akira Sezuki et al.Differential licalization and expression of αandβisoenzymes of protein kinase C in the rat retina.Journal of Neuroscience Research.1998;54:655-663
21. Bozena Fyk-kolodziej,Wenhui Cai,Roberta G.Distribution of protein kinase C in the cat reina[J].Visual Neurosscience.2002;19,549-562
22. Taekyun SHIN,Seungjoon KIM,et al.An immunohistochemical study of protein kinase C in the bovine retina.J.Vet.Med.Sci.2006;68(1):71-74
23. Receptor for Activated C Kinase-1 Facilitates Protein Kinase C Dependent Phosphorylation and Functional Modulation of GABAA Receptors with the Activation of G-Protein-Coupled Receptors. Nicholas J. Brandon,1 Jasmina N. Jovanovic,1 Trevor G. Smart,2 and Stephen J. Moss1Received Jan. 22, 2002; revised April 10, 2002; accepted May 10, 2002.
24. Pin J. P. and Duvoisin R. Review: Neurotransmitter receptors I; The metabotropic glutamate receptors: Structure and functions. Neuropharmacology 1995;34, 1-26.
25. Natalie D.Bull and Nigel L.Barnett.Antagonists of protein kinase C inhibit rat retinal glutamate transport activety in situ.Journal of Neurochemistry;2002;81,472-480
26. Nishizuke Y.Intracelular signaling by hydrolysis of phospholipids and activation of protein kinase C.Science,1992,258:607—613
27. Azzi A,Boscoboinik D,Hensey C.Th e protein kinase C family.Eur J Blochem ,1992.208:547—557
28.Hecht N B,KIeene K C,Yelick P C,Johnson P A,Pravtcheva D D, Ruddle F H .Mapping of haploid expressed genes:genes for both mouse protamines are located on chromosome 16.Somat Cell Mol Gene,1986, 12:19l— 195
29 Liao YF,Huang YC,Chang WH,et a1.The PKC deha inhibitor,rottlerin, induces apoptosis of haematopoietic cell lines through mitochondfial membuane depolarization and easpases cascade[J].Life sci.2005,77(6):707-719.
30 Musashi M ,Shuichi O.The role of protein kinase C isoforms in cell proliferation and apoptosis.Int J Hematol,2000,72:12～19
1 Takai Y, Kishimoto A, Nishizuka Y, et al. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J Biol Chem. 1977;252(21):7603-9.
2 Shin T,Kim S,Ahn M, et al. An immunohistochemical study of protein kinase C in the bovine retina. Vet Med Sci, 2006,68:71-74.
3 Caminos E, Velasco A, Jarrín M,et al. A comparative study of protein kinase C-like immunoreactive cells in the retina. Brain Behav Evol, 2000,56:330-339.
4 Behrens UD, Borde J, Mack AF, et al. Distribution of phosphorylated protein kinase C alpha in goldfish retinal bipolar synaptic terminals: control by state of adaptation and pharmacological treatment. Cell Tissue Res, 2007,327:209-220.
5 Fyk-Kolodziej B, Cai W, Pourcho RG. Distribution of protein kinase C isoforms in the cat retina. Vis Neurosci, 2002,19:549-562.
6 Moriarty P, Dickson AJ, Erichsen JT,et al.Protein kinase C isoenzyme expression in retinal cells.Ophthalmic Res ,2000,32:57-60.
7 Bull ND,Wood JP,Osborne NN, et al.Protein kinase C-mediated modulation of glutamate transporter activity in rat retina.Curr Eye Res. 2007 ,32(2):123-31
8 Carvalho AL, Correia S, Faro CJ,et al. Phosphorylation of GluR4 AMPA-type glutamate receptor subunit by protein kinase C in cultured retina amacrine neurons. Eur J Neurosci. 2002 Feb;15(3):465-74.
9 Chen NS, Li B, Murphy TH, et al. Site within N-methyl-D-aspartate receptor pore modulates channel gating. Mol Pharmacol, 2004, 65(1): 157-164.
10 Zhang DR,Yeh HH.Protein kinase C-like immunoreactivity in rod bipolar cells of the rat retina: a developmental study.Vis neurosci,1991,6(5):429-437.
11 Wu DY,Zheng JQ, Mcdonald MA, et al.PKC isozymes in the enhanced regrowth of retinal neurites after optic nerve injury.Invest Ophthalmol Vis Sci,2003,44:2783-2790.
12 Ivankovic-Dikic I, Gronroos E, Blaukat A, et al. Pyk2 and FAK regulate neuriteoutgrowth induced by growth factors and integrins.Nat Cell Biol,2000,2:574–581.
13 Kolkova K,Stensman H,Berezin V,et al. Distinct roles of PKC isoforms in NCAM-mediated neurite outgrowth. J Neurochem. 2005 ,92(4):886-94.
14 He Q, Dent EW, Meiri KF. Modulation of actin filament behavior by GAP-43 (neuromodulin) is dependent on the phosphorylation status of serine 41, the protein kinase C site.J Neurosci. 1997 ,17(10):3515-24.
15 Schmidt JT,Fleming MR,Leu B.Presynaptic protein kinase C controls maturation and branch dynamics of developing retinotectal arbors: possible role in activity-driven sharpening. J Neurobiol ,2003,58:328-340.
16 Aiello OP.Endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo an d suppressed by an orally efective β-isoform -selection inhibitor.Diabetes ,1997,46:1473.
17 Kowluru RA.Diabetes-induced elevations in retinal oxidative stress, protein kinase C and nitric oxide are interrelated.Acta Diabetol,2001,38:179-185.
18 Aiello LP, Clermont A, Arora V, et al. Inhibition of PKC beta by oral administrationof ruboxistaurin is well tolerated and ameliorates diabetesinduced retinal hemodynamic abnormalities in patients.Invest Ophthalmol Vis Sci ,2006,47:86-92.
19 The PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study(PKC-DRS) multicenter randomized clinical trial. Diabetes 2005,54:2188-9.
20 Campochiaro PA, C99-PKC412-003 Study Group. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest Ophthalmol Vis Sci ,2004,45:922-31.
2. C,epko CL,Austin CP,Yang x,et e1.Cell fate determination in the vertebrate retina[J].ProcNatlAcadSci USA,1996,93(2):589—595.
3. John P.M.Wood,Roobert J.Mccord,Osboene.N. Retinal protein kinase C Neurochem.Int.1997,Vol.30:119-136.
4.Caminos E,Velasco A. A comparative study of protein kinase C-like immunoreactive cells in the retina.Brain Behav Evol ,2000,56:330-339.
5.Zhang DR,Yeh HH.Protein kinase C-like immunoreactivity in rod bipolar cells of the rat retina: a developmental study.Vis neurosci,1991,6(5):429-437.
6. Larry IB,Aryeh R,GAP43:an intrinsic determinant of neuronal development and planticty.TINS,1997;20(2):84
7. He Q, Dent E W, Meiri KF.Modulation of actin Filament behavior by GAP-43(Neuromodulin)is dependent on the phosphorylation status of serine 41,the protein kinase C site[J]. J Neurosci,1997,17(10):3515-351
8. Yoshida K,Miki Y,Kufe D.Activation of SAPK/JNK signaling by PKCδ in response to DNA damage[J].J Biol Chem,2002.277(50):48372-48378.
9.Eitel K,Staiger H,Rieger J,et al.Protein kinase C Delta activation and translocation to the nucleus are required for fatty acid--induced apoptosis ofinsulin-secreting cells[J].Diabetes,2003,52(4):991—997.
10. Mellor H.Parker PJ.The extended Protein Kinase C superfamily. Biochem J.1998;332:281- 292.
11 Patrick Moriarty,Alan J.Dickson J,Erichsen Mike Boulton.Protein kinase C isoenzyme expression in retinal cells.Ophthalmic Res ,2000,32:57-60.
12. Jun kosaka,Akira Sezuki et al.Differential licalization and expression of αandβisoenzymes of protein kinase C in the rat retina.Journal of Neuroscience Research.1998;54:655-663
13. Kjell Johansson,1 Anitha Bruun, et al.Immunohistochemical Analysis of theDeveloping Inner Plexiform Layer in Postnatal Rat Retina.Investigative Ophthalmology & Visual Science, January 2000, Vol. 41, No. 1
14.Da-Yu Wu,Marisa A.Mcdonald et al.PKC isozymes in the enhanced regrowth of retinal neurites after optic nerve injury[J].Invest Ophthalmol VisSci,2003;44:2783-2790
15.Kateryna kolkova,Helena Stensman et al.Distinct roles of PKC isoforms in NCAM-mediated neurite out growth[J].Journal of Neurochemistry,2005,92:886-894
16. Franco W. and Pico Caroni.Phosphorylation-site mutagenesis of the growth-assciated protein GAP43 modulates its effects on cell spreading and morphology.Journal of cell Biology,Volume 120,1993.
17. John T,Schmidt,et al.Presynaptic Protein kinase C controls maturation and branch dynamics of developing retinotectal arbors:possible role in activity-driven sharpening.[J] J Neurobiol 2003;58:328-340
18. Helen C. Gallagher, Keith J. Murphy, Andrew G.Protein kinase C delta regulates neural cell adhesion molecule polysialylation state in the rat brain。J. Neurochem. (2001) 77, 425-434.
19. Zhang DR,Yeh HH.Protein kinase C-like immunoreactivity in rod bipolar cells of the rat retina: a developmental study[J].Vis neurosci,1991,6(5):429-437
20. Jun kosaka,Akira Sezuki et al.Differential licalization and expression of αandβisoenzymes of protein kinase C in the rat retina.Journal of Neuroscience Research.1998;54:655-663
21. Bozena Fyk-kolodziej,Wenhui Cai,Roberta G.Distribution of protein kinase C in the cat reina[J].Visual Neurosscience.2002;19,549-562
22. Taekyun SHIN,Seungjoon KIM,et al.An immunohistochemical study of protein kinase C in the bovine retina.J.Vet.Med.Sci.2006;68(1):71-74
23. Receptor for Activated C Kinase-1 Facilitates Protein Kinase C Dependent Phosphorylation and Functional Modulation of GABAA Receptors with the Activation of G-Protein-Coupled Receptors. Nicholas J. Brandon,1 Jasmina N. Jovanovic,1 Trevor G. Smart,2 and Stephen J. Moss1Received Jan. 22, 2002; revised April 10, 2002; accepted May 10, 2002.
24. Pin J. P. and Duvoisin R. Review: Neurotransmitter receptors I; The metabotropic glutamate receptors: Structure and functions. Neuropharmacology 1995;34, 1-26.
25. Natalie D.Bull and Nigel L.Barnett.Antagonists of protein kinase C inhibit rat retinal glutamate transport activety in situ.Journal of Neurochemistry;2002;81,472-480
26. Nishizuke Y.Intracelular signaling by hydrolysis of phospholipids and activation of protein kinase C.Science,1992,258:607—613
27. Azzi A,Boscoboinik D,Hensey C.Th e protein kinase C family.Eur J Blochem ,1992.208:547—557
28.Hecht N B,KIeene K C,Yelick P C,Johnson P A,Pravtcheva D D, Ruddle F H .Mapping of haploid expressed genes:genes for both mouse protamines are located on chromosome 16.Somat Cell Mol Gene,1986, 12:19l— 195
29 Liao YF,Huang YC,Chang WH,et a1.The PKC deha inhibitor,rottlerin, induces apoptosis of haematopoietic cell lines through mitochondfial membuane depolarization and easpases cascade[J].Life sci.2005,77(6):707-719.
30 Musashi M ,Shuichi O.The role of protein kinase C isoforms in cell proliferation and apoptosis.Int J Hematol,2000,72:12～19
1 Takai Y, Kishimoto A, Nishizuka Y, et al. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J Biol Chem. 1977;252(21):7603-9.
2 Shin T,Kim S,Ahn M, et al. An immunohistochemical study of protein kinase C in the bovine retina. Vet Med Sci, 2006,68:71-74.
3 Caminos E, Velasco A, Jarrín M,et al. A comparative study of protein kinase C-like immunoreactive cells in the retina. Brain Behav Evol, 2000,56:330-339.
4 Behrens UD, Borde J, Mack AF, et al. Distribution of phosphorylated protein kinase C alpha in goldfish retinal bipolar synaptic terminals: control by state of adaptation and pharmacological treatment. Cell Tissue Res, 2007,327:209-220.
5 Fyk-Kolodziej B, Cai W, Pourcho RG. Distribution of protein kinase C isoforms in the cat retina. Vis Neurosci, 2002,19:549-562.
6 Moriarty P, Dickson AJ, Erichsen JT,et al.Protein kinase C isoenzyme expression in retinal cells.Ophthalmic Res ,2000,32:57-60.
7 Bull ND,Wood JP,Osborne NN, et al.Protein kinase C-mediated modulation of glutamate transporter activity in rat retina.Curr Eye Res. 2007 ,32(2):123-31
8 Carvalho AL, Correia S, Faro CJ,et al. Phosphorylation of GluR4 AMPA-type glutamate receptor subunit by protein kinase C in cultured retina amacrine neurons. Eur J Neurosci. 2002 Feb;15(3):465-74.
9 Chen NS, Li B, Murphy TH, et al. Site within N-methyl-D-aspartate receptor pore modulates channel gating. Mol Pharmacol, 2004, 65(1): 157-164.
10 Zhang DR,Yeh HH.Protein kinase C-like immunoreactivity in rod bipolar cells of the rat retina: a developmental study.Vis neurosci,1991,6(5):429-437.
11 Wu DY,Zheng JQ, Mcdonald MA, et al.PKC isozymes in the enhanced regrowth of retinal neurites after optic nerve injury.Invest Ophthalmol Vis Sci,2003,44:2783-2790.
12 Ivankovic-Dikic I, Gronroos E, Blaukat A, et al. Pyk2 and FAK regulate neuriteoutgrowth induced by growth factors and integrins.Nat Cell Biol,2000,2:574–581.
13 Kolkova K,Stensman H,Berezin V,et al. Distinct roles of PKC isoforms in NCAM-mediated neurite outgrowth. J Neurochem. 2005 ,92(4):886-94.
14 He Q, Dent EW, Meiri KF. Modulation of actin filament behavior by GAP-43 (neuromodulin) is dependent on the phosphorylation status of serine 41, the protein kinase C site.J Neurosci. 1997 ,17(10):3515-24.
15 Schmidt JT,Fleming MR,Leu B.Presynaptic protein kinase C controls maturation and branch dynamics of developing retinotectal arbors: possible role in activity-driven sharpening. J Neurobiol ,2003,58:328-340.
16 Aiello OP.Endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo an d suppressed by an orally efective β-isoform -selection inhibitor.Diabetes ,1997,46:1473.
17 Kowluru RA.Diabetes-induced elevations in retinal oxidative stress, protein kinase C and nitric oxide are interrelated.Acta Diabetol,2001,38:179-185.
18 Aiello LP, Clermont A, Arora V, et al. Inhibition of PKC beta by oral administrationof ruboxistaurin is well tolerated and ameliorates diabetesinduced retinal hemodynamic abnormalities in patients.Invest Ophthalmol Vis Sci ,2006,47:86-92.
19 The PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study(PKC-DRS) multicenter randomized clinical trial. Diabetes 2005,54:2188-9.
20 Campochiaro PA, C99-PKC412-003 Study Group. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest Ophthalmol Vis Sci ,2004,45:922-31.